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Unraveling Interactions Between Anesthetics and the Endothelium: Update and Novel Insights

Aguirre, José A. MD, MSc*; Lucchinetti, Eliana PhD; Clanachan, Alexander S. PhD; Plane, Frances PhD; Zaugg, Michael MD, MBA, FRCPC†‡

doi: 10.1213/ANE.0000000000001053
Cardiovascular Anesthesiology: Review Article
Continuing Medical Education

The vascular endothelium is one of the largest organs in the body and consists of a single layer of highly specialized cells with site-specific morphology and functions. Endothelial cells play a vital role in the regulation of vascular tone in arterial, venous, microvascular, and lymphatic vascular beds. The endothelium also coordinates angiogenesis and controls cell adhesion, fluid homeostasis, and both innate and adaptive immunity. Fundamental research has shown that general and local anesthetics markedly modulate the biological activities of endothelial cells under aerobic and ischemia-reperfusion conditions, making the endothelium an important target of anesthetics in the cardiovascular system. Halogenated volatile anesthetics provide significant anti-inflammatory actions and protect the endothelium against ischemia-reperfusion injury, despite their inhibiting effects on endothelium-dependent vasorelaxation. They provide not only acute but also potential long-term, beneficial effects. Although many effects of IV anesthetics on endothelial function are controversial, or completely unexplored, propofol and opioids appear to have the most favorable profile with respect to the preservation of endothelial function. Some opioids and ketamine have stereoselective effects on the endothelium. Finally, there is experimental evidence to suggest important effects of anesthetics on the regulation of vascular permeability, proliferation of stem cells, including endothelial progenitor cells, and promotion or inhibition of tumor growth, potentially related to alterations in angiogenesis. However, most of these findings are from in vitro experiments and await confirmation in an in vivo setting. Thus, the clinical implications of these interactions remain uncertain.

From the *Department of Anesthesiology, Balgrist University Hospital, Zurich, Switzerland; and Departments of Anesthesiology and Pain Medicine, and Pharmacology, University of Alberta, Edmonton, Canada.

Accepted for publication August 21, 2015.

Funding: Supported by grants from the Heart and Stroke Foundation of Canada (MZ, FP, ASC).

The authors declare no conflicts of interest.

JAA and EL contributed equally to the work.

Reprints will not be available from the authors.

Address correspondence to Michael Zaugg, MD, MBA, FRCPC, Department of Anesthesiology and Pain Medicine, University of Alberta, 2-150 Clinical Science Bldg., Edmonton, AB, T6G 2G3 Canada. Address e-mail to michael.zaugg@ualberta.ca.

The 10 billion endothelial cells of the human body are derived from hemangioblasts1 and form a single layer lining the interior surface of all blood and lymphatic vessels throughout the entire circulatory system. They form a highly specialized “organ” with a surface area of approximately 1000 m2 and approximately the volume of the liver.2 The endothelium is continuous in most vascular beds. However, in liver and renal glomeruli, it is discontinuous, and in glands, mucosae, and renal cortex, it has perforations (fenestrae). The average life span of a single endothelial cell has been estimated as approximately 1 year. Endothelial dysfunction is a pathological state of the endothelium, whereby its physiological functions, including regulation of vascular tone, blood flow, revascularization, cell adhesion, inflammatory and immune reactions, and intravascular fluid management, are unbalanced and ultimately deranged. Endothelial cell dysfunction is thought to be a critical event in the initiation of many diseases, including hypertension, coagulation disorders, atherosclerosis, ischemia-reperfusion injuries, and cardiovascular aging.3,4 Readers interested in cell physiology in different vascular beds (arterial, venous, microvascular, and lymphatic) are referred to several excellent and comprehensive reviews.3,5–8

This update will briefly recapitulate the fundamentals in endothelial physiology and subsequently focus on novel insights into interactions between commonly used anesthetics and endothelial cells under aerobic and ischemia-reperfusion conditions.

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BASIC FUNCTIONS OF THE ENDOTHELIUM

Anticoagulation

Table 1

Table 1

The endothelium primarily functions as a barrier to prevent blood from contacting the highly thrombogenic subendothelial matrix (basal lamina or basal membrane). Nonetheless, beside its anticoagulant function,9 it also has strong procoagulant properties. In intact endothelial cells, the anticoagulant state clearly predominates and is mediated by nitric oxide (NO) and prostacyclin (PGI2), which induce vasodilation and inhibit platelet adhesion. However, when endothelial cells are damaged, they express multiple adhesion proteins on their surface and release procoagulant factors, including factor VIII, von Willebrand factor, and tissue factor (Table 1), promoting platelet aggregation and activating the coagulation cascade and complement system to culminate in the formation of a firm fibrin clot.

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Endothelium-Dependent Vasodilation

Endothelium-dependent vasodilation is mediated by diffusible substances, such as NO (previously named endothelium-derived relaxing factor), PGI2, and by endothelium-dependent hyperpolarization (EDH) of smooth muscle cells (Table 1; Fig. 1A). NO,10 a highly lipophilic radical with low molecular weight, is generated from L-arginine as a result of oxidation of its guanidine-nitrogen terminal in response to increases in intracellular calcium (from outside through transient receptor potential vanilloid Ca2+ channels and from the endoplasmic reticulum via the ryanodine receptor) stimulated by increases in blood pressure (shear stress) and oxygen demand and through stimulation of endothelial membrane receptors by acetylcholine, bradykinin, interleukins, thrombin, and substance P.11,12 The catalyzing enzyme is NO synthase III, which is primarily expressed in endothelial cells (endothelial nitric oxide synthase [eNOS]),13 but also present in vascular smooth muscle and multiple blood cells. NO rapidly diffuses to adjacent vascular smooth muscle cells, where it stimulates guanylate cyclase to generate cyclic guanosine monophosphate (cGMP). The subsequent increase in cGMP levels activates cGMP-dependent protein kinase G to phosphorylate numerous target proteins, such as phospholamban, resulting in reductions in intracellular Ca2+ levels and relaxation of vascular smooth muscle cells.14,15

Figure 1

Figure 1

PGI2 is produced by metabolism of phospholipase A2–released arachidonic acid through the cyclooxygenase (COX) pathway in endothelial cells.16 On diffusing to smooth muscle cells, short-lived PGI2 acts on Gs-coupled receptors linked to activation of adenylate cyclase and production of cyclic adenosine monophosphate (cAMP). Protein kinase A (PKA) is the primary mediator of cAMP-mediated smooth muscle relaxation as PKA-mediated phosphorylation of plasmalemmal and sarcoplasmic reticulum Ca2+-ATPases reduces intracellular Ca2+ levels.17 However, recent evidence suggests that Epacs (exchange proteins directly activated by cAMP) may also play a role through attenuation of Rho kinase activity.18 Release of PGI2 is stimulated by endothelium-dependent vasorelaxants such as acetylcholine, but its contribution to vascular relaxation shows significant variation among vascular beds and animal species, generally playing a less prominent role than NO or EDH.19 This concept is supported by in vivo data showing that pharmacologic blockade of COX does not substantially affect resting blood pressure, whereas pharmacologic blockade or genetic ablation of eNOS or components of the EDH pathway do have profound effects.20

Although NO and PGI2 induce vasorelaxation mainly by changing Ca2+ signaling in smooth muscle cells, enhanced K+-conductance either through activation of cGMP-dependent ATP-sensitive K+ channels, cGMP and PKG-dependent K+ channels, or by direct effects on various other K+ channels (Kir, Kv, BKCa, and Na+/K+ ATPase) may also play a role. Vasodilator responses that are insensitive to blockade of NO and PGI2 synthesis are mediated by EDH.21

Numerous factors have been suggested to underlie EDH-dependent vasodilation, including K+ ions,22 hydrogen peroxide (H2O2),23 epoxyeicosatrienoic acids generated by cytochrome P450-monooxygenase,19 and 15(S)-hydroxy-11, 12-epoxyeicosatrienoic acids generated by 15-lipoxygenase.24 However, in most blood vessels, EDH-mediated relaxation can be accounted for by passive transfer of charge through intercellular gap junctions.25 The initiating step in the EDH response is an elevation in endothelial Ca2+ levels followed by hyperpolarization of the endothelium. Endothelial hyperpolarization can be stimulated by both mechanical and chemical stimuli, such as increases in shear stress26 and the receptor agonists acetylcholine and bradykinin,27 and is mediated by the opening of endothelial small (SKCa)- and intermediate (IKCa)-conductance calcium-activated K+ channels.25,28 The spread of membrane hyperpolarization from endothelial to smooth muscle cells via myoendothelial gap junctions reduces the open probability of voltage-operated Ca2+ channels and deactivates phospholipase C in smooth muscle cells, thereby causing relaxation (Fig. 1A).29–33 CO, H2S, adenosine, and natriuretic peptide C are also reportedly produced by the endothelium and are thought to mediate vasodilation.34 EDH-mediated responses are specifically pronounced in pulmonary, cerebral, and coronary arteries, are more important in smaller than larger vessels, and remain better preserved than NO-mediated responses after ischemia-reperfusion injury. The same gap junctions responsible for EDH responses also provide feedback from smooth muscle cells to endothelial cells when contractile agonists induce muscle contraction. This phenomenon, known as “myoendothelial feedback,” is induced mainly by inositol trisphosphate (IP3) and explains the well-known fact that arterial vasoconstriction in response to agonists is limited by the endothelium.31,35 Recently, sex steroids have also been shown to induce vasodilation via a nongenomic mechanism.36–38 Following their release and binding to surface membrane receptors, sex steroids activate multiple signaling cascades, resulting in increased NO, PGI2, and EDH response.

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Endothelium-Dependent Vasoconstriction

In addition to relaxing factors, endothelial cells produce and release vasoconstricting factors, such as endothelin-1 (ET-1), thromboxane A2 (TXA2), angiotensin II, and isoprostanes (Table 1; Fig. 1B).39,40 ET-1 is a 2492-Da peptide produced constitutively by the endothelium, which acts through G-protein–coupled ET-1 receptors located on vascular smooth muscle cells to produce a slow but sustained vasoconstriction.41 This response is mediated by IP3-mediated release of Ca2+ from the sarcoplasmic reticulum, Ca2+ influx via voltage-operated Ca2+ channels, and sensitization of contractile proteins to Ca2+42 and may persist even after ET-1 is removed from the receptor.43 In an autocrine and counter-regulatory manner, ET-1 acting on ETB receptors localized on endothelial cells elicits vasodilation via NO, PGI2, and EDH,44 whereas NO inhibits ET-1 release.45 The physiological significance of this mechanism for maintaining blood pressure is demonstrated by the rapid ET-1–mediated arterial pressure elevation observed after acute eNOS inhibition in vivo.46 TXA2, a product of the sequential actions of COX and TXA2 synthase on arachidonic acid,47 stimulates aggregation of platelets and acts on specific thromboxane/prostaglandin receptors to cause smooth muscle cell contraction.48 TXA2 also negatively regulates EDH-mediated responses through inhibition of endothelial SKCa channels,49 and elevated levels of TXA2 have been associated with endothelial dysfunction in disease states.50

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Angiogenesis and Tissue Repair

Postnatal angiogenesis is the growth of new blood vessels as a result of the sprouting and extension of new capillary networks and is essential in both tissue repair and tumor growth (Fig. 2). Postnatal angiogenesis51 is stimulated by injury or damage to the vascular endothelium after ischemia-reperfusion or development of malignant tumors. Hypoxia, the driving force for angiogenesis, stimulates increased stabilization and nuclear translocation of hypoxia-inducible transcription factor (HIF-2α) in endothelial cells.52 In the nucleus, HIF-2α binds to hypoxia response elements in the promoter regions of hundreds of genes involved in angiogenesis, such as tyrosine kinase Tie-2, matrix metalloproteinases, and vascular endothelial growth factor (VEGF).53 Tie-2 plays a key role in endothelial cell migration, survival, sprouting, and periendothelial cell recruitment.54

Figure 2

Figure 2

The first step in the formation of new capillaries is the proteolytic degradation of the subendothelial matrix to allow migration of endothelial cells into the neighboring tissue. This process is mediated by the plasminogen activator system and matrix metalloproteinases.55,56 After their migration, proliferation of endothelial cells and pericytes (perivascular multipotent cells)57–59 is accelerated by stimulation through multiple growth factors. Proangiogenic growth factors can be divided into 3 main classes60: (1) the VEGF family and angiopoietins, which act specifically on endothelial cells; (2) cytokines such as fibroblast growth factor-2, chemokines, and angiogenic enzymes that activate a broad range of endothelial and nonendothelial target cells61; (3) tumor necrosis factor-α (TNF-α), and members of the transforming growth factor-β (TGF-β) superfamily. TGF-β itself stimulates the expression of TNF-α, fibroblast growth factor-2, platelet-derived growth factor, and VEGF in attracted inflammatory cells. Angiogenesis relies heavily on cell-cell interactions.62 The most important regulators responsible for cell adhesion are the selectins (P-selectin, E-selectin), the vascular endothelial cadherins (VE-cadherins), the integrins, and the immunoglobulin supergene family (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). Endothelial progenitor cells originating from the bone marrow further participate in re-endothelialization, neovascularization, and contribute to tissue repair through paracrine secretion of angiogenic factors.63,64

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Vascular Permeability

Figure 3

Figure 3

The endothelium controls the passage of solutes and cells (mainly paracellular but also transcellular) into the perivascular space (Fig. 3).65 The endothelial glycocalyx with its predominant polysaccharide constituents (proteoglycans such as syndecan and heparans) forms a labile coating (20 nm–2 μm thick) of the luminal membrane of endothelial cells, significantly contributing to its barrier function.64,66 It is highly sensitive to ischemia-reperfusion and inflammation but is usually not affected by anesthetics or surgery itself during aerobic conditions.67 Pericytes are contractile cells that are embedded in the basal membrane and wrap around the endothelium. They regulate vascular permeability, closely communicate with endothelial cells and are specifically essential in the formation of the blood-brain barrier, which is required for the protection of the central nervous system.68 Pericytes build tight junctions, control vesicle trafficking, and inhibit the expression of molecules that increase vascular permeability.69 Modulation of the cytoskeleton (actomyosin) and regulation of tight/gap junctions via VE-cadherins and other proteins such as occludins, claudins, catenins, and tight junction protein ZO-1 by kinases/phosphatases (e.g., tyrosine phosphorylation of VE-cadherin via Src) determines vascular permeability.70 During ischemia, β-catenin translocates from the plasma membrane into the cytoplasm and increases endothelial permeability, most probably triggered by HIF-induced upregulation of VEGF.71 VEGF and reactive oxygen species are among the most potent enhancers of vascular permeability, whereas the presence of abundant NO maintains low permeability. Vascular permeability is further increased by the interaction of the endothelium with leukocytes (rolling, adhesion, transendothelial migration).72

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EFFECTS OF VOLATILE ANESTHETICS ON THE ENDOTHELIUM

Nitrous Oxide

A comprehensive study in pigs showed vasoconstrictive effects (+20%) on exposure to 70 vol.% nitrous oxide (N2O).73 That study suggested that the underlying mechanism may involve inhibition of the endothelium-dependent norepinephrine turnover, indicating an increased activation of the sympathetic nervous system. Exposure to N2O and the resulting increase in plasma homocysteine concentrations have also been linked to endothelial dysfunction in humans.74 However, a recent large randomized trial evaluating the effects of N2O in patients with known or suspected coronary artery disease undergoing major noncardiac surgery (ENIGMA-II trial) failed to show an increased risk of death or cardiovascular complications from N2O exposure.75 Moreover, the ENIGMA-II trial investigators did not find a decreased incidence of surgical wound infections,75 although N2O was reported to reduce the inflammatory reaction in vitro and to prevent both TNF-α–induced activation of nuclear factor-κB and the expression of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVEC)76 when applied as a preconditioning agent. An in vivo study in Mongolian gerbils revealed that prolonged anesthesia (7 hours) with isoflurane plus N2O (70 vol.%) induces markedly higher degrees of inflammation of the cerebral microcirculation compared with isoflurane alone.77

N2O is also a potent vasodilator of the brain vasculature when given alone78 or when coadministered with volatile anesthetics79 and increases cerebrovascular permeability at higher blood pressure levels.80 Prolonged N2O exposure to tumor cells may have antiproliferative effects,81 likely linked to its oxidizing effects on vitamin B12 and inhibition of homocysteine methyltransferase. However, in those studies, allogeneic tumor models were used wherein direct effects on tumor cells cannot be clearly separated from effects on the host immune system. In fact, shorter use of N2O in tumor-bearing mice significantly accelerates the progression of postoperative metastases.82 Whether this is because of its effects on endothelial function and angiogenesis or on the immune system will require further exploration.

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HALOGENATED VOLATILE ANESTHETICS

Endothelium-Dependent Vasodilatation

The volatile anesthetics currently in use decrease systemic vascular resistance, but the mechanisms underlying the loss of vascular tone are not clearly deciphered.83 Several studies have failed to show that vasodilation is because of the enhanced release of NO from endothelial cells.84–86 In fact, multiple studies have shown impairment of agonist-induced endothelium-dependent relaxation.87–91 Hence, based on the currently available literature, the concept emerges that volatile anesthetics inhibit endothelium-dependent vasorelaxation but promote endothelium-independent smooth muscle relaxation via reduction of intracellular Ca2+ availability and sensitivity to contractile proteins.83,92,93 The combined result of these 2 opposing effects is, in general, a loss of vascular tone. Nonetheless, one should remember that in certain vascular beds, such as in coronary microvessels, isoflurane was reported to elicit vasodilation in a predominantly endothelium-dependent manner, ultimately mediated by ATP-sensitive K+ channels localized in smooth muscle cells.94 Stone and Johns95 observed endothelium-dependent augmentation of cAMP levels with subsequent vasodilation in vascular smooth muscle cells exposed to halothane and isoflurane, whereas other studies suggest inhibition of NO-dependent cGMP production in vascular smooth muscle. Johns et al.96 showed that halothane and isoflurane had no effect on cGMP production in cultured vascular smooth muscle cells, but in the presence of endothelial cells, NO-dependent cGMP production was inhibited. Similar observations were made by Jing et al.97 who also reported competition for guanylate cyclase between volatile anesthetics (halothane and isoflurane) and carbon monoxide (CO), a chemically close relative to NO. In addition, EDH-mediated responses are inhibited by volatile anesthetics,98–100 an effect which is, at least in part, mediated by the direct effects of volatile anesthetics on endothelial K+ channels101–103 and/or gap junctions.104 Collectively, these studies imply inhibition of the endothelium-dependent vascular relaxation by most volatile anesthetics.

One of the earliest studies of sevoflurane and endothelial function indicated that sevoflurane selectively impairs endothelium-dependent relaxation in canine mesenteric arteries by a reactive oxygen species–dependent mechanism, mainly because of inactivation of NO.105 A subsequent study by Akata et al.98 showed that halogenated anesthetics (1 minimum alveolar concentration [MAC] enflurane, isoflurane, sevoflurane) have inhibitory effects on the NO pathway, but that these effects were offset by a direct vasodilating effect of the anesthetics on vascular smooth muscle cells. Using porcine aortic endothelial cells, Az-ma et al.106 demonstrated that sevoflurane attenuates vasodilation by inhibiting bradykinin-induced Ca2+ efflux from endoplasmic stores, Ca2+ influx through membrane Ca2+ channels, and the release of NO from the endothelium. These findings were confirmed by Yamaguchi and Okabe107 in a rabbit mesenteric artery model and by Lischke et al.100 in a rabbit carotid artery model. Nakamura et al.108 suggested that mechanisms responsible for the inhibition of endothelium-dependent relaxation may differ among volatile anesthetics. Isoflurane appears to alter the acetylcholine-induced relaxation, mainly by decreasing the production of NO in the endothelium, halothane by inhibiting the action of NO in vascular smooth muscle cells, and sevoflurane by directly inactivating NO.

Multiple studies suggest that desflurane is a powerful coronary vasodilator.109 In contrast to the above-mentioned studies, Beaussier et al.110 demonstrated that desflurane-induced decreases in coronary vascular resistance are largely because of the simultaneous release of PGI2 and NO. It should be emphasized at this point that desflurane-induced hypertension in response to rapid increases in administered concentrations appears to be because of the acute increase in efferent sympathetic activity111 independent of the endothelium.112 Importantly, in contrast to the vasodilator response just described, multiple studies show that volatile anesthetics (halothane, isoflurane, sevoflurane) enhance the vasoconstrictor response to norepinephrine and phenylephrine in the presence of the endothelium,113–115 whereas their response is decreased in the absence of endothelial cells. However, this endothelium-mediated constricting effect is only short-lived, whereas the endothelium-independent vasodilating effect of volatile anesthetics (isoflurane, sevoflurane, enflurane) is persistent.116

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Cell Adhesion and Inflammation

One of the earliest indications of the cytoprotective effect of volatile anesthetics on the endothelium came from Möbert et al.117 Using HUVECs, that study found a decreased adhesion of polymorphonuclear neutrophils to activated endothelial cells following isoflurane, sevoflurane, and halothane exposure in vitro. Several subsequent studies confirmed these remarkable protective actions of volatile anesthetics on the endothelium. de Rossi et al.118 demonstrated a MAC-dependent inhibition of leukocyte activation by isoflurane in vitro, which was accompanied by reduced expression of the adhesion molecules CD11a, CD11b, and L-selectin. They also suggested that volatile anesthetics may modulate the formation of platelet-neutrophil aggregates and the expression of P-selectin on platelets,119 an effect that differs significantly among the various volatile anesthetics.120–122 In canine coronary arteries exposed to activated polymorphonuclear neutrophils in vitro, isoflurane inhibited the ability of platelets to induce endothelial dysfunction.123 Similarly, Hisano et al.124 demonstrated an inhibitory effect of isoflurane and sevoflurane on E-selectin–mediated leukocyte adhesion to cytokine-activated HUVECs, and Weber et al.76 showed protection of HUVECs by only 0.5 MAC isoflurane against TNF-α–induced damage. Also, endothelial cells are stimulated by isoflurane to produce cardioprotective factors such as HIF-1α that may contribute to the protection of cardiomyocytes (endothelial-cardiomyocyte crosstalk).125

The first in vivo evidence that volatile anesthetics indeed protect the endothelium against ischemia-reperfusion injury in humans was published in 2007. Using a forearm model of ischemia-reperfusion in volunteers, Lucchinetti et al.126 demonstrated that peri-ischemic administration of sevoflurane, even at low sedative concentrations (<2 vol.%), preserved the postischemic hyperemic blood flow response and inhibited activation of leukocytes. Consistent with this notion, Wacker et al.122 showed, in a similar human volunteer model, that inhalation of equally low sevoflurane concentrations further inhibits agonist-induced granulocyte-platelet interactions up to 24 hours after its administration. Results of an in vitro test of human endothelial cells suggest that administration of 1.5 vol.% isoflurane for 30 minutes produces an early and late window of endothelial protection.127 This protection appears to be the result of mitochondrial, but not cell membrane, KATP channel activation. Changes in gene expression in peripheral blood cells after inhalation of volatile anesthetics have been shown to occur within only 10 to 15 minutes of exposure in humans,128 and these changes may affect cardiovascular clinical outcome.129,130 Accordingly, Garcia et al.129 reported that sevoflurane preconditioning of patients undergoing coronary artery bypass grafting decreases the expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) (CD31) in cardiac tissue and improves 1-year cardiovascular outcome by decreasing the risk of coronary artery occlusion and new episodes of congestive heart failure. PECAM-1 is expressed at the intercellular junctions of coronary endothelial cells controlling leukocyte migration through the endothelium. The authors suggest that reduced PECAM-1 expression may prevent stable-to-vulnerable plaque transition in the perioperative period, and thus delay progression of coronary artery disease and contribute to improved long-term cardiovascular outcome. More recent literature suggests that endothelial PECAM-1 regulates basal eNOS activity131 and mediates endothelial-cardiomyocyte communication.132 Hence, volatile anesthetics not only have acute effects on endothelial function but may also have significant long-term effects on coronary arteries.

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Angiogenesis, Tumor Growth, and Stem Cell Activity

Endothelial progenitor cells play a pivotal role in tissue repair133,134 and are used for cell replacement therapies in trials of regenerative medicine.135 Lucchinetti et al.136 isolated mononuclear cells from peripheral blood of healthy donors, preconditioned them with sevoflurane (3 times 30 minutes at 2 vol.% interspersed by 30 minutes of air), and determined colony-forming units of endothelial progenitor cells (VEGFR2+/CD133+/CD34+) after 9 days in culture. In the same study, endothelial progenitor cells were also enriched from human umbilical cord blood, and expression of VEGF, VEGFR2, granulocyte colony-stimulating factor, signal transducer and activator of transcription 3 (STAT3), c-kit, and CXCR4 was determined after sevoflurane preconditioning. Finally, in a supplementary volunteer study with crossover design, it was tested whether sevoflurane inhalation would mobilize endothelial progenitor cells from the bone marrow niche into the circulation. Interestingly, sevoflurane exposure enhanced the colony-forming capacity of endothelial progenitor cells and increased their expression level of VEGF. Also, sevoflurane inhalation in healthy volunteers increased the number of colony-forming units of endothelial progenitor cells but did not further mobilize endothelial progenitor cells from the bone marrow. These data may suggest that sevoflurane, and possibly other halogenated volatile anesthetics, promote growth and proliferation of human endothelial progenitor cells and thus may be used to promote vascular/wound healing and to support cell replacement therapies, particularly when given for a short period (anesthetic preconditioning).

In the meantime, multiple studies have confirmed activating (when given as a preconditioning agent)137,138 and also inhibiting actions (upon prolonged exposure)138,139 on other cells with regenerative potential. However, the negative side of this fascinating discovery may be that volatile anesthetics may support tumor growth by enhancing angiogenesis and tumor cell survival in hypoxic environments. Future studies should specifically investigate the effects of volatile anesthetics on “tumor endothelial cells.” These cells play a pivotal role in tumor progression and metastasis formation, feature characteristic abnormalities, such as irregular diameters, holes and leakiness, and derive not only from endothelial cells of nearby vessels but also from circulating endothelial progenitor cells, as well as transdifferentiated myeloid and mesenchymal lineage cells.140 As early as 1981, halothane and N2O were found to increase the formation of metastases to the lungs and liver in tumor-bearing mice.82 More recently, sevoflurane has been found to increase proliferation and migration of breast cancer cells when concentrations >2 mM were used in an in vitro cell system.141 Similar results were obtained with other tumor cell lines.142 In contrast, the noble gas, xenon, has opposite effects and decreases migration and production of proangiogenic factors in breast adenocarcinoma cells.143 So far, retrospective studies appear to support the view that patients undergoing cancer surgery with sevoflurane may have worse survival rates than those receiving propofol anesthesia.144

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Vascular Permeability

Volatile anesthetics only marginally affect vascular permeability under aerobic clinical (i.e., nonischemic and <2 MAC145) conditions, but isoflurane, compared with sevoflurane increases brain edema in a mouse model of traumatic head injury by modulating endothelial tight junction protein expression.146 It has been shown that isoflurane inhibits occludin expression via upregulation of HIF-1α.71 Similarly, isoflurane, but not sevoflurane, enhances lung edema in isolated lungs and increases transendothelial albumin permeability,145 probably via Src-mediated caveolin phosphorylation. Nonetheless, in a zymosan-induced mouse model of peritonitis, isoflurane reduced the inflammation peak and further accelerated its resolution, whereas lidocaine, a local anesthetic, rather delayed the onset of the inflammatory response and its resolution but did not diminish the peak of the inflammatory response.147 This observation clearly underlines the potent anti-inflammatory power of isoflurane. In support of this, postinjury isoflurane administration was reported to attenuate blood-brain barrier disruption after subarachnoid hemorrhage in mice.35 This observation is in contrast to the effects of isoflurane in traumatic head injury,146 but differences in treatment modalities and the type of injury (trauma versus hemorrhage) may well explain the seemingly opposing effects of isoflurane on vascular permeability in the 2 studies.35,146 It has been also shown that sevoflurane, but not propofol, reduces lung damage in lipopolysaccharide (LPS)-induced lung injury in vivo148 and preserves endothelial glycocalyx against ischemia-reperfusion-induced heparan sulfate shedding in an in vivo pig model149 and in isolated guinea pig hearts.150 In contrast, desflurane increases pulmonary alveolar-capillary membrane permeability after aortic occlusion-reperfusion in rabbits.151 Collectively, the effects of halogenated volatile anesthetics on vascular permeability depend on the individual drug, the dosing, and duration of exposure, as well as the type of injury.

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Clinical Perspectives

Table 2

Table 2

The use of halogenated volatile anesthetics combined with the avoidance of N2O appears to be most promising with respect to preservation of endothelial function in clinical practice (Table 2). Despite their inhibiting effects on endothelium-dependent vasorelaxation, halogenated volatile anesthetics provide significant anti-inflammatory actions and protect the endothelium against ischemia-reperfusion damage. In contrast, N2O impairs endothelial function. New studies further suggest that sevoflurane promotes the growth not only of endothelial progenitor cells but also of certain tumor cells, possibly including tumor endothelial cells. However, the clinical significance of these findings requires further exploration. Experimental data also suggest that specifically isoflurane, and possibly desflurane, may impair capillary permeability in the pulmonary and cerebral vascular beds.

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EFFECTS OF IV AND LOCAL ANESTHETICS ON THE ENDOTHELIUM

Propofol

Propofol decreases blood pressure by decreasing systemic vascular resistance in a predominantly endothelium-independent manner.152,153 In vitro experiments with vessels from different vascular beds and species have shown that the vasodilating effects of propofol are independent of an intact endothelium.154–159 Yamanoue et al.154 concluded that propofol-induced vasodilation in the porcine coronary artery involves inhibition of Ca2+ channels. However, in smaller rat distal coronary arteries, propofol-induced vasodilation is, at least in part, mediated by endothelium-derived factors,160 and Liu et al.161 suggested that the synthesis of vasodilator prostanoids may be involved in the propofol-induced relaxation of the rat renal arterioles. Likewise, propofol was reported to enhance acetylcholine-mediated vasodilation in mesenteric arteries of aged rats.162 Interestingly, treatment of aged rats with the angiotensin-converting enzyme inhibitor, captopril, increases endothelial-dependent vasodilation in the presence of propofol,163 which may explain the strong vasodilation in angiotensin-converting enzyme-inhibitor–treated patients exposed to propofol. In contrast to systemic vascular beds, propofol was found to inhibit EDH-mediated vasorelaxation in canine pulmonary artery164 and to attenuate endothelium-dependent KATP channel–mediated relaxation in canine pulmonary veins.165 Obviously, the effects of propofol on the vascular tone are site-specific.

Propofol’s chemical structure resembles phenol-based free radical scavengers such as vitamin E, and there are strong indications that propofol can reduce free radical levels in vitro and in vivo.166–168 Coronary vascular conductance corrected by left ventricular work significantly increased after sevoflurane treatment in isolated working rat hearts, whereas the opposite occurred during propofol administration, possibly because of propofol’s scavenging effects on the endogenous vasodilator H2O2.169 However, results of numerous experimental investigations suggest that propofol provides protection against oxidative injury in various types of tissues such as the myocardium,170 the brain,171 erythrocytes,172,173 and hepatocytes.174 A study by Chen et al.175 also confirmed the protective effects of propofol against oxidative stress in HUVECs, and Wang et al.176 showed that propofol reduces apoptosis in H2O2-stimulated HUVECs through decreased caspase-3 activity and increased eNOS production, which is primarily protein kinase C-dependent.177 Propofol also upregulates the antioxidant enzyme heme oxygenase-1 in an extracellular signal-regulated kinase (ERK)-dependent manner,178 an effect that could be potentially useful in the prevention of cisplatin-induced endothelial cell damage.179 Propofol may prevent high-glucose–induced endothelial dysfunction, given that it restores eNOS coupling in HUVECs exposed to high glucose concentrations.180 However, propofol was most recently found to exacerbate insulin resistance in type-2 diabetic hearts, implying that it may not be the ideal anesthetic for diabetic patients.181 Moreover, propofol reduces the activation of polymorphonuclear neutrophils182 and suppresses the expression of ICAM-1 and VCAM-1 in reoxygenated HUVECs.183 Collectively, these findings support the notion that propofol provides protection during the reperfusion period, most probably through a decrease in free radicals and pro-oxidants, Ca2+ influx, and postischemic adhesion of polymorphonuclear neutrophils. Propofol also improves endothelial dysfunction in septic rats184 and protects endothelial cells against LPS-induced barrier dysfunction by inhibiting nuclear factor-κB activation,185 but it was also found to reinforce LPS effects.186 However, this was only found at the transcriptional and not the protein expression level.

There is currently some evidence supporting the concept that propofol may inhibit tumor growth, at least in mice,187 but whether this is related to its effects on endothelial cells or angiogenesis is not known. However, propofol is also known to activate Akt,188 which has an important role in tumor growth and metastasis formation, to boost the production of a potent growth factor TGF-β1 in HUVECs, and to increase its plasma levels in patients undergoing propofol anesthesia.189 It is currently not known whether propofol affects endothelial progenitor cells or endothelial tumor cells, but it has been reported to promote proliferation of cultured adult rat hippocampal neural stem cells.190 Hence, future studies are required to confirm the “tumoristatic” effect of propofol in other species and tumor models. Finally, it has been shown that a propofol overdose administered into the peritoneal cavity can increase peritoneal vascular permeability and induce apoptosis of vascular endothelial cells through a glycogen synthase 3β-dependent mechanism.191

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Ketamine

Numerous studies describe the effects of ketamine on the regulation of vascular resistance, but the role of the endothelium is still unclear. Ketamine increases vascular tone by enhancing the release of catecholamines, but it is capable of reversing vasoconstriction in vitro in a dose-dependent and endothelium-independent manner.159,192 Ketamine’s effects appear to be stereoselective as vasorelaxation by S(+) ketamine is significantly weaker than by R(–) ketamine.193 However, ketamine impairs vasodilation mediated by NO and EDH in vitro by inhibiting the endothelial Ca2+ transient,159,194 an effect not observed in the rat cremaster muscle microcirculation in vivo.195 Racemic ketamine inhibits KATP channel–mediated pulmonary vasodilation in the rat aorta196 and in the canine pulmonary artery,197 whereas S(+) ketamine shows no effect.196 Ketamine also affects the leukocyte-endothelium interactions. Brookes et al.198 showed that hemorrhage-induced leukocyte adhesion in postcapillary venules was reduced under ketamine anesthesia in the rat. This effect is stereoselective because leukocyte adhesion to the coronary vasculature after cardiac ischemia/reperfusion was inhibited by S(+) ketamine.199 Interestingly, S(+) ketamine may also modulate vascular permeability and reduce albumin extravasation in a model of chemical peritonitis.200 Ketamine was also found to promote metastasis formation in tumor-bearing mice,82 an effect possibly related to its effects on the immune system (suppression of natural killer cell activity201). Although the effects of ketamine on proliferation, differentiation, and survival of neuronal stem cells are known,202–204 it is not clear to date whether ketamine also affects endothelial progenitor cells or mesenchymal stem cells.

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Etomidate

Etomidate is an induction agent with remarkable hemodynamic stability. Unlike ketamine, etomidate’s effects on vessels in vitro are predominantly endothelium-dependent.194,197,205–207 Sohn et al.205 showed that etomidate, at clinically relevant concentrations, attenuates acetylcholine-induced endothelium-dependent relaxation in rat aorta. Kessler et al.206 further reported that etomidate inhibits the EDH pathway in the human renal artery. Shirozu et al.207 observed that etomidate influences the norepinephrine response in rat mesenteric arteries through endothelium-dependent enhancing effects at lower concentrations and endothelium-independent inhibitory effects at higher concentrations. In contrast, in a study by Gursoy et al.,192 etomidate caused endothelium-independent relaxation in human radial artery in vitro. Interestingly, etomidate directly stimulates α2B-adrenoceptors on smooth muscle cells, which may be ultimately responsible for its well-appreciated cardiovascular stability in clinical practice.208 In contrast to most other anesthetics, etomidate does not reduce postischemic adhesion of neutrophils to coronary endothelial cells in isolated hearts subjected to ischemia-reperfusion injury.209 There are also no data showing that etomidate affects endothelial barrier function, angiogenesis, and tumor growth. However, as inhibitor of adrenal steroidogenesis and of adrenal cell proliferation, it may be potentially useful in the treatment of adrenocortical tumors.210

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Barbiturates

The effects of barbiturates on systemic vascular resistance have been investigated in numerous studies but the precise role of the endothelium in barbiturate-induced loss of vascular tone remains unclear. Terasako et al.211 found that thiopental and pentobarbital at a concentration of 300 µM significantly reduced phenylephrine-induced contraction in the rat aorta but not in canine mesenteric arteries in vitro. The lower concentration (100 µM) was ineffective. The same authors also reported the attenuation of acetylcholine-induced endothelium-dependent vasodilation by thiopental in the rat aorta and in the canine mesenteric artery at 300 µM but not at 100 µM, whereas sodium nitroprusside–induced endothelium-independent vasodilation was reduced irrespective of the concentration used. Thiopental at 300 µM also inhibited EDH-mediated vasorelaxation in human renal artery.206 Moreover, Kassam et al.212 found that thiopental induces relaxation in rat thoracic aortic rings through an endothelium-independent pathway and that the endothelium rather attenuated relaxation through angiotensin II/endothelin-dependent mechanisms. Methohexital and thiopental decrease expression of VEGF in hypoxic porcine brain microvascular endothelial cells213 and thus may decrease hypoxia-induced angiogenesis and vascular permeability. Interestingly, coadministration of pentoxifylline with thiopental induces acute pulmonary edema in rats, possibly by completely blocking NO production.214 Reduced VEGF production by barbiturates may also potentially reduce tumor growth, but this has not been observed.82 After hemorrhage, leukocyte adhesion and CD11b expression increased during thiopental anesthesia in rats,198 whereas Szekely et al.209 reported that thiopental reduced leukocyte adhesion in postischemic coronary arteries of guinea pig hearts. It appears that thiopental attenuates cell adhesion locally after ischemia-reperfusion but enhances it systemically after marked blood loss.

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Benzodiazepines

Benzodiazepines blunt baroreflexes in a dose-dependent manner and diminish the baroreceptor response to hypotension.215 This has been proposed as possible mechanism of benzodiazepine-induced relaxation of vascular216 and airway smooth muscle.217 However, endothelium-dependent vasodilating effects in rat aortic rings after administration of diazepam218 and midazolam219 were also reported, albeit at supraclinical concentrations. At lower concentrations, midazolam did not affect endothelium-dependent and endothelium-independent vasorelaxation,159 but it attenuated the vasoconstrictive response to adrenergic stimuli.220 In the endothelium-denuded rat aorta, Galindo et al.221 found a phosphodiesterase inhibitory activity of diazepam at supraclinical concentrations. Benzodiazepines also have anti-inflammatory actions.222–224 Midazolam appears to inhibit TNF-α–induced endothelial activation via the peripheral benzodiazepine receptor (a protein now renamed to “translocator” protein) localized in the mitochondrial outer membrane.225 In isolated perfused guinea pig hearts subjected to ischemia-reperfusion, midazolam reduced polymorphonuclear neutrophil adhesion to the coronary endothelium,209 a crucial step in the development of ischemic myocardial injury. Ghori et al.226 showed protective effects of midazolam against ischemia-reperfusion injury in mouse cerebral endothelial cells through a decreased expression of the adhesion molecules ICAM-1 and P-selectin. So far, no studies have evaluated the effects of benzodiazepines on vascular permeability or angiogenesis, although midazolam stimulates the release of VEGF, a strong mitogen for vascular endothelial cells, from aortic smooth muscle cells via p38 and c-Jun N-terminal kinase pathways.227 Conversely, high doses of diazepam reduce carrageenan-induced paw edema and vascular permeability in rats by increasing the release of corticosterone from the adrenal glands.228 Benzodiazepines are also known to inhibit the growth of mesenchymal stem cells229,230 and to diminish proliferation and differentiation of neuronal stem cells,231 although their effects on endothelial progenitor cells, angiogenesis, and tumor growth are unknown.

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Opioids

Evidence supports the view that opioids have a much broader spectrum of activities than traditionally proposed, because of the widespread expression of opioid receptors (in particular μ- and δ-opioid receptors), not only in the central and peripheral nervous systems but also in the cardiovascular system.232 In vitro, opioids cause a dose-dependent, mostly endothelium-independent, relaxation.233–235 Interestingly, tramadol, a weak µ-opioid receptor agonist, stereoselectively attenuates vasodilation in a partially endothelium-dependent manner at higher concentrations only,236,237 whereas R(–) tramadol is ineffective. However, it is not clear whether this is a direct opioid receptor effect.236,237 Tramadol may have also effects on serotonergic and adrenergic pathways. Hofbauer et al.238 described anti-inflammatory actions of opioids by altering the neutrophil-endothelial interaction in HUVECs. They demonstrated that remifentanil and fentanyl reduce polymorphonuclear neutrophil adhesion in a dose-dependent manner through a decreased neutrophil transmigration and ICAM-1 expression. Conversely, fentanyl is unable to reduce postischemic adhesion of neutrophils in the coronary system of isolated perfused guinea pig hearts.209 These opposing observations may be related to the differential expression of opioid receptors in certain vascular beds of different species. Morphine potentiates LPS-induced increase in vascular permeability and apoptosis of vascular endothelial cells.239 It has been shown that morphine increases the expression of platelet-derived growth factor in human microvascular endothelial cells,240 which is known to enhance vascular permeability. Interestingly, µ-opioid receptors have recently been found to enhance proinflammatory toll-like receptor-4 signaling in brain endothelial cells,241 whereas stimulation of κ-opioid receptors delays endothelial apoptosis in vitro, potentially diminishing blood-brain barrier dysfunction.242

In pulmonary endothelial cells, morphine-, thrombin-, and LPS-induced increase in vascular permeability can be blocked by methylnaltrexone, a μ-opioid receptor antagonist.243 In contrast, in hemorrhagic shock where levels of endogenous opioids (endorphins) are already markedly increased and may potentially modify morphine-induced actions, morphine appears to attenuate shock-related hyperpermeability in a PKA-dependent manner.244 Balasubramanian et al.245 found that morphine dose-dependently reduced the secretion of VEGF in hypoxic HUVECs, an effect reversed by naloxone. Morphine, the most commonly used opioid for pain treatment, may stimulate angiogenesis.246,247 The proangiogenic effect of morphine was inhibited by methylnaltrexone, a peripherally acting µ-opioid receptor antagonist.247 However, morphine’s angiogenic potential is still controversial, as some studies have shown that morphine may suppress tumor angiogenesis.248 Recently, it has been discovered that κ-opioid receptors are highly expressed in endothelial progenitor cells and inhibit endothelial cell differentiation and angiogenesis via cAMP/PKA signaling.249 Moreover, specific activation of κ-opioid receptors was shown to suppress VEGFR2 expression and inhibit tumor angiogenesis.250 Irrespectively, µ-opioid receptors were reported to promote proliferation, migration, and epithelial to mesenchymal transition in human lung cancer cells.251 Also, morphine accelerated cancer progression and impaired survival in mouse models with breast cancer252 and non–small-cell lung cancer.253 The effects of opioid receptor agonists, specifically morphine, on tumor growth and metastasis formation are still controversial and currently subject to intensive scrutiny.254

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Local Anesthetics

Most local anesthetics, except for cocaine, are vasodilators and decrease systemic vascular resistance. Differences in the vasodilating effects of local anesthetics can be clearly visualized when injected intradermally, qualitatively by monitoring changes in skin color255 or quantitatively by the use of laser Doppler imaging.256,257 When tested in vitro, most local anesthetics display a biphasic action with vasoconstriction at lower concentrations and vasorelaxation at higher concentrations.258–263 The mechanisms contributing to the vasodilating and/or constricting effects of local anesthetics remain controversial. Timponi et al.262 found that ropivacaine-induced vasoconstriction in murine mesenteric arterioles was endothelium-dependent and largely because of locally produced vasoconstrictive prostanoids. Choi et al.263 implicated the lipoxygenase pathway in levobupivacaine-induced vasoconstriction of rat aortic rings, which was attenuated by increasing the release of NO. In contrast, mepivacaine-induced vasoconstriction appears to be mainly endothelium-independent and involves activation of Rho kinases and protein kinase C,264 as well as ERK1/2.265 Likewise, Gherardini et al.259 reported that the contractile response to ropivacaine and lidocaine was endothelium-independent in human mammary artery preparations. The biphasic response, that is, vasoconstriction at lower and vasodilation at higher concentrations, to most amide local anesthetics in rat aortic preparations appears to be because of Ca2+-sensitization mechanisms.261 The ester local anesthetic, procaine, was found to relax porcine coronary arteries in an endothelium-dependent (NO release) and endothelium-independent (K+ channel activation, inhibition of Ca2+ influx) manner.266 Local anesthetics have been also shown to inhibit the vascular responsiveness to vasoconstrictors in an endothelium-dependent manner when present at a concentration of 0.1 mM.267 Lidocaine, bupivacaine, and mepivacaine at a concentration of 10 µM all reduced endothelium-dependent relaxations to bradykinin in the isolated porcine ciliary artery.268 However, bupivacaine (tested at concentrations of 1 µM and 10 µM) was also shown to attenuate TXA2-induced contraction in rat aortic rings in an exclusively endothelium-independent manner.269

Local anesthetics also exert marked anti-inflammatory actions (for an excellent review, see Hollmann and Durieux270). Ropivacaine reduces the inflammatory response in LPS-induced lung injury in rats by mitigating adhesion and neutrophil-induced cytotoxicity in pulmonary artery endothelial cells.271 Protection of endothelial cells by amide local anesthetics against LPS-induced toxicity appears to be mediated by mitochondrial KATP channels, whereas the ester local anesthetics tetracaine and procaine have no protective effects.272 Berger et al.273 reported that lidocaine reduces neutrophil recruitment in septic patients by abolishing neutrophil-induced arrest and transendothelial migration. Thoracic epidural anesthesia using local anesthetics was found to reduce endotoxin-induced endothelial dysfunction,274 to reverse sepsis-induced hepatic hyperperfusion,275 and to improve pulmonary endothelial dysfunction in the rat.276 Thoracic epidural anesthesia also attenuated hemorrhage-induced impairment of intestinal perfusion in rats.277 Onan et al.278 further reported that thoracic epidural anesthesia preserves flow and NO production of the internal thoracic artery in coronary artery bypass graft surgery in patients. Likewise, Budic et al.279 showed that regional anesthesia and propofol, as opposed to sevoflurane, diminish biomarkers of oxidative stress and endothelial dysfunction after tourniquet release in children. The beneficial effects on the endothelium by regional anesthetics may be mediated indirectly by inhibition of the sympathetic nervous system and directly by low levels of systemically circulating local anesthetics. It has also been shown that local anesthetics are capable of providing significant endothelial barrier protection. Piegeler et al.280 demonstrated in vitro that local anesthetics inhibit the recruitment of p85 regulatory subunit of PI3K kinase to TNF-α receptor 1, reducing Src activation, and ultimately leukocyte adhesion via ICAM-1 and endothelial hyperpermeability. However, infusion of local anesthetics unexpectedly worsened ischemia-reperfusion damage in the rat kidney in vivo by increasing ICAM-1 protein expression and adhesion of inflammatory cells.281 Clearly, these findings exemplify the complex and often unpredictable interactions between local anesthetics and endothelial cells. Unlike volatile anesthetics, lidocaine impairs the timely resolution of the acute inflammatory reaction.147 Cocaine increases the expression of tissue factor in human aortic endothelial cells, which activates factor X and promotes thrombin formation.282 Cocaine also promotes endothelial dysfunction by increasing ET-1 production and ET-1 receptor protein expression and by decreasing NO production and expression of eNOS in human aortic endothelial cells.283 Local anesthetics were found to be toxic to many cell types, including endothelial cells.284 They also exert antiproliferative effects on mesenchymal stem cells in vitro by inhibiting mitochondrial respiration, blocking the cell cycle at G1, and changing the transcriptional program.285 Finally, local anesthetics have been reported to reduce the metastatic potential of tumor cells in vitro.286,287 Preliminary data link the use of local anesthetics to reduced recurrence rates and improved survival in tumor patients.288 However, the role of angiogenesis and endothelial progenitor cells in the antitumor effects elicited by local anesthetics remains elusive.

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Clinical Perspectives

Although many effects of IV anesthetics on endothelial function are controversial or completely unexplored, propofol and opioids appear to have the most favorable profile with respect to preservation of endothelial function for clinical practice (Table 2). Propofol has strong antioxidant, anti-inflammatory, and, as recently discovered, some promising tumoristatic effects. The use of local anesthetics, either IV or in the context of regional anesthetics (inhibition of the sympathetic nervous system), potentially protects the endothelium against inflammation and ischemia-reperfusion injury.

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CONCLUSIONS

Recent studies have increased our understanding of the complex and often context-sensitive interactions between anesthetics and endothelial cells. However, there remain important knowledge gaps. Results of numerous investigations describe the regulatory effects of anesthetics on the vascular tone, but in many cases the precise role of the endothelium and the underlying mechanisms remain controversial. Endothelial cells are also key players in tumor growth, angiogenesis, vascular permeability, and regenerative activities, all of which are markedly modulated by general and local anesthetics. So far, available data investigating the effects of anesthetics on the diseased endothelium are scarce. In particular, potentially beneficial and/or detrimental effects of anesthetics on the hypertensive, atherosclerotic, diabetic, nicotine/smoke-stressed, and tumor-related endothelium should be explored. Our review of currently available data implies that the choice of anesthetics for “background anesthesia” in animal and clinical studies could significantly affect study results and may explain controversies between studies, as well as the poor translation of experimental work into the clinical arena. Clearly, more experimental and translational studies are needed to decipher the molecular signaling pathways involved in the effects of anesthetics on the biology of endothelial cells.

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DISCLOSURES

Name: José A. Aguirre, MD, MSc.

Contribution: This author helped prepare the manuscript and the first draft of the illustrations.

Attestation: José A. Aguirre approved the final manuscript.

Name: Eliana Lucchinetti, PhD.

Contribution: This author helped prepare the manuscript and the final draft of the illustrations.

Attestation: Eliana Lucchinetti approved the final manuscript.

Name: Alexander S. Clanachan, PhD.

Contribution: This author helped prepare the manuscript.

Attestation: Alexander S. Clanachan approved the final manuscript.

Name: Frances Plane, PhD.

Contribution: This author helped prepare the manuscript.

Attestation: Frances Plane approved the final manuscript.

Name: Michael Zaugg, MD, MBA, FRCPC.

Contribution: This author helped prepare the manuscript.

Attestation: Michael Zaugg approved the final manuscript and is the corresponding author.

This manuscript was handled by: Martin J. London, MD.

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