Propofol (2,6-di-isopropylphenol) has been extensively used as an IV anesthetic drug since 1986,1 and as a sedative in the intensive care unit for nearly 20 years.2 It is known for its rapid onset, short duration of action, minimal side effects, and rapid elimination.3–6 It is also known to produce undesirable hypotension, which may be related to a decrease in cardiac output, peripheral vascular resistance, or both, an increase in venous capacitance,7 or a decrease in sympathetic nervous system basal activity.8 A decrease in peripheral vascular resistance may be related to propofol's direct or indirect vasodilator effects on vascular smooth muscle cells. Relaxation of the smooth muscle can occur via 2 mechanisms: the endothelium (E)-dependent mechanism and the E-independent mechanism. The E-dependent mechanism includes nitric oxide (NO) formation, prostanoid synthesis, and the release of E-derived hyperpolarizing factor followed by the activation of the K+ channel in the smooth muscle cells.9 The E-independent relaxation mechanism includes direct activation of the K+ and Ca2+ channels in smooth muscle cells, or through interfering with the availability of free cytosolic Ca2+ via the voltage gated Ca2+ channel.6,10–13 There has been much discrepancy on whether propofol-induced relaxation occurs via the E-dependent4,10,14 or -independent mechanism.3,6,12,15
Perivascular adipose tissue (PVAT) is situated outside the adventitial layer and surrounds most of the systemic blood vessels. Studies have shown that PVAT is able to attenuate vessel contraction to various agonists including phenylephrine (PHE), serotonin, angiotensin (Ang) II, and U 46,619, as is demonstrated in the aorta and the mesenteric arteries16–18 and vein19 from rats, and internal thoracic arteries of humans.20 PVAT is now recognized as an important modulator of vascular functions, and PVAT function is altered under pathological conditions such as hypertension,21–23 obesity,17 and diabetes.24 We have reported that PVAT modulates the relaxation response of blood vessels through an E-dependent pathway, which involves the release of NO, followed by the activation of K+ channels; and an E-independent pathway involving the production of hydrogen peroxide (H2O2) by PVAT and the subsequent activation of soluble guanylyl cyclase (sGC).25 In the E-dependent pathway, the results on the specific type of K+ channels involved in the relaxation response varied with the vessel type and animal species: adenosine triphosphate (ATP)– dependent K+ (KATP) channels were involved in rat aorta,18 and voltage-dependent K+ channels (Kv) were involved in the mesenteric arteries of Sprague–Dawley rats16; whereas calcium-dependent K+ channels (KCa) channels were involved in both aorta from Wistar rats25 and human internal thoracic artery.20
The aim of this study was to examine the effects of propofol-induced vasodilation in both the presence and absence of PVAT. Also, the mechanisms of the relaxation response were studied. Here we report that propofol-induced vasodilation in rat aorta occurs via both the E-dependent and -independent pathways, and more important, the relaxation effect of propofol is enhanced by PVAT.
Male Wistar rats (300 to 350 g) were obtained from Harlan (Indianapolis, IN). This protocol was in accordance with the guidelines of the Canadian Council on Animal Care and the Guide for the Care and Use of Laboratory Animals (USA), and was approved by the Animal Research Ethics Board of McMaster University.
Preparation of Aortic Rings and Contractile Studies
The procedure for the preparation of aortic rings has been described in our previous reports.17 Briefly, the rat was anesthetized with an overdose of sodium pentobarbital (60 mg/kg, intraperitoneal), and the thoracic aorta was collected in an oxygenated physiological salt solution (PSS) with the following composition (in mM): NaCl, 119; KCl, 4.7; KH2orally4, 1.2; MgSO4, 1.2; NaHCO3, 25; CaCl2, 1.6; and glucose, 11. Paired aortic rings with or without PVAT (PVAT+ and PVAT−, 4 mm long for each) were prepared with either intact E (E+) or with E removed (E−) using the middle segment of the thoracic aorta. Removal of PVAT was performed under microscopic observation, typically yielding 4 to 6 aortic rings. The E of the aortic rings was removed by gently rubbing the internal surface with a fine wooden stick 5 or 6 times. Successful removal of the E was confirmed by the absence of a relaxation response to carbamylcholine chloride (CCh, 1 μM) in rings precontracted with PHE (1 μM). Aortic rings were suspended on stainless steel hooks in tissue baths containing PSS. A computerized myograph system was used to record the isometric tension of the aortic rings. After equilibration for at least 90 minutes at 3 g of preload, which is the optimal preload defined in our previous experiment,17 the arterial rings were challenged with 60 mM KCl twice at an interval of 30 minutes. Contractile response to agonists was expressed as a percentage of the KCl contraction.
To study the direct relaxation effect induced by propofol, a cumulative concentration-dependent response curve for propofol was constructed in vessels precontracted with PHE (10−6 M). Propofol was applied in its commercially available 10% Intralipid emulsion (10 mg/mL propofol, 100 mg/mL soybean oil, 12 mg/mL egg lecithin, 22.5 g/mL glycerin) in a cumulative manner to obtain concentrations of 10−6 M, 3 × 10−6 M, 10−5 M, 3 × 10−5 M, 10−4 M, and 3 × 10−4 M. Each new dose was added after the contraction had reached a steady state from the preceding dose, usually 10 minutes. In a separate series of control experiments, volumes of 10% Intralipid identical to those used to yield each of the propofol-induced responses were used to study the specific effect of Intralipid. The relaxation responses recorded with increasing concentrations of the test drugs were expressed as the percentage relaxation from the precontracted load. NO synthase inhibitor N-nitro-L-arginine (L-NNA, 10−4 M); inhibitors of K+ channels: nonspecific calcium-dependent K+ (KCa) inhibitor, tetraethylammonium (TEA, 10−3 M); KATP channel inhibitor, glibenclamide (GLY, 10−5 M); voltage-dependent K+ (Kv) channel inhibitor, 4-aminopyridine (4-AP, 10−3 M); Ang-(1–7) specific Mas receptor antagonist (A779, 10−6 M); H2O2 scavenger catalase (1000 U/mL); and sGC inhibitor, 1H-(1,2,4) oxadiazolo (4,3-A) quinazoline-1-one (ODQ, 3x10−5 M) were incubated for 25 to 30 minutes to study the relaxation mechanism induced by propofol. To test the involvement of the K+ channels in propofol-induced relaxation, we precontracted vessels with 60 mM KCl, followed by application of propofol in a cumulative concentration-dependent manner using the same concentrations as mentioned above. The concentration of the channel blocker/ enzyme inhibitor was chosen on the basis of our previous studies showing the effective concentration for rat aorta.25
The following chemicals were used: A779, carboxy-PTIO (potassium salt), catalase, CCh, GLY, Intralipid, L-NNA, ODQ, PHE, TEA, 4-AP (Sigma-Aldrich, St. Louis, MO), and propofol (NovoPharm, Toronto, Ontario, Canada).
Results are expressed as means ± SEM in which n represents the number of rats. Statistical analysis was performed by 2-way repeated measurements or 1-way analysis of variance (ANOVA) followed by post hoc t test to determine any significant difference between the concentration-dependent response curves with the presence of PVAT or E, or PVAT or E removed. A difference was considered significant when P ≤ 0.05.
Contraction to KCl in Aortic Rings With or Without PVAT and Endothelium
The presence or absence of PVAT and E did not affect the maximal tension induced by 60 mM of KCl (Fig. 1A). These results showed that the presence of PVAT did not pose a physical constraint on the ability of the aorta to contract, and the procedure to remove PVAT, E, or both did not damage or affect the contractility of the aorta.
Effects of Propofol on Aortic Rings
Contraction induced by PHE was different among the 4 types of vessels, with vessels denuded of PVAT and E showing the highest response, in comparison with vessels with both PVAT and E present showing the lowest response because of the relaxation factors released by the E and PVAT (data not shown). This type of difference was also present in rat aorta when serotonin was used as the agonist.25 Because the baseline contraction induced by PHE was different among the 4 types of vessels, we normalized the relaxation response induced by propofol as a percentage of the PHE-induced contraction to account for the difference in the level of contraction among these 4 vessel preparations. In PHE precontracted vessels, PVAT+E+ vessels showed the most relaxation in response to propofol in comparison with vessels with both PVAT and E− (P = 0.04, Fig. 1B). In contrast, vessels with either PVAT or E− showed a similar relaxation response to propofol, and these responses were lower than PVAT+E+ vessels but higher than PVAT−E−vessels (P = 0.01). When administered in concentrations equivalent to those of propofol, Intralipid emulsion had minimal vascular effects in the 4 types of vessels, indicating that the relaxation effect was related to propofol and not its solvent Intralipid (Fig. 1B).
Vessels precontracted with PHE showed a concentration- dependent relaxation response to propofol, and this response was highest when both PVAT and E were present, as opposed to when both were absent (Fig. 2A). Both in the presence and absence of E, relaxation induced by propofol was higher in the presence of PVAT than that in vessels denuded of PVAT (Fig. 2A). In vessels precontracted with KCl (60 mM), propofol also induced a relaxation response, but there was no difference among the 4 types of vessels, indicating that neither PVAT nor E were involved in this relaxation response in KCl-contracted vessels (Fig. 2B).
Involvement of NO and K+ Channel Activation in Propofol-Induced Endothelium-Dependent Vascular Relaxation
Potassium channels and NO are involved in the relaxation induced by PVAT.25,26 We therefore studied the role of K+ channels and NO in the relaxation response induced by propofol involving PVAT. In vessels with intact E and PVAT, and in vessels with either PVAT or E−, both KCa (TEA) and KATP (GLY) channel blockers, and NO synthase inhibitor (L-NNA) significantly reduced the propofol-induced relaxation (Fig. 3).
Involvement of Ang-(1–7) and Voltage-Dependent K+ Channel (Kv) in Propofol- Induced Relaxation
Ang-(1–7) has been identified as one of the relaxation factors released by PVAT that causes the release of NO from the E to induce vascular relaxation.26 We therefore studied whether the release of Ang-(1–7) is involved in the relaxation induced by propofol. In vessels with E+ or E− and in both the presence and absence of PVAT, incubation with either Ang-(1–7) specific Mas receptor antagonist A779 or Kv channel blocker 4-AP did not affect the relaxation response induced by propofol (data not shown).
Involvement of sGC and H2O2 in Propofol Induced Endothelium-Independent Vascular Relaxation
In the E-independent relaxation pathway induced by PVAT, the production of H2O2 and subsequent activation of sGC are involved.25 In the 4 types of vessel preparations, the sGC inhibitor ODQ significantly reduced the relaxation response to propofol (Fig. 4). H2O2 scavenger catalase (1000 U/mL) significantly reduced the propofol-induced relaxation response in vessels with PVAT (P < 0.05, n = 6 rats/group) but not in vessels with PVAT removed (data not shown).
The novel findings of the present study are that propofol induces relaxation via both the E-dependent and -independent pathways. This relaxation response is enhanced in the presence of PVAT. In the E-dependent pathway, propofol stimulates the E to release NO and subsequent activation of K+ channels, leading to relaxation of the smooth muscle. Propofol also induces the release of NO from PVAT directly to cause relaxation of the smooth muscle. In the E-independent pathway, propofol stimulates PVAT to generate H2O2 and subsequent activation of the smooth muscle sGC. We also found that propofol causes direct activation of the smooth muscle sGC, leading to vasorelaxation. This is the first report to show that PVAT enhances the effect of propofol, causing relaxation of the smooth muscle through both the E-dependent and -independent pathways, therefore adding new insights to our current knowledge about the mechanisms used by propofol to modulate vessel function.
Previous studies on the effect of propofol on vascular functions have reported conflicting findings on whether the E is involved in propofol-induced relaxation. Some studies reported the involvement of E in propofol-induced relaxation,27,28 whereas other studies showed no significant difference between the relaxation observed in the presence of the E and the relaxation in the absence of the E.6,10,11 Our study clearly showed that relaxation of smooth muscle cells induced by propofol occurred both in the presence and absence of E, and PVAT enhanced this relaxation response, as discussed below.
In the E-dependent pathway, our results showed that after incubation with NO synthase inhibitor L-NNA, the relaxation response to propofol was significantly reduced in all types of vessels except in the PVAT-E− vessels. Therefore, propofol was stimulating the E to release NO to cause relaxation. Petros et al.28 also found that propofol stimulated NO release from cultured porcine aortic endothelial cells. In the vasculature, NO activates various K+ channels to cause relaxation of the smooth muscle.29 In our study, to investigate whether K+ channels are involved in propofol-induced relaxation, we compared the relaxation response of the 4 types of vessels with propofol in vessels precontracted with either PHE or KCl. The rationale was that in vessels precontracted with KCl, K+ channels would not be operable. We found that relaxation induced by propofol was higher in vessels precontracted with PHE than that precontracted with KCl, showing that relaxation induced by propofol—which acts through PVAT or E, or both—involved K+ channels.
To further investigate which K+ channels were involved, we used 3 K+ inhibitors to study the relaxation induced by propofol. We found that Kv channels were not involved because 4-AP did not affect the responses to propofol. After incubation with KATP channel blocker GLY or KCa channel blocker TEA, the relaxation response to propofol was significantly reduced by the same degree, demonstrating the involvement of these 2 K+ channels. A similar finding was found in the rat mesenteric vascular bed for which both KCa and KATP channels were involved in the relaxation response induced by propofol.30 To study whether the blocking of both KCa and KATP channels had an additive effect, we incubated the aorta with both GLY and TEA and found that the degree of reduction in relaxation was not enhanced in comparison with when these inhibitors were used singly (data not shown), showing that at the concentration used in our study, blocking either 1 of these 2 K+ channels was sufficient to exert a maximal effect in affecting relaxation in smooth muscle in response to propofol.
In the E-dependent pathway, relaxation induced by propofol was enhanced by PVAT, based on our results that the relaxation response induced by propofol was higher in vessels with intact PVAT, both in the presence and absence of E. This enhancing effect was due to the release of NO because the NO synthase inhibitor L-NNA was effective in reducing the relaxation effect of propofol in vessels with either PVAT or E, or both. One source of NO was from the E, because the relaxation effect was higher in the presence of E in both PVAT+ and PVAT− vessels. However, the propofol effect was also higher in PVAT+ vessels in comparison with PVAT− vessels in the absence of E, indicating that NO was also released by PVAT in response to propofol. We have recently reported that one of the relaxation factors released by PVAT is Ang-(1–7), which acts on the Mas receptors on the E to release NO to cause relaxation of the vessels.26 We therefore investigated whether this pathway was involved in response to propofol. Our results showed that this pathway was not involved because the Mas receptor blocker A779 did not affect the relaxation response induced by propofol in the 4 types of vessels.
In the E-independent relaxation pathway involving PVAT, we have previously reported that superoxide production by PVAT and its dismutation by superoxide dismutase, which produces H2O2 and subsequent activation of the sGC in smooth muscle, are involved.25 In isolated endothelial cells, acetylcholine-induced H2O2 production and catalase, a scavenger of H2O2, prevented its release.31 To measure H2O2 production in an intact vessel is difficult. We therefore used catalase as an indirect measure of H2O2 release. Here we found that in PVAT+E− vessels, incubation with catalase significantly reduced the relaxation response induced by propofol, indicating that the production of H2O2 by PVAT was involved in the response to propofol. H2O2 can then diffuse to the smooth muscles to increase cyclic guanosine monophosphate (cGMP) levels to cause relaxation.25
Relaxation Pathway Independent of PVAT and E
In the absence of both PVAT and E, a significant relaxation response (30%–32%) was observed in response to propofol, indicating a direct effect of propofol on the blood vessels. Our results showed that the production of sGC was involved because incubation with ODQ, which inhibits sGC, significantly reduced propofol-induced relaxation in the 4 types of vessel preparation. Therefore in the absence of both PVAT and E, propofol can directly activate sGC, leading to an increase in cGMP and ultimately relaxation of the smooth muscles. Furthermore, ODQ did not completely eliminate the relaxation effect of propofol in the absence of PVAT and E, indicating the presence of another mechanism. In porcine tracheal smooth muscle cells32 and rat aortic smooth muscle cells,13 propofol was found to inhibit calcium entry through the L-type channels, so that this mechanism may explain the persistence of the relaxation effect of propofol in the presence of ODQ in vessels with both PVAT and E removed.
We have summarized the pathways involved in the response of the aorta to propofol in Figure 5. Propofol-induced relaxation occurs through 5 mechanisms. (a) In the E-dependent pathway, propofol induces E to release NO and subsequent activation of the KCa and KATP channels to cause relaxation. (b) Propofol also induces the release of NO from PVAT, thereby producing an additive effect in propofol-induced relaxation in the E-dependent pathway. (c) In the E-independent pathway, propofol induces PVAT to produce H2O2 and subsequent activation of sGC. (d) Propofol acts directly on smooth muscle cells to produce sGC to cause vasodilation. (e) Propofol inhibits calcium entry through the L-type channels as reported by others discussed above.
During clinical anesthesia, the peak plasma concentration of propofol after bolus injection (25 μg/mL, 140 μM) or short infusion (∼35 μg/mL, 196 μM) was higher than those with approximately 10 μg/mL (56 μM) in both target-controlled infusion and long infusion.33 The range of propofol concentration we had used in this study (1 μM to 300 μM) obviously was within the peak plasma concentration (i.e., 140 to 196 μM) at the low concentration range but higher than that observed in the plasma of patients at the higher concentration range. In pharmacological studies of the mechanism of action of drugs, it is inevitable that the concentration used will exceed the physiological concentration in the high concentration range. However, the tissue level of propofol in PVAT is unknown. PVAT is a highly vascularized tissue with a rich supply of capillaries among all the adipocytes (R.M.K.W. Lee, unpublished observation, McMaster University, Hamilton, Ontario, Canada, 2006). Adipocytes in PVAT of rat aorta are also connected through gap junctions (Sandow and Lee, unpublished observation, University of New South Wales, Sydney, Australia, 2008). Therefore any drug such as propofol that enters the bloodstream will enter PVAT rapidly to exert its effect.
Clinical studies on the hemodynamic effects of propofol have reported conflicting results with respect to its effects on cardiac output and systemic vascular resistance. Some studies reported that hypotension arose as a result of a decrease in systemic vascular resistance with little to no change in cardiac output,34 and others have suggested that marked hypotension was due to a decrease in cardiac output without any change in systemic vascular resistance.35 Our finding that PVAT enhanced the vascular relaxation effect of propofol could be of clinical importance. Studies in animals showed that the vasodilatory property of PVAT was impaired in animals with obesity17 and hypertension.22,23 In contrast, under acute and chronic hyperglycemic conditions, the vasodilatory effect of PVAT was enhanced.24 A total absence of fat tissue, as in the case of lipoatrophic mice, is also unhealthy because these mice exhibit hypertension.36 In view of the profound effect that PVAT has in enhancing the relaxation effect induced by propofol found in our study, and the fact that PVAT function is altered in diabetes and hypertension, the effect of propofol on arterial blood pressure control in patients suffering from hypertension, diabetes, or obesity in a clinical setting should be studied, with the aim of providing better intraoperative care for these patients.
In conclusion, we found that PVAT enhances the relaxation induced by propofol, therefore showing the ability of PVAT to modulate drug action such as the action of propofol. This may have clinical relevance in the intraoperative management of blood pressure in patients with metabolic diseases such as obesity and diabetes.
Name: Saira I. Kassam.
Contribution: Study design, conduct of study, data analysis, manuscript preparation.
Name: Chao Lu, MD.
Contribution: Study design, conduct of study, data analysis, manuscript preparation.
Name: Norman Buckley, MD.
Contribution: Idea for the study, study design, manuscript preparation.
Name: Robert M. K. W. Lee, PhD.
Contribution: Study design, conduct of study, manuscript preparation.
We thank the staff of the Central Animal Facility of McMaster University for animal care.
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