Reactivity Of Superior Mesenteric Artery Research Articles

Kang Le Xin Reduces Blood Pressure Through Inducing Endothelial-Dependent Vasodilation by Activating the AMPK-eNOS Pathway

Hypertension is a major risk factor for stroke and cardiovascular events in clinic, which is accompanied by the abnormality of vascular tone and endothelial dysfunction of small artery. Here we report that Kang Le Xin (KLX), a novel anthraquinones compound, could reduce blood pressure and the underlying mechanisms involves that KLX induces endothelium-dependent vasodilation. KLX significantly decreases the arterial blood pressure of spontaneous hypertensive rats (SHR), decreases the contractile reactivity of superior mesenteric artery to phenylephrine and increases the vasodilatory reactivity of superior mesenteric artery to carbachol in a dose-dependent manner. Besides, KLX reduces vascular tension of endothelium-intact mesenteric artery pre-constricted with phenylephrine in a dose-dependent manner, while this effect is inhibited by depriving vascular endothelium or pretreating vascular rings with L-NAME (endothelial nitric oxide synthase inhibitor) or compound C (AMP-activated protein kinase inhibitor). Moreover, KLX increases nitric oxide (NO) generation, endothelial nitric oxide synthase (eNOS), AKT and AMP-activated protein kinase (AMPK) phosphorylation in cultured human umbilical vein endothelial cells (HUVECs), while these effects are inhibited by pretreating cells with compound C. In conclusion, KLX is a new compound with the pharmacological action of reducing arterial blood pressure. The underlying mechanism involves KLX induces endothelium-dependent vasodilation through activating AMPK-AKT-eNOS signaling pathway.

ERK and miRNA-1 target Cx43 expression and phosphorylation to modulate the vascular protective effect of angiotensin II

Aims and methodsWe previously reported that angiotensin II (AngII) restores the vascular reactivity diminished by hemorrhagic shock. In this study, we investigated whether the beneficial effects of AngII are related to regulation of gap junctions (GJs) and connexin43 (Cx43), and the implication of MAPK signaling and microRNA (miR-1) in this process. Key findingsOur results show that after hemorrhagic shock or hypoxia, the blockade of GJs or knockdown of Cx43 inhibits the AngII-induced increase in vascular reactivity of superior mesenteric arteries and the contractile response of vascular smooth muscle cells (VSMCs). AngII treatment increases Cx43 expression and phosphorylation at Ser262, and restores gap-junctional communication (GJIC) between VSMCs after hypoxia. The AngII-induced up-regulation of Cx43 expression and phosphorylation is blocked in cells transduced with ERK-siRNA, but is not blocked in cells transduced with p38-siRNA. miR-1 levels are elevated after hypoxia; AngII treatment reverses the up-regulation of miR-1, while ERK-siRNA abolishes that effect of AngII. In hypoxic cells, transfection of a miR-1 mimic into VSMCs decreases Cx43 expression and VSMC reactivity, whereas a miR-1 inhibitor increases both. Also in hypoxic cells, miR-1 eliminates the restoration effects of AngII on Cx43 expression and VSMC reactivity. SignificanceAngII provides protection of vascular function through the restoration of the expression and phosphorylation of Cx43 and its mediated GJIC in VSMCs. It is ERK that mediates the AngII-induced phosphorylation of Cx43 at Ser262. Additionally, miR-1 is involved in this process, and AngII may exert its protective effect partially by inhibiting miR-1 elevation via ERK signaling.

Organ-specific changes in vascular reactivity and roles of inducible nitric oxide synthase and endothelin-1 in a rabbit endotoxic shock model.

Hemorrhagic shock-induced changes in vascular reactivity appear organ-specific. In the present study, we examined the hypothesis that vascular reactivity induced by septic shock similarly displays organ-specific differences and is regulated by inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1). Endotoxic shock was induced in rabbits by administration of lipopolysaccharide (LPS) (1 mg/kg), and organ specificity of vascular reactivity of superior mesenteric artery (SMA), celiac artery (CA), and left renal artery (LRA) as well as the potential involvement of iNOS and ET-1 examined. Vascular reactivity of SMA, CA, and LRA was increased at the early stages and decreased at the late stages after LPS administration. Superior mesenteric artery showed the greatest decrease in vascular reactivity in response to norepinephrine (NE) (34.9%) and acetylcholine (Ach; 32.3%), followed by LRA (NE, 33.7%; Ach, 30.5%) and CA (NE, 16.2%), whereas the relaxation reactivity of CA in response to Ach was increased to 159%. The mRNA and protein levels of iNOS and ET-1 in SMA, CA, and LRA were not affected at the early stages of endotoxic shock after LPS administration but significantly increased at the late stages. Expression levels were higher in SMA than CA and LRA and negatively correlated with the decrease in vascular reactivity. The iNOS and ET-1 inhibitors, aminoguanidine (20 mg/kg) and PD-142893 (0.02 mg/kg), respectively, induced significant improvements in vascular reactivity and organ perfusion and stabilized the hemodynamic parameters in rabbits subjected to endotoxic shock. Changes in vascular reactivity during endotoxic shock are organ-specific. Differential expression patterns of iNOS and ET-1 in different blood vessels contribute to the organ specificity of vascular reactivity. Therapeutic study, level II.

Inhibition of complement C3 might rescue vascular hyporeactivity in a conscious hemorrhagic shock rat model

BackgroundVascular hyporeactivity in severe hemorrhagic shock could induce refractory hypotension and is an important cause of death. The global acute inflammatory response induced in shock triggers the over-expression of reactive oxygen species, NO, ET1 and TNF-α, which play essential roles in the pathology of vascular hyporeactivity. This leads to a hypothesis that inhibition of the complement system, the mediator of the inflammatory cascade, might be a promising therapeutic exploration for vascular hyporeactivity. MethodsWe use cobra venom factor (CVF) and the soluble form of CR1 (sCR1) which deplete or inhibit complement C3 respectively to examine its role in vascular hyporeactivity in a conscious hemorrhagic shock rat model. ResultsWe first confirmed the over-activation of C3 during shock and the down-regulation effects of CVF and sCR1 on C3. Then, both CVF and sCR1 could significantly mitigate the over-expression of serum NO, ET-1, TNF-α and reactive oxygen species. Finally, the vascular reactivity of superior mesenteric arteries (SMA) was examined in vitro, which confirmed the massive reduction of vascular reactivity in shock, which was significantly rescued by both CVF and sCR1. ConclusionsInhibition of C3 might improve the reactivity of SMA to norepinephrine during hemorrhagic shock possibly through the downregulation of NO, ET1, TNF-α and reactive oxygen radicals.

Beneficial effect of cyclosporine A on traumatic hemorrhagic shock

BackgroundVascular hyporeactivity plays an important role in severe trauma and shock. We investigated the beneficial effect of cyclosporine A (CsA) on traumatic shock and its relationship to vascular reactivity improvement and mitochondrial permeability transition pore (MPTP). Materials and methodsSodium pentobarbital-anesthetized rats were used to induce traumatic hemorrhagic shock by left femur fracture and hemorrhage, the beneficial effects of CsA (1, 5, and 10 mg/kg, intravenously) on animal survival, cardiovascular function, tissue blood perfusion, and mitochondrial function of vital organs were observed. In addition, hypoxia-treated vascular smooth muscle cells from normal rats were used to investigate the relationship of this beneficial effect of CsA to Rho-associated serine/threonine kinase (ROCK) and protein kinase C. ResultsCsA prolonged the survival time and increased the 24-h survival rate of traumatic hemorrhagic shock (31%, 56%, and 56% in 1, 5, and 10 mg/kg CsA group versus 25% in lactated Ringer solution group). Five milligrams per kilogram of CsA had the best effect, which stabilized and improved the hemodynamics, increased the tissue blood flow, and improved the liver and kidney function including its mitochondrial function in shock rats. CsA had no significant influences on the production of inflammatory mediators and cardiac output after traumatic hemorrhagic shock. Further results indicated that CsA significantly improved the vascular constriction and dilation reactivity of superior mesenteric artery to norepinephrine and acetylcholine, which was antagonized by ROCK inhibitor, Y27632, but not by protein kinase C inhibitor, staurosporine. Further studies showed that CsA restored hypoxia-induced decrease of ROCK activity and inhibited the opening of MPTP in hypoxia-treated vascular smooth muscle cells. ConclusionsCsA is beneficial for the treatment of traumatic hemorrhagic shock. The mechanism is mainly through improving the vascular reactivity, stabilizing the hemodynamics, and increasing tissue perfusion. This beneficial effect of CsA is related to the inhibitory effect of CsA on MPTP opening. ROCK is an important regulator molecule in this process.

Interleukin 1β attenuates vascular α1 adrenergic receptors expression following lipopolysaccharide-induced endotoxemia in rabbits

Studies have shown that interleukin 1β (IL-1β) participates in the down-regulation of vascular reactivity via both nitric oxide-dependent and nitric oxide-independent mechanisms during shock. However, the precise mechanisms of nitric oxide-independent pathway remain to be established. The effect of IL-1β on the expression of α1 adrenergic receptors (α1AR) and the relationship with Janus kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway were observed using a rabbit model of lipopolysaccharide (LPS)-induced endotoxemia and superior mesenteric arteries (SMAs) in vivo and in vitro, respectively. The vascular reactivity of SMAs to α1AR agonist (phenylephrine) displayed a biphasic change after LPS (significantly increased at 0.5 hour following LPS and then markedly decreased after 2 hours), the α1A, α1B and α1DAR messenger RNA (mRNA) and protein expression seemed a time-dependent decrease following LPS administration, α1A and α1DAR decreased more obviously than α1BAR. IL-1ra (4 µg/mL) partly reversed LPS-induced the decrease of vascular reactivity and down-regulation of α1AR expression. In vitro incubation with IL-1β (12.5-50 ng/mL) significantly decreased the vascular reactivity of SMA to phenylephrine and the expression of α1AR mRNA and protein and elevated the DNA binding ability of STAT3. AG490 (10 µmol/L), an inhibitor of JAK2, partly reversed the IL-1β-induced down-regulation of vascular reactivity and α1AR mRNA and protein expression and suppressed the DNA binding ability of STAT3. IL-1β participates in the regulation of vascular hyporeactivity following endotoxemia in rabbit. The mechanism is related to the down-regulation of α1AR expression through activating the JAK2-STAT3 pathway.

Angiopoietins regulate vascular reactivity after haemorrhagic shock in rats through the Tie2-nitric oxide pathway

Vascular reactivity shows biphasic changes after severe trauma or shock. Our aim was to elucidate the mechanisms of biphasic-changed vascular reactivity after haemorrhagic shock by observing the regulation of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) on it. Haemorrhagic-shock Sprague-Dawley rats, hypoxia-treated superior mesenteric arteries (SMAs) with intact endothelia, and a cell mixture of vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) were adopted to evaluate the regulatory effects of Ang-1 and Ang-2 on vascular reactivity and their relationship to Tie2 (receptor tyrosine kinase)-Akt-endothelial nitric oxide synthase (eNOS) and Tie2-extracellular signal-regulated kinase (Erk)-inducible nitric oxide synthase (iNOS) signal pathways. Ang-1 expression, Tie2 phosphorylation, and nitric oxide (NO) release were increased at early shock. Exogenous Ang-1 maintained the vascular reactivity of SMAs after early hypoxia. Tie2-blocking antibody and the antagonists of Akt and eNOS antagonized Ang-1-induced maintenance in vascular reactivity and a slight release in NO at the early stage of shock. Ang-2 expression, Tie2 phosphorylation, and NO release were greatly increased at late shock, but exogenous Ang-2 further decreased the vascular reactivity of SMAs after late hypoxia. Tie2-blocking antibody and the antagonists of Erk and iNOS andtagonized the Ang-2-induced decrease in vascular reactivity and a large release of NO at the late stage of shock. Ang-1 and Ang-2 participated in the regulation of vascular reactivity after haemorrhagic shock. Ang-1 was mainly responsible for the hyperreactivity at early shock through the Tie2-Akt-eNOS pathway and an appropriate amount of NO release. Ang-2 was mainly responsible for the hyporeactivity at late shock through the Tie2-Erk-iNOS pathway and the release of a large amount of NO.

Pinacidil Pretreatment Improves Vascular Reactivity After Shock Through PKCα and PKC[Latin Small Letter Open E] in Rats

We investigated the beneficial effect of pinacidil pretreatment on vascular reactivity, calcium sensitivity, and animal survival after hemorrhagic shock, its relationship to protein kinase Cα (PKCα), protein kinase Cε (PKCε), and adenosine. Using hemorrhagic shock rats, the protective effects of different extents of pinacidil pretreatment on vascular reactivity and in which the roles of PKCα, PKCε, and adenosine were observed. Pinacidil pretreatment significantly improved shock-induced decrease of vascular reactivity of superior mesenteric artery, which was antagonized by the PKCα antagonist Gö-6976 (5 × 10 mole/L) and PKCε pseudosubstrate inhibitory peptide (1 × 10 mole/L). Pinacidil pretreatment induced the translocation of PKCα and PKCε from the cytoplasm to the membrane. This translocation of PKCα and PKCε was eliminated by adenosine A1 receptor antagonist DPCPX (1 × 10 mole/L). As compared with simple fluid resuscitation, combination with pinacidil pretreatment significantly improved the vascular reactivity and survival rate of hemorrhagic-shocked rats. These results suggested that pinacidil pretreatment could induce good protective effects on vascular reactivity and calcium sensitivity after hemorrhagic shock mainly through the activation of PKCα and PKCε via adenosine A1 receptor, and this protective effect made an important contribution to the overall outcome of shock therapy.

Changes of extracellular signal-regulated kinase activity following hemorrhagic shock and its role in regulation of vascular reactivity

Objective To investigate the changes of extracellular signal-regulated kinase (ERK) activity and its role in regulation of vascular reactivity following hemorrhagic shock. Methods In 72 SD rats, the hemorrhagic shock model was adopted, the activity of ERK in the superior mesenteric artery ( SMA) of rats after shock was measured, and the vascular reactivity of SMA after shock was observed. The effect of altered ERK activity on the regulation of vascular reactivity of SMA after shock was investigated.Results After shock, the activity of ERK in SMA was increased about 2. 6 folds as compared to normal group ( P ＜0. 01) , and it reached the peak at 30 min after shock. The activity of ERK 2 h after shock was reduced to 56. 1 % of normal group ( P ＜ 0. 05 ). At the same time, the vascular reactivity of SMA was also increased at early shock and decreased at late shock. Angiotensin II ( AngII) increased the activity of ERK to 1. 9 folds as compared to shock 2-h group (P ＜0. 01) , and AngII also increased the vascular reactivity of SMA at 2 h shock. PD98059, the ERK antagonist, antagonized the effect of AngII on ERK activity and vascular reactivity of the SMA. Conclusion ERK may play an important role in the regulation of vascular reactivity after hemorrhagic shock. Key words: Hemorrhagic shock; Extracellular signal-regulated kinase; Vascular reactivity

Effects of the Balance in Activity of RhoA and Rac1 on the Shock-Induced Biphasic Change of Vascular Reactivity in Rats

To investigate the effects of the balance in activity of RhoA and Rac1 on the shock-induced biphasic change in vascular reactivity and the related mechanism. Vascular reactivity after hemorrhagic shock shows a biphasic change. RhoA and Rac1 are the main members of a family of Rho GTPases; whether and how they participate in the regulation of the biphasic change in vascular reactivity after shock is not known. The relationship of the balance of the activity RhoA and Rac1 with the changes in vascular reactivity after hemorrhagic shock, the effects of artificially changing the balance of RhoA and Rac1 activity on vascular reactivity, and the roles of Rho kinase and p21-activated kinase (PAK) in RhoA/Rac1 regulation of vascular reactivity were observed in isolated superior mesenteric arteries (SMAs) from hemorrhagic shocked rats and hypoxia-treated vascular smooth muscle cells (VSMCs). The reactivity of SMAs and VSMCs to norepinephrine after shock or hypoxia was positively correlated with changes in the RhoA and Rac1 activity ratio. Artificially changing the balance in activity of RhoA and Rac1 significantly changed the shock-induced biphasic response of vascular reactivity. Specific antagonist of Rho kinase and PAK (Y-27632 and PAK-18) respectively abolished the effect of activation of RhoA and Rac1. Activation of RhoA significantly increased the activity of Rho kinase and inhibited the activity of Rac1 in SMAs. Rac1 activation significantly increased the activity of PAK and decreased the activity of RhoA. The balance in the activity of RhoA and Rac1 participated in the biphasic vascular reactivity seen after hemorrhagic shock. RhoA and Rac1 regulation of the vascular reactivity after shock are closely related to Rho kinase and the PAK pathway. RhoA regulates vascular reactivity mainly through activation of Rho kinase and inhibition of Rac1. Rac1 regulates vascular reactivity mainly through inhibition of RhoA and activation of PAK. These findings have potential significance for the treatment of vascular hyporesponsiveness.

PKC plays an important mediated effect in arginine vasopressin induced restoration of vascular responsiveness and calcium sensitization following hemorrhagic shock in rats

The present study investigated the mediated effect of protein kinase C (PKC) in arginine vasopressin (AVP)-induced restoration of vascular responsiveness and calcium sensitization following hemorrhagic shock. Using both isolated superior mesenteric artery from hemorrhagic shock rats and hypoxia-treated vascular smooth muscle cell (VSMC), we investigated the roles of PKC-α, δ and ε isoforms in AVP-induced restoration of vascular reactivity and calcium sensitivity. Meanwhile, effects of their specific inhibitors on the activity of myosin light chain phosphatase (MLCP), myosin light chain kinase (MLCK), and the phosphorylation of myosin light chain (MLC 20) in VSMC were observed. The results indicated that AVP improved the reactivity of superior mesenteric artery and VSMC to norepinephrine and calcium following hemorrhagic shock and hypoxia. PKC-α inhibitor and PKC-ε inhibitory peptide antagonized these effects of AVP, while PKC-δ inhibitor only partially antagonized these effects of AVP. AVP up-regulated the expression of PKC-α and ε in the particulate fractions of hypoxia-treated VSMC with the decrease of the activity of MLCP and the increase of the phosphorylation of MLC 20. These effects of AVP were inhibited by PKC-α inhibitor and PKC-ε inhibitory peptide, but not by the PKC-δ inhibitor. The results suggested that PKC plays an important role in AVP-induced restoration of vascular reactivity and calcium sensitivity following hemorrhagic shock. PKC-α and ε may be the main isoforms involved in this process and play effect via MLC 20 phosphorylation dependent mechanism, while PKC-δ may be partially involved in AVP action by other mechanisms.

Role of V 1a Receptor in AVP-Induced Restoration of Vascular Hyporeactivity and Its Relationship to MLCP-MLC 20 Phosphorylation Pathway

Our previous study showed that small dosage of arginine vasopressin (AVP) had beneficial effect on shock by improving the shock-induced vascular hyporeactivity. But the mechanism is not clear. The objective of the present study is to investigate the role of V(1a) and V(2) receptors in AVP-mediated restoration of hemorrhage-induced vascular hyporesponsiveness and its relationship to protein kinase C (PKC), myosin light chain phosphatase (MLCP), and myosin light chain (MLC(20)) phosphorylation signal transduction pathway. We used isolated superior mesenteric artery (SMA) from hemorrhagic shock rats (40 mmHg for 2 hours) and 90 minutes hypoxia-treated vascular smooth muscle cell (VSMC) to study the effects of V(1a) and V(2) receptor inhibitors on AVP-mediated regulation of vascular reactivity and calcium sensitivity. Meanwhile the effects of AVP and V(1a) and V(2) receptor antagonists on the activity of MLCP and myosin light chain kinase (MLCK), and the phosphorylation of MLC(20), and the expression of PKC-alpha, delta, and epsilon isoforms were also studied. AVP significantly improved the reactivity of SMA to norepinephrine (NE) and Ca(2+) following hemorrhagic shock and increased the hypoxia-induced decrease of contractile response of VSMC to NE. The PKC-alpha and epsilon expression in particulate fractions of VSMC following hemorrhagic shock and hypoxia was also increased by treatment with AVP. V(1a) receptor inhibitor significantly antagonized these effects of AVP. AVP treatment resulted in a significant increase of MLC(20) phosphorylation in SMA and a significant decrease of MLCP activity in VSMC, which was also inhibited by V(1a) receptor inhibitor. V(1a) receptor, not V(2) receptor, played an important role in AVP-mediated regulation of vascular reactivity and calcium sensitivity following hemorrhagic shock. The mechanism is mainly through PKC-MLCP-MLC(20) phosphorylation calcium sensitivity pathway.

Beneficial effect of arginine vasopressin on hemorrhagic shock through improving the vascular reactivity

The vascular reactivity and calcium sensitivity were decreased following hemorrhagic shock. Arginine vasopressin (AVP) was beneficial to endotoxic, infectious/spetic and hemorrhagic shock. Our previous studies found that Rho kinase played an important role in the occurrence of calcium desensitization following shock. It was reported that AVP was with stimulation effect of Rho kinase. So we hypothesized that AVP might have beneficial effect on shock via activation of Rho kinase to regulate the calcium sensitivity and vascular reactivity. Hemorrhagic shock (40 mmHg for 2 h) Wistar rats in vivo were adopted to observe the effects of small dose of AVP on hemodynamics, 24-h survival rate, the pressor effect of norepinephrine (NE) and the contractility of superior mesenteric artery (SMA). Isolated SMAs from hemorrhagic shock rats were adopted to observe the effects of AVP on vascular reactivity and calcium sensitivity and its relationship to Rho kinase with an isolated organ perfusion system. The results show that AVP at the concentration of 0.1 U/kg and 0.4 U/kg significantly improved the hemodynamic parameters and the 24-h survival rate of hemorrhagic shock rats. Meanwhile, these dosages of AVP significantly increased the pressor effect of NE and the contractile response of SMA to NE. Y-27632 (3 μg/kg), a Rho kinase specific inhibitor, abolished the beneficial effects of AVP. In vitro, the calcium sensitivity and vascular reactivity of SMA to calcium and NE were significantly decreased following hemorrhagic shock. AVP at the concentration of 0.5 nmol/L and 5 nmol/L significantly increased the calcium sensitivity and vascular reactivity. These effects of AVP were abolished by Y-27632 (10 μmol/L). Taken together, the results suggest that AVP at 0.1 U/kg and 0.4 U/kg is beneficial to hemorrhagic shock by improving the vascular reactivity, which involves activation of Rho kinase.

Decreased vascular reactivity in metformin-treated fructose-hypertensive rats

We have previously demonstrated that long-term metformin treatment prevents the development of hyperinsulinemia and hypertension in fructose-hypertensive (FH) rats; however, the exact nature of its antihypertensive effects remains elusive. Since hyperinsulinemia has been proposed to be a strong stimulus for norepinephrine (NE) release, the present study examined the effects of long-term metformin treatment (500 mg/kg/d for 10 weeks) on the reactivity of superior mesenteric arteries to NE in FH rats. Metformin treatment prevented the development of hyperinsulinemia and hypertension in FH rats. Mesenteric arteries from FH rats exhibited an increased cross-sectional area ([CSA] 0.45 ± 0.07 mm 2 v 0.32 ± 0.05 in controls, P < .05), which was prevented by long-term metformin treatment (0.34 ± 0.04 mm 2, P > .05 v untreated FH). Interestingly, mesenteric arteries from metformin-treated fructose and control rats exhibited a reduction in maximum responsiveness to NE both with and without the endothelium. These data suggest that metformin directly reduces catecholamine constrictor responses in resistance arteries of rats, which may contribute to its antihypertensive effects in rats.