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Advances in Vascular Hyporeactivity After Shock

The Mechanisms and Managements

Duan, Chenyang; Yang, Guangming; Li, Tao; Liu, Liangming

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doi: 10.1097/SHK.0000000000000457
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Shock, the common critical illness, is one of the main causes resulting in the mortality after severe trauma at early and late stages. Vascular hyporeactivity, the common complication of shock, means vasculature has low or no response to vasoactives after severe or prolonged shock. It is the main reason that leads to poor tissue perfusion, refractory shock, multiple organ dysfunction syndrome (MODS), and even death (1). Besides, vascular hyporeactivity can severely interfere with the therapy of shock, especially interfere with the applications of vasoactive agents. As reported by a great deal of studies, a number of factors may interfere with the vascular reactivity following shock. Acidosis, nitric oxide (NO), endothelin (ET), inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, endogenous opioid peptides (EOP) such as β-endorphin, angiopoietin (Ang), and the post-shock mesenteric lymph (PSML) have been proposed as major contributors to the vascular hyporeactivity after shock (2).

However, the exact mechanisms of vascular hyporeactivity after shock are not fully understood. This review will discuss the recent advances in the mechanisms and treatment measures for vascular hyporeactivity after shock.


There were some scattered reports about the characteristics and change rules of vascular reactivity in septic and burn shock in the past. In recent years, lots of studies were concentrated on traumatic and hemorrhagic shock, in which the vascular reactivity appeared different characteristics and change rules as compared with septic or endotoxic shock such as biphasic change, vasculature difference, and gender/age-differences.

Characteristics of vascular reactivity after hemorrhagic shock

Biphasic change

Studies showed vascular reactivity appeared biphasic change after hemorrhagic shock (3–7)(3–7)(3–7)(3–7)(3–7). It is significantly increased at early-stage shock (10 min and 30 min after shock) and decreased at late-stage or prolonged shock (2 h after shock) (4). Available studies showed that the balance of RhoA/Rac and Ang1/Ang2 participate in the occurrence of the hemorrhagic shock-induced biphasic change of vascular reactivity (Fig. 1). RhoA/Rac, the important member of small G protein family, was found participated in the regulation of biphasic change of vascular reactivity after hemorrhagic shock (5–7)(5–7)(5–7). Li et al. (8) found that in early stage of shock, the activity of RhoA was increased, the activity of Rac1 was decreased, whereas in late stage of shock, the activity of RhoA was decreased, and the activity of Rac1 was increased, the changes of the ratio of RhoA/Rac1 was positively correlated with the vascular reactivity. RhoA/Rac plays the regulatory effects mainly through their downstream molecules, Rho kinase, and P21-activated kinase (PAK). Rho A may activate Rho kianse and inhibit PAK to increase the vascular reactivity, whereas Rac may activate PAK and inhibit Rho kianse to decrease the vascular reactivity (7–10)(7–10)(7–10)(7–10). Further study found Rho kinase regulates vascular reactivity mainly through inhibition of myosin light chain phosphatase (MLCP) and induction of 20-kDa myosin light chain (MLC20) dephosphorylation. PAK regulates vascular reactivity mainly through inhibition of myosin light chain kinase (MLCK) and MLC20 phosphorylation (9).

Fig. 1
Fig. 1:
Biphasic-changed vascular reactivity after three types of shock.Vascular reactivity is increased at early-stage shock and decreased at late-stage shock after hemorrhagic shock. Endotoxic shock has the same trend as hemorrhagic shock but appears later and more serious. Available data are not clear if burn shock also exists biphasic vascular reactivity. Data show here is a speculated curve (dash line). Akt, a serine/threonine-specific protein kinase; Ang-1, Angiopoietin-1; Ang-2, Angiopoietin-2; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; iNOS, induced nitric oxide synthase; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PAK, P21-activated kinase; Rac, Ras-related C3 botulinum toxin substrate; RhoA, Ras homolog gene family member A; Tie2, a endothelial cell-selective receptor tyrosine kinase.

Angiopoietin (Ang), the important factor promoting angiogenesis and repairing, includes Ang-1 and Ang-2. The study of Xu et al. (11) showed that Ang participated in the occurrence of biphasic change of vascular reactivity following hemorrhagic shock. They found the expression of Ang-1 was increased at early shock, which was positively correlated with the changes of vascular reactivity after hemorrhagic shock, whereas the expression of Ang-2 was increased at late stage of shock, which was negatively correlated with the changes of vascular reactivity after hemorrhagic shock (11). Exogenous administration of Ang-1 maintained vascular hyper-reactivity at early-stage shock and improved hypo-reactivity at late-stage shock, whereas exogenous administration of Ang-2 suppressed vascular hyper-reactivity at early-stage shock and aggravated hypo-reactivity at late-stage shock. These findings suggest that Ang-1 and Ang-2 participate in the regulation of biphasic-changed vascular reactivity after hemorrhagic shock.

Ang-1 and Ang-2 participate in the regulation of vascular reactivity mainly through regulation of the endothelial cell-selective receptor tyrosine kinase Tie2 (11,12)(11,12). Xu and Brindle et al. found that Ang-1 participates in the incidence of vascular hyper-reactivity at early-stage shock mainly through activation of the Tie2-Akt- eNOS pathway resulting in the appropriate amount of nitric oxide release, which brings the protection of vascular endothelial cells, whereas Ang-2 participates in the incidence of vascular hypo-reactivity mainly through Tie2-ERK-iNOS pathway at late-stage shock leading to considerable amount of NO release, which brings the damage to vascular endothelial cells (Fig. 2).

Fig. 2
Fig. 2:
Signal transduction for Ang-1 and Ang-2 in the regulation of biphasic-changed vascular reactivity after shock.Ang-1 and Ang-2 participate in the regulation of biphasic-changed vascular reactivity after hemorrhagic shock. Ang-1 is mainly responsible for hyper-reactivity and induces an appropriate amount of NO release at early shock through Tie2-Akt-eNOS pathway, whereas Ang-2 is mainly responsible for hypo-reactivity and induces a large amount of NO release at late shock through Tie2-ERK-iNOS pathway. Akt, a serine/threonine-specific protein kinase; Ang-1, Angiopoietin-1; Ang-2, Angiopoietin-2; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; iNOS, induced nitric oxide synthase; NO, nitric oxide; Tie2, a endothelial cell-selective receptor tyrosine kinase.

Vasculature bed difference

Studies showed hemorrhagic shock-induced vascular hyporeactivity presents vascular bed diversity, which means blood vessels in different places or organs have different change features in vascular reactivity following shock including different decrease speed and extent in vascular reactivity following shock. For example, Liu et al. (13,14)(13,14) found that following hemorrhagic shock, the vascular reactivity of superior mesenteric artery (SMA), renal artery (RA), femoral artery (FA), celiac artery (CA), and middle cerebral artery (MCA) was all significantly blunted in response to norepinephrine (NE) but the loss of reactivity in SMA, RA, and FA was more severe and rapid than that in CA and MCA. SMA, RA, and FA vascular beds appeared more sensitive to hemorrhage insult than CA and MCA.

As for the reason for the different vascular reactivity in different vasculatures, it may be related to the redistribution of blood and tissue perfusion after hemorrhagic shock (15). This may be correlated with Poiseuille Law and Vascular Waterfall in hemodynamics (16). The decrease in blood pressure is bound to bring the reduction in irrigation flow to many tissues and organs. For example, when systolic pressure decreases below 50 mmHg, the autoregulation of the blood flow in cerebral Willis artery circles would become weaken gradually, whereas the glomerular filtration pressure would drop directly to zero and the urine formation would completely stop at this situation, which indicates that the vasculature bed differences of vascular reactivity following hemorrhagic shock are closely related to blood redistribution and the decrease of tissue perfusion.

Besides, further studies showed that vasculature difference in vascular reactivity was also correlated with different expressions of cytokines and inflammatory mediators in various vasculatures. The study of Liu et al. showed that the expression of cytokines and inflammatory mediators (IL-1β, TNF-α, ET-1, etc.) in intestinal and kidney tissues was significantly higher than that in brain and liver tissues after shock (17). These inflammatory mediators have been confirmed as inducing factors to vascular hypo-reactivity (12,18–21)(12,18–21)(12,18–21)(12,18–21)(12,18–21).

Gender- and age difference

Studies demonstrated that the host responses to trauma and hemorrhagic shock presented age and gender diversity. Chaudry et al. (22) found that females tolerated trauma stimuli much better than males, and found that estrogen played a protective role in this process. Angele et al. found that, in patients younger than 50-year old, male patients had higher risks of death than females after severe blunt trauma, whereas the difference was not evident any more in patients older than 50-year old, which suggests that postmenopausal women without the protection of estrogen has no longer advantages against trauma insult (23–24)(23–24). Besides, Maranon et al. found that premenopausal women avoided more cardiovascular events as compared with men under the same age period. However, after menopause, the advantage was diminished as compared with premenopausal women (25). These results suggest that estrogens make important contribution to the protection of organ function following trauma and hemorrhagic shock.

Studies showed that gender- and age differences not only exist in the tolerance and outcome of trauma, but also exist in vascular reactivity. Proctor and Newcomer (26) found that the 7-week-old rats had the higher vascular reactivity than other ages of rats, as the increase of age, the vascular reactivity was gradually decreased. Our studies also found that female rats in reproductive age had higher vascular reactivity and better tolerance to traumatic shock than male rats in the same age period or female rats under and over the reproductive age. The same result was also observed in healthy and trauma patients (27). Further studies (27) showed that exogenous supplementation of estrogen (17-βestradiol) played the protective effects in vascular reactivity in normal and traumatic shock rats at reproductive age (8–24 weeks) but not in older rats (1–1.5 y). Estrogen and its receptor (GPR 30)-mediated activation of Rho kinase and PKC may lead to the protective effects on vascular reactivity. These findings are of importance for the individual treatment to estrogen-induced gender-/age-related diseases.

Changes of vascular reactivity after endotoxic shock and burn shock

Studies showed that vascular reactivity after endotoxic shock also appears biphasic change and vasculature difference as compared with hemorrhagic shock (28,29)(28,29). As compared with hemorrhagic shock, endotoxic shock-induced vascular hyporeactivity appeared late but more serious (30,31)(30,31). Chen et al. found that vascular reactivity was increased within 1 h after endotoxic shock, whereas after 2 h after endotoxic shock, the vascular reactivity was rapidly and seriously decreased. The vascular reactivity had only 20% of normal level at 4 h after endotoxic shock (32). Same results were also observed in the study of Li et al. (33). The study of Chen et al. (32) also found that there was vasculature difference in vascular reactivity after endotoxic shock. They found that in the early endotoxic shock, the increase of vascular reactivity in superior mesenteric artery was not obviously, whereas in celiac artery and renal artery was obviously, in the late endotoxic shock, the vascular reactivity in superior mesenteric artery decreased most (reduced by 34.8%), next for renal artery (33.7%) and celiac artery (16.7%). As for the vasodilation to Ach, superior mesenteric artery showed significant hypo-reactivity whereas celiac artery showed hyper-reactivity and renal artery had no obvious change. These results may be correlated with the blood redistribution in various vasculatures after shock, but its underlying mechanisms are not clear. Some studies showed that in the late stage of endotoxic shock, the vascular endothelial cells are seriously destroyed and appear dysfunction (34). Whether endothelial cell dysfunction influences the vascular reactivity to Ach in different vasculatures needs further investigation.

As for gender- and age differences in vascular reactivity after endotoxic shock, research showed that males and aged individuals are proved to be risk for the development of sepsis and multiple organ failure after severe trauma (35,36)(35,36). Bone (37) reported males with sepsis had more morbidity and mortality as compared with females. Schroder et al. (38) found that women had a significantly higher survival rate (74%) as compared with men (31%) following the onset of sepsis, which are consistent with the results in hemorrhagic shock.

As for burn shock, most studies were focused on the change in vascular permeability (39–41)(39–41)(39–41), only few studies on vascular reactivity. Zhao et al. (42) observed the changes of mean artery pressure after burn injury and they found that the mean artery pressure was gradually decreased at 6 and 12 h after burn injury. They did not show the changes of vascular reactivity in more detail. Garcia and Horton (43) examined the effect of burn injury on coronary vascular reactivity in rabbit models. They found that the coronary perfusion pressure and coronary vascular resistance were progressively decreased during the early post-burn period but reversed to the normal value by 24 h after burn. Available data cannot clearly show the change patterns of vascular reactivity after burn injury. Therefore, continuous investigations on vascular reactivity after burn shock are needed. Nevertheless, we speculated that the change of vascular reactivity after burn shock might be similar to that in endotoxic shock because severe burn injury may induce more incidences of sepsis and septic shock in the late stage of burn shock. However, this speculation needs further investigation.


The present available documents showed there are three mechanisms responsible for the occurrence of vascular hypo-reactivity after shock: receptor desensitization mechanism; membrane hyper-polarization mechanism; and calcium desensitization mechanism.

Receptor desensitization mechanism

Most investigations on receptor desensitization mechanism of vascular hyporeactivity are mainly concentrated in endotoxic shock, few studies are in hemorrhagic shock. It has been reported that the adrenergic receptors (ARs) are desensitized following shock (44). Following shock, high concentration of catecholamine stimulation could cause receptors desensitization. In addition, shock-induced ischemia and hypoxia, the release of cytokines as well as endogenous opioid peptide (EOP) may also inhibit the functions of adrenergic receptors and result in the receptor desensitization. Receptor desensitization includes receptor amount down-regulation, receptor affinity drop, and receptor uncoupling (44).

Down-regulation of receptor amount

Down-regulation of the receptor number is one of the important mechanisms for receptor desensitization. Sandrini et al. (45) conducted an investigation on the changes of ARs in brain, heart, and spleen in rats after hypovolemic shock and found that there were no obvious changes in Bmax and Kd of α1-, α2-, and β-ARs, but the amount of α-, β-ARs in heart, and α2-ARs in spleen were significantly reduced. Tait and Onuma et al. (46,47)(46,47) also found the β-ARs were down-regulated in liver and heart in traumatic-hemorrhagic shock rats.

Down-regulation of the receptor number includes two steps. The first step is the decrease of receptor number on the cell membrane surface, but the receptor's total quantity in each cell has not changed. The second step is the decrease in receptor's total quantity, which means the real down-regulation of receptors. In the early stage of shock, receptor desensitization may mainly attribute to the decrease of receptor amount on the cell membrane surface and this is possibly correlated to the internalization of surface receptors, which had been confirmed by Maisel et al. (48). The real down-regulation of receptors is related to the degradation of internalized receptors and the decrease of receptor expression, which appears at 3–5 h even 1–2 d after the first step (Figs. 3, 4)

Fig. 3
Fig. 3:
Timing events for receptor desensitization mechanism.AC, adenylyl cyclase; AR, adrenergic receptor; GDP, guanosine diphosphate; GTP, guanosine triphosphate; P, phosphorus.
Fig. 4
Fig. 4:
Signal transduction for receptor desensitization mechanism.The signal transductions for receptor desensitization include three pathways. One is the internalization of surface receptors, the second pathway is receptor transcription regulation through JAK2-STAT3 and NF-kB-related pathways. Both of these two pathways might down-regulate the receptor amount. The third pathway is receptor uncoupling and receptor affinity regulation through G-proteins. AC, adenylyl cyclase; AR, adrenergic receptor; EOP, endogenous opioid peptide; GPCR, G protein coupled receptor; JAK2, Janus activating kinase 2; STAT3, signal transducer and activator of transcription 3.

Lots of factors including high concentration of catecholamine and cytokines during shock may down-regulate the adrenergic receptors. High concentration of catecholamine can result in the internalization of adrenergic receptor (44). Cytokines such as TNF-a and IL-1β may down-regulate the amount of adrenergic receptors via inhibition of the transcription of the adrenergic receptor. For example, Liang et al. (20) found that in vitro incubation with IL-1β (12.5–50 ng/mL) could significantly decrease the vascular reactivity of superior mesenteric artery to phenylephrine and down-regulate the mRNA expression of α1-adrenergic receptors (α1-AR). AG490 (10 μmol/L), an inhibitor of Janus kinase 2 (JAK2), partly reversed IL-1β-induced down-regulation of α1-AR mRNA and suppressed the DNA binding ability of signal transducer and activator of transcription 3 (STAT3). These results indicate that IL-1β down-regulates the expression of α1-AR mainly through activating JAK2-STAT3 pathway (33).

Receptor affinity drop and receptor uncoupling

Drop in receptor affinity may be another important mechanism for AR desensitization and it often happens before the decrease of receptor number on the cell membrane surface. Previous studies showed that the receptor affinity of β-AR was generally declined, but the affinity of α-AR remained constant during endotoxic and hemorrhagic shock (49,50)(49,50). Drop in receptor affinity may also lead to receptor uncoupling and thereby decrease the binding ability of AR to agonists and the activity of adenylyl cyclase (AC). Therefore, the coupling obstacles between AR and AC may be the most important factor for receptor desensitization. Except for resulting in the internalization of AR, high concentration of catecholamine, EOP, and cytokines can also cause the drop of AR affinity following shock. Romano et al. (51) investigated the characteristics of the reaction between β-AR and AC under agonists in endotoxic shock rats and the results indicated that agonist-induced receptor desensitization was mainly correlated with the phosphorylation of AR in the early stage of shock. Besides, Shepherd et al. (49) investigated the influence of lethal-dose endotoxin to adrenergic response in rat heart and found that the reduction of adrenergic response was closely related to the inhibition of AC activity. These findings suggest that the inhibition of AC activity may be the key point to affect the coupling between AR and AC in the early-stage shock (Figs. 3 and 4Figs. 3 and 4). The mechanism for the down-regulation of AC activity may be correlated with G proteins. For example, EOP and TNF-α inhibit AR affinity mainly through inhibition of Gs protein and lead to the decrease of the activity of adenylyl cyclase (AC) (52,53)(52,53). However, the precise mechanisms that these factors regulate the interaction of AR, G protein, and AC are not clear and need further investigation.

Membrane hyperpolarization mechanism

Studies showed after hemorrhagic and burn shock, vascular smooth muscle cell (VSMC) would occur the membrane hyperpolarization. Membrane hyperpolarization is another crucial mechanism to vascular hyporeactivity after shock. Membrane hyperpolarization mechanism of vascular hyporeactivity mainly involves two kinds of potassium channels—ATP-dependent K+ channel (KATP) and large conductance Ca2+-activated K+(BKCa) channel (Fig. 5).

Fig. 5
Fig. 5:
Signal transduction for membrane hyperpolarization mechanism.The membrane hyperpolarization of vascular smooth cell after shock is mainly involved in two channels: KATP channel and BKCa channel. The membrane hyperpolarization of vascular smooth cell may inhibit the open of VOC, and via which results in the decrease of intracellular [Ca2+] and vascular hyporeactivity. KATP channel, ATP-dependent K+ channel; BKCa channel, large conductance Ca+-activated K+ channel; CO, carbon oxide; EOP, endogenous opioid peptide; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; VOC, voltage-dependent calcium channel;.

ATP-dependent K+ (KATP) channel

In physiological conditions, cytoplasm ATPs are in mMol magnitude, which is enough to completely close the KATP channels on cell membrane (54). While in some pathophysiological conditions such as shock, the disorders of the cell oxidative metabolism or the huge reduction of ATP would cause the open of KATP channels on cell membrane (55,56)(55,56). The over-open of KATP channels in VSMC would result in the membrane hyperpolarization of VSMC. This event would inhibit the potential dependent calcium channel and decrease the Ca2+ inflow, and finally result in the vascular hyporeactivity. The inducing factors that cause the opening of KATP channels include acidosis, nitric oxide (NO), and so on.


Intracellular acidosis induced by hypoxia markedly reduces the inhibitory effect of ATP on KATP channels in excised patches from VSMCs. The research of Liu et al. (57) showed that, in the absence of ATP, a decrease of intracellular pH (pHi) significantly reduced the conductance of single channel. The open time and time constant of the channel were slightly increased. While in the presence of ATP, a decrease of pHi significantly increased the conductance of single channel and the open probability of channel. So the results suggest that intracellular acidosis activates KATP channels in the presence of ATP, which may be one of the mechanisms for acidosis decreasing vascular reactivity. However, with the treatment of NaHCO3, there was no significant difference in pHi, and the vascular reactivity was only partly recovered (58), which suggests that intracellular acidosis is not the only inducing factor to vascular hyporeactivity after shock.

Nitric oxide (NO)

NO has the strong activity to dilate the vascular vessels. In physiological conditions, the endothelial NO synthase (eNOS) in vascular endothelial cell (VEC) may catalyze the continuous synthesis of NO, which makes great contribution to normal blood pressure and blood flow regulation. In the early stage of hemorrhagic shock, NO is slightly increased, which makes the vascular reactivity a little bit increase. In the late stage of hemorrhagic shock, NO is significantly increased and large amount of OONO is generated with superoxide anion, which induces the VSMCs membrane hyperpolarization, resulting in vascular hyporeactivity though over-opening the KATP channels (59).

Large conductance Ca2+-activated K+ (BKCa) channel

Although KATP channel makes a great contribution on VSMC membrane hyperpolarization and vascular hypo-reactivity following shock, its distribution is only one channel per 10 μm2 on membranes. However, the large conductance Ca+-activated K+ (BKCa) channel, which can be activated by voltage and intracellular Ca+, not only broadly distributes on VSMCs (one to four channels per μm2) but also plays an important role in the regulation of vascular reactivity (60). The BKCa channel consists of α-subunit and accessory β-subunit, which coinfluence the characteristics of its physiology and pathophysiology (61). Nelson et al. (60) reported that Ca2+ sparks are the physiological activators of BKCa channels. A single Ca2+ spark may cause the open of its surrounding and K+ outflow, which forms spontaneous transient outward current (STOC) (60). This process may induce membrane hyperpolarization. In turn, over-opened BKCa channels decrease the external calcium influx and finally make the VSMCs in the state of hyporeactivity. As the same as the KATP channel, many factors such as nitric oxide (NO) and endogenous opioid peptide (EOP) can regulate the opening of the Bkca channel.

Nitric oxide and endothelin (ET)

Studies showed that NO regulates the opening of BKca channel following hemorrhagic shock mainly through the tyrosine phosphorylation of BKCa α subunit. Zhou et al. found that this tyrosine phosphorylation of BKCa α subunit is further regulated by protein tyrosine kinase (PTK) and/or protein tyrosine phosphatase (PTP) (13,62,63)(13,62,63)(13,62,63). Besides, Wu et al. (64) reported that after the treatment with Dehydrosoyasaponin (DHS, a BKCa β subunit probe), the open probability of BKCa channel did not change, whereas the excitatory effect of sodium nitroprusside (SNP) on the BKCa channel was reduced. This suggests that SNP regulates BKCa channel mainly through β subunit of BKCa channel, but the precise mechanisms need further investigation. In addition, although endothelin (ET) is a peptide with vasoconstrictor properties, research showed that long-time ET stimulation could also induce vascular hyporeactivity through cAMP-PKA pathway and BKCa channel activation (63).

Carbon monoxide (CO)

The study of Wu et al. (64) showed that CO is able to increase the open probability of BKCa channel and its current amplitude. In rat tail VSMCs, the record of patch clamp showed that CO may increase the calcium sensitivity of BKCa channel. Since β subunit of BKCa is correlated with calcium sensitivity, CO may directly activate BKCa channel in VSMCs without the help of secondary messengers such as cGMP or cAMP. In HEK 293 cells incubated with cSlo-α (a clone that encodes BKCa channel), the CO donor –DMDC (1 μM) could activate cSlo-α subunit current, which suggests that CO may act on the α subunit of BKCa channel. In addition, there were some evidences proving that CO may also act on other regulating factors such as heme. Heme can inhibit BKCa in physiological concentration. Xi et al. (65) found that CO can combine with heme, and thus relieve the inhibitory effect of heme on BKCa. These findings suggest that the mechanism that CO activates BKCa includes two ways: one is direct effect on BKCa channel, another is via inhibiting the effect of heme.

Endogenous opioid peptide (EOP)

It was reported that the concentration of endogenous opioid peptides is increased in trauma-induced hemorrhagic shock. Opioid receptors play an important role in the pathogenesis of shock (66,67)(66,67). Previous studies showed that naloxone (10 μM), a nonselective opioid receptor antagonist, significantly down-regulates the activity of BKCa by reducing its open probability and open frequency. Naltrindole (δ-opioid receptor antangonist) and nor-binaltorphimine (κ-opioid receptor antagonist) have the similar effects to naloxone, whereas no significant effect was found on the activity of channels afterr β-funaltrexamine (μ-opioid receptor) treatment. These results suggested that δ- and κ-opioid receptors, but not μ-receptors, participate in the regulation of BKCa channel after hemorrhagic shock (62).

Calcium desensitization mechanism

An interesting phenomenon should be concerned is that restoration of adrenergic receptor, K+ and Ca2+ channels’ functions cannot return the vascular reactivity to normal level, which suggests that there are other ways to regulate the vascular reactivity following shock. The key event of receptor desensitization and membrane hyperpolarization mechanism responsible for vascular hyporeactivity is the decrease of intracellular [Ca2+]. While at late stage of shock or in severe shock, the intracellular calcium in VSMCs is over loaded, but the vascular hyporeactivity still exists (5). This phenomenon indicates that there exists calcium desensitization in VSMC after shock and calcium desensitization plays a critical role in vascular hypo-reactivity (68). Further studies found that Rho kinase pathway and PKC pathway are the two main pathways in the regulation of vascular reactivity and calcium sensibility following shock. Studies on the calcium desensitization mechanism of vascular hyporeactivity are mainly concentrated in hemorrhagic shock (Fig. 6).

Fig. 6
Fig. 6:
Signal transductions for calcium desensitization mechanism.RhoA regulates vascular reactivity mainly through activation of Rho kinase and inhibition of Rac1, whereas Rac1 regulates vascular reactivity mainly through inhibition of RhoA and activation of PAK. Rho kinase may be through three pathways to exert effect: directly activate MLC20, inhibit MLCP, and via CPI-17. ZIPK and ILK are the important downstream molecules of PKC. ZIPK may directly bind with CPI-17. ERK and p38MAPK play effect mainly through ILK and ZIPK or CPI-17. A1AR and A3AR may enhance the activity of PKCε and RhoA, whereas A2aAR and A2bAR may inhibit the activity of RhoA and PKCε. AR, adenosine receptor; CPI-17, protein kinase C-dependent phosphatase inhibitor of 17 kDa; ERK, extracellular signal-regulated kinase; ILK, integrin linked kinase; MAPK, mitogen-activated protein kinase; MLC20, 20-kDa myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PAK, P21-activated kinase; PKC, protein kinase C; Rac, Ras-related C3 botulinum toxin substrate; RhoA, Ras homolog gene family member A; ZIPK, zipper-interacting protein kinase.

Impact of Rho kinase pathway on calcium sensitivity

Rho kinase, a Ser/Thr protein kinase, is identified as a GTP-Rho binding protein. A number of previous studies showed that Rho kinase participates in the regulation of many biological cellular functions, such as proliferation, differentiation and migration of tumor cells, the migration and invasion of trophoblast cells, etc. (69). Li and Schmitz et al. reported that Rho kinase played an important role in the regulation of vascular reactivity and calcium desensitization following hemorrhagic shock (4,69)(4,69).

The calcium sensitivity regulation of VSMC depends on the phosphorylation and dephosphorylation of myosin light chain (MLC), which is respectively regulated by myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) (70,71)(70,71). Studies showed that there are three ways for Rho kinase to regulate the calcium sensitivity of VSMC (Fig. 6). First, Rho kinase phosphorylate MLC20 directly. But, the extent of Rho kinase to phosphorylate MLC20 is far less than MLCK does. The strength of Rho kinase phosphorylating MLC20 is about one third of MLCK (72). So this way is not the main way that Rho kinase regulates calcium sensitivity after hemorrhagic shock. Second, the main way of Rho kinase regulating calcium sensitivity is that Rho kinase phosphorylates myosin-binding subunits (MBS) of MLCP at Thr2695, Thr2850, and Ser2854, and via which inhibits the activity of MLCP and increases the phosphorylation level of MLC20(73). Third, Rho kinase can also activate CPI-17 via phosphorylation of the Thr238 site of CPI-17. The activated CPI-17 enhances the phosphorylation of MLC20 through inhibiting the MLCP.

Impact of PKC pathway on calcium sensibility

Protein kinase C (PKC)

A Ser/Thr protein kinase plays a critical role in cell adaptability to extracellular environment. PKC is also involved in varieties of physiologic functions including cell proliferation, differentiation and migration, cytoskeletal structure, and apoptosis (74,75)(74,75). PKC is a big family consisting of at least 12 isoforms, and the main isoforms distributed in the vascular system are PKC α, ε, δ, and ξ. Basic research showed that the various isoforms of PKC, especially α and ε isoforms, may be activated through subcellular redistribution and transfer from cytoplasm to membrane, and then trigger a series of cascade reactions that ultimately interacts with the contractile myofilaments and leads to VSMC contraction (76).

Many studies showed that PKC participated in the regulation of vascular reactivity and calcium sensitivity following shock. Our previous study found that PKC agonist, phorbol-12-myristate-13-acetate (PMA), could improve and stabilize the hemodynamic parameters and play beneficial effect for hemorrhagic shock in rats through improving the vascular reactivity and calcium sensitivity (8,19)(8,19). There are several mechanisms that PKC regulates the vascular reactivity and calcium sensitivity (76–78)(76–78)(76–78). First, the study of Woodsome et al. (76) showed that PKC may phosphorylate CPI-17, and then inhibits the MLCP activity, via which increases the MLC20 phosphorylation and calcium sensitivity of VSMC. Second, our recent studies showed that the inhibitory effect of PKC on MLCP is not only related to CPI-17 but also related to zipper-interacting protein kinase (ZIPK) (78) and integrin-linked kinase (ILK) (77,78)(77,78). Our results showed that ZIPK and ILK may be the direct downstream molecules of PKC α and ε, in which CPI-17 may play an indirect modulating role on MLCP. Our very recent study found that Rho kinase is the downstream molecule of ILK and ZIPK, and the upstream molecule of CPI-17 (Fig. 6) (27).

Impact of MAPK in calcium sensibility

Mitogen-activated protein kinases (MAPKs) belong to a family of serine/threonine protein kinases, which include extracellular-signal regulated kinase (ERK), jun NH2 -terminal kinase (JNK), and p38 MAPK in mammals. It was reported that they mediated the fundamental biological process to external signals, such as cytokines and inflammatory mediators (5).

Previous studies showed that MAPK had a critical role in regulating cell differentiation, proliferation, and cell death (79,80)(79,80). Recent study of Yang et al. (5) focused on the potential role of MAPK in the regulation of vascular reactivity after hemorrhagic shock and interestingly found that the changes in ERK and p38MAPK activity were positively correlated with the biphasic change of vascular reactivity after hemorrhagic shock (4). In SMAs, ERK and p38MAPK activity was significantly increased at early shock (0.5 h) and decreased at late shock (2 h), ERK and p38MAPK inhibitors could decrease the vascular reactivity following shock. This finding suggests that MAPK pathway participates in the regulation of vascular reactivity and calcium sensitivity following shock.

Impact of adenosine and its receptor in calcium sensibility

Adenosine is one of the most important endogenous modulators released excessively after severe trauma and ischemia or hypoxia in tissue. It has been demonstrated that adenosine mainly produces the marked effect through adenosine receptor in VSMC. There are four types of adenosine receptor (AR) reported in VSMCs, including A1AR, A2aAR, A2bAR, and A3AR. Adenosines that combine with specific AR may cause vasoconstriction (A1AR) or vasodilatation (A2aAR, A2bAR). The study of Srinivas et al. (81) reported that exogenous adenosine may reduce the phosphorylation of MLC in bovine cornea epithelial cells. However, the report of Lai et al. (82) demonstrated that exogenous adenosine may induce MLC phosphorylation on VSMCs and increase its calcium sensitivity. The results suggest that adenosine is closely correlated with vascular reactivity and calcium sensitivity.

Huang et al. (73) demonstrated that A1AR agonist (N6-cyclopentyladenosine, CPA, 10−5 mol/L) can induce renal artery constriction, which can be antagonized by Rho kinase inhibitor (Y-27632). This indicates that Rho kinase is correlated with A1AR in the regulation of vascular tone. The study of Tawfik et al. (83) showed that PKC inhibitor U-73122 could abolish the vasoconstriction induced by A1AR and A1AR agonist may enhance the activity of PKCε. This indicates that A1AR regulating vascular calcium sensitivity is also related to PKC pathway.

However, A2aAR and A2bAR can activate adenylate cyclase that causes the increase in cAMP concentration and PKA activation. The activated PKA may inhibit the activity of Rho kinase. This will induce MLC dephosphorylation and vascular smooth muscle dilation. Besides, the study of Gardner et al. showed that A2aAR may down-regulate the activity of PKC and A2aAR agonist CGS21680 may inactivate PKCε (84).

The study of Zhou and Abbracchio et al. found that A3AR is also involved in the modulation of vasoreactivity following shock and this regulation is closely related to Rho kinase pathway (85,86)(85,86). Furthermore, Zhao et al. reported that the A3AR agonist IB-MECA could up-regulate PKCδ activity and A3AR antagonist MRS-1191 could counteract this function (72), which suggests that A3AR regulating vascular reactivity and calcium sensitivity is related to PKCδ pathway.


Based on the various vascular hypo-reactivity theories and its inducing factors, the therapeutic approaches may occur through blocking the related pathways (Table 1).

Table 1
Table 1:
Abbreviations of related signals and mediators and the role

Based on receptor desensitization

Glucocorticoid (GC) may promote the catecholamine biosynthesis and potentiate the vasoconstriction effect of vasopressin (AVP), Angiotensin II, and endothelin (ET) by increasing the sensitivity of their receptors (87–89)(87–89)(87–89). Besides, cortisol has significant inhibitory effect on proinflammatory mediators, such as TNF-α and IL-1β, which are confirmed to be correlated with receptor desensitization (90). A recent study showed that dexamethasone may rapidly reverse LPS-induced hyporeactivity of VSMC to NE and this effect of dexamethasone is related to increasing the phosphrylation of MLC20 via increasing activity of the RhoA-Rho kinase pathways. This finding demonstrated that glucocorticoid increasing the vascular reactivity is not only related to increasing the sensitivity of related receptors, but also related to increasing the calcium sensitivity of VSMC (91).

Laciolle et al. (92) also designed a randomized animal study recently and tested the hemodynamics in vivo and vascular reactivity in vitro after administration of fludrocortisone and hydrocortisone in normal and endotoxemic rats. The results also verified the effect of hydrocortisone but not fludrocortisone on improving catecholamine response (88).

There still remains controversy about the application of small doses of GC in patients with trauma or shock. The Surviving Sepsis Campaign Guidelines (2012) (93) suggest do not use intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. In case this is not achievable, intravenous hydrocortisone alone is recommended at a dose of 200 mg per day. Besides, the guidelines also suggest do not use the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone. In treated patients, taper hydrocortisone when vasopressors are no longer required and do not administer corticosteroids for the treatment of sepsis in the absence of shock (93).

Based on membrane hyperpolarization

Glybenclamide is a kind of KATP channel antagonist. Zhao et al. (94) found that the vascular reactivity was significantly increased after use of glybenclamide combined with NaHCO3 in hemorrhagic rats. The blood pressures, arteriolar blood flow, as well as the 24-h survival rate were also markedly increased in shock rats after treatment, which indicates that glybenclamide combined with NaHCO3 is an effective regimen in the treatment of severe hemorrhagic shock.

Studies showed NO generated OONO with superoxide anion can induce the membrane hyperpolarization of VSMC though activation of KATP channels (59). Yang et al. found that superoxide anion scavenger Tiron may block this effect of OONO in hemorrhagic shock rats, inhibit the membrane hyperpolarization of VSMC, and improve shock-induced vascular hyporeactivity (95).

As a hotspot in recent years, mitochondrial function has important value in the genesis of many diseases, such as cardiovascular diseases, Alzheimer disease, Parkinson disease, and so on. Mitochondrial dysfunction also takes part in the occurrence of vascular hyporeactivity after shock. Polydatin is a kind of mitochondrial protector and the study of Zhao et al. showed that Polydatin can protect vascular smooth muscle mitochondria and restore vascular reactivity in hemorrhagic shock rats (96). Our recent study found that cyclosporine A (CsA), an inhibitor of mitochondrial permeability transition pore, improved the vascular reactivity of traumatic hemorrhagic shock rats (97).

Based on RhoA-Rho kinase pathway

In view of recent “calcium desensitization mechanism of vascular hyporeactivity,” Rho kinase and PKC pathway are two important potential targets to the treatment of hemorrhagic shock and endotoxic shock. Studies showed arginine vasopressin (AVP) and its analog terlipressin (TP) have important role in vasodilatory shock animal and patients (98). Some previous reports showed that the anti-shock effect of AVP was mainly related to its V1a receptor activation and then the increase in intracellular Ca2+(99–103)(99–103)(99–103)(99–103)(99–103). Our recent study found that AVP (0.03 U/kg/h) and TP (2.6 μg/kg/h) significantly improved the decreased vascular reactivity in hemorrhagic shock and endotoxic shock rats and rabbits, This effect of AVP and TP is closely related to activation of Rho A-Rho kinase pathway (29,104,105)(29,104,105)(29,104,105).

Further studies showed that ischemic preconditioning may activate Rho A-Rho kinase pathway and improve the vascular reactivity in hemorrhagic shock rats (106). Hu et al. (107) observed the effects of ischemic preconditioning on vascular reactivity after hemorrhagic shock in rats and found that 5% hemorrhage for 30 min before hemorrhagic shock may prevent the decrease in vascular reactivity and calcium sensitivity after hemorrhage. The study showed that hemorrhagic shock may attenuate Rho-kinase activity, whereas ischemic preconditioning may reverse this process.

Based on PKC pathway

Phorbol-12-myristate-13-acetate (PMA), a non-specific PKC isoform agonist, was found to have good protective effect on shock. Fang et al. observed the beneficial effect of PMA in hemorrhagic shock rats. They found 1 μg/kg PMA could significantly enhance the vascular reactivity and calcium sensitivity of hemorrhagic shock rats and improve the hemodynamic indexes as well as hepatorenal function (19). Although PMA is not used in clinic now, these findings provide a rational ground to develop this kind of drug or search for other approaches to induce or activate PKC to play protective effect on shock in clinic.

Pinacidil, an adenosine triphosphate-sensitive potassium channel (KATP) opener, is a common agent to be used to induce preconditioning protection against ischemia insult (107–110)(107–110)(107–110)(107–110). Xu et al. (111) used 25 μg/kg of pinacidil administered 30 min before hemorrhagic shock to mimic ischemic preconditioning in rats and they found that pinacidil pretreatment could activate PKC α and ε and improve the vascular reactivity and calcium sensitivity in hemorrhagic shock rats. This finding suggests that pretreatment with pinacidil can improve the vascular reactivity and calcium sensitivity after hemorrhagic shock, the mechanism is closely related to the activation of PKC α and ε.


Vascular hypo-reactivity often happens after severe trauma, shock, and their associated complications such as systemic inflammatory response syndrome (SIRS) and multiple organ dysfunctions (MODS). Many inducing factors have been proposed to be involved in the development of vascular hypo-reactivity. Present data show there are three mechanisms responsible for vascular hyporeactivity after shock including receptor desensitization mechanism; membrane hyperpolarization mechanism and calcium desensitization mechanism and some pertinent treatment measures have been introduced based on these mechanisms. However, there are still some issues that need further investigation such as the more detailed mechanisms and target-directed treatment approaches.


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PKC; Rac; Rho kinase; shock; therapy; vascular hyporeactivity; vascular reactivity

© 2015 by the Shock Society