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Biomedical subjects

R Clinton Webb

Publications and source records attributed to R Clinton Webb.

At least 19 recordsLinked to original sources
PubMed2004

Hypertension and RhoA/Rho-kinase signaling in the vasculature: highlights from the recent literature.

Under normal conditions, contractile activity in vascular smooth muscle is initiated by either receptor activation (norepinephrine, angiotensin II, etc.) or by a stretch-activated mechanism. After this activation, several signaling pathways can initiate a Ca2+-calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca2+ sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase thereby maintaining force generation. In opposition to force generation, NO is released from endothelial cells and causes vasodilation through inhibition of the RhoA/Rho-kinase signaling pathway. This brief review will highlight recent studies demonstrating a role for the RhoA/Rho-kinase signaling pathway in the increased vasoconstriction characteristic of hypertension.

Animals↗
PubMed2004

Disruption of microtubular network attenuates histamine-induced dilation in rat mesenteric vessels.

Cytoplasmic microtubules are important in many cellular homeostatic processes in the cell. They regulate cell shape and movement as well as serving as a network by which vesicles and membrane-bound organelles can travel. Lately, there have been many studies demonstrating that microtubules are involved in regulation of intracellular signaling and, therefore, affect vascular reactivity. In this study, we tested the hypothesis that microtubule disruption attenuates agonist-induced endothelium-dependent vasodilation. Isolated mesenteric arterial bed from normotensive rats was preconstricted with phenylephrine, and dose-response curves for histamine, acetylcholine (ACh), sodium nitroprusside (SNP), and pinacidil were performed before and after incubation with nocodazole or colchicine. Treatment of the vascular beds with nocodazole or colchicine significantly attenuated histamine relaxation but did not change the ACh-, SNP-, or pinacidil-induced vasorelaxation. Nocodazole did not cause an additional attenuation of the histamine-mediated dilation in mesenteric vessels in the presence of Nomega-nitro-L-arginine methyl ester, high extracellular K+, or K+ channel blockers. These data suggest that disruption of microtubules affects an essential endothelial component of histamine-mediated vasodilation in the mesenteric arterial bed. The mechanism(s) involved in this effect might be related to an impairment of endothelial NO synthesis, which might not be as important for the ACh as for the histamine vasodilator response in rat mesenteric vessels. These results demonstrate the importance of the microtubular system for endothelium-dependent NO-mediated smooth muscle relaxation.

Animals↗
PubMed2004

Decreased epoxygenase and increased epoxide hydrolase expression in the mesenteric artery of obese Zucker rats.

Previous studies suggest that epoxyeicosatrienoic acids (EETs) are vasodilators of the mesenteric artery; however, the production and regulation of EETs in the mesenteric artery remain unclear. The present study was designed 1) to determine which epoxygenase isoform may contribute to formation of EETs in mesenteric arteries and 2) to determine the regulation of mesenteric artery cytochrome P-450 (CYP) enzymes in obese Zucker rats. Microvessels were incubated with arachidonic acid, and CYP enzyme activity was determined. Mesenteric arteries demonstrate detectable epoxygenase and hydroxylase activities. Next, protein and mRNA expressions were determined in microvessels. Although renal microvessels express CYP2C23 mRNA and protein, mesenteric arteries lacked CYP2C23 expression. CYP2C11 and CYP2J mRNA and protein were expressed in mesenteric arteries and renal microvessels. In addition, mesenteric artery protein expression was evaluated in lean and obese Zucker rats. Compared with lean Zucker rats, mesenteric arterial CYP2C11 and CYP2J proteins were decreased by 38 and 43%, respectively, in obese Zucker rats. In contrast, soluble epoxide hydrolase mRNA and protein expressions were significantly increased in obese Zucker rat mesenteric arteries. In addition, nitric oxide-independent dilation evoked by acetylcholine was significantly attenuated in mesenteric arteries of obese Zucker rats. These data suggest that the main epoxygenase isoforms expressed in mesenteric arteries are different from those expressed in renal microvessels and that decreased epoxygenases and increased soluble epoxide hydrolase are associated with impaired mesenteric artery dilator function in obese Zucker rats.

Acetylcholine↗
PubMed2004

Sympathetic and angiotensin-dependent hypertension during cage-switch stress in mice.

The goal of this study was to determine the dependence of the acute hypertensive response to a novel model of acute psychosocial stress on the sympathetic and renin-angiotensin systems. Baseline mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured with telemetry in mice for a 1-h period and averaged 98 +/- 1 mmHg, 505 +/- 3 beats/min, and 5 +/- 1 counts, respectively. Stress was induced by placing a mouse into a cage previously occupied by a different male mouse, and this increased MAP, HR, and activity in the control group by 40 +/- 2 mmHg, 204 +/- 25 beats/min, and 68 +/- 6 counts, respectively. Each variable gradually returned to baseline levels by 90 min after beginning cage switch. Pretreatment with terazosin (10 mg/kg ip) significantly reduced the initial increase in MAP to 12 +/- 6 mmHg, whereas MAP for the last 45 min was superimposable on control values. Atenolol (10 mg/ml drinking water) had no effect to blunt the initial increase in MAP but had a growing effect from 10 min onward, decreasing MAP all the way to baseline by 60 min after starting cage switch. Captopril (2 mg/ml drinking water) treatment caused a very similar response. All three treatments significantly decreased the area under the blood pressure curve, and the blood pressure effect could not be attributed uniformly to effects on HR or activity. These data suggest that our novel model of psychosocial stress causes an initial alpha(1)-receptor-dependent increase in MAP. The later phase of the pressor response is blocked similarly by a beta(1)-receptor antagonist and an ACE inhibitor, independent of HR, suggesting that the beta(1)-dependent blood pressure effect is due, in large part, to the renin-angiotensin system.

Angiotensins↗
PubMed2004

Hypertensive response to acute stress is attenuated in interleukin-6 knockout mice.

This study tested the hypothesis that the inflammatory cytokine, interleukin-6, contributes to the hypertensive response to acute psychosocial stress, caused by switching male mice to a cage previously occupied by a different male mouse. Male C57BL6 (WT) and interleukin-6 (IL-6) knockout (KO) mice were implanted with biotelemetry devices to monitor mean arterial pressure, heart rate, and motor activity in the unrestrained state. Baseline mean arterial pressure was 98+/-1 and 103+/-1 for WT and IL-6 KO mice. Cage switch increased mean arterial pressure by 42+/-2 mm Hg in WT mice, but this was blunted significantly in KO mice (31+/-3 mm Hg peak increase). Area under the curve for the first 90 minutes also was significantly less. Heart rate and motor activity increased similarly, and there also were no differences in the increases in plasma renin activity or plasma norepinephrine concentration between WT and KO mice. Thus, the acute hypertensive response to psychosocial stress depends significantly on IL-6, and the effect appears to be specific for blood pressure rather than to a global impairment in the response to stress. However, because perfusion of the isolated mesenteric bed with phenylephrine and chronic infusion of angiotensin II caused similar responses in WT and IL-6 KO mice, it is clear that future studies are needed to determine to what extent the acute blood pressure effect of IL-6 is stress-specific.

Acute Disease↗
PubMed2004

RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction.

Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA/Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rho-kinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA/Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZ-diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA/Rho-kinase in the penis, we evaluated the effects of an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA/Rho-kinase and eNOS and erectile function in vivo in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA/Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.

Adenoviridae↗
PubMed2004

Increased vascular sensitivity and connexin43 expression after sympathetic denervation.

OBJECTIVE: Following denervation, arteries demonstrate a heightened sensitivity to alpha-adrenergic agonists and increased oscillatory contractions that may partly result from increased gap junction expression. Hence, we wanted to study the effect of sympathetic denervation on connexin43 (Cx43) expression and agonist-induced contractility in the vascular smooth muscle (VSM). METHODS: Effects of denervation with reserpine (3 mg/kg/day, i.p.) or topical 5% phenol-glycerol on VSM contractions and expression of the gap junction Cx43 mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting for Cx43 protein were examined. Wistar-Kyoto (WKY) rat tail arteries were exposed to norepinephrine (NE) (10(-9)-10(-5) M). Reactivity was also examined in the carotid arteries and thoracic aortas from Cx43 heterozygote deficient (KO) mice. RESULTS: The concentration for NE-induced contraction was lower in reserpine- and phenol-treated vessels than controls (p<0.05). NE-induced oscillatory activity (OA) was seen in 5/5 reserpine- and 5/8 phenol-treated vessels vs. 0/12 controls (p<0.05). Spontaneous OA was observed more frequently in carotid and aortic rings from WT than Cx43 KO rings. Cumulative OA in response to alpha-adrenergic stimulation was significantly greater in WT carotid (429+/-101 vs. 128+/-7 mN s, p<0.05) and aortic rings (337+/-85 vs. 134+/-11 mN s, p<0.05) than in Cx43 KO rings. Following denervation, RT-PCR showed significantly increased levels of Cx43 mRNA (p<0.05). Western blot analysis revealed near doubling of Cx43 protein (p<0.05). CONCLUSION: We conclude that sympathetic denervation results in increased expression of Cx43, which in turn, contributes to increased spontaneous and agonist-induced OA in VSM.

Animals↗
PubMed2004

Vasoactive factors in sickle cell disease: in vitro evidence for endothelin-1-mediated vasoconstriction.

While systemic plasma endothelin-1 (ET-1) levels are increased during acute crisis in sickle cell disease, the relative levels of potent vasoactive factors that contribute to the regulation of vascular function, such as ET-1, NO, and cell-free hemoglobin, during the course of periodic vaso-occlusive episodes remain unclear. Moreover, whether and to what extent sickling-induced release of ET-1 alters vascular tone is not completely understood. To investigate the sequential changes in circulating vasoactive factors, we measured plasma ET-1, NO metabolites (NOx), and cell-free hemoglobin (Hb) before (steady-state), during (crisis), and after a vaso-occlusive (post-crisis) episode. Steady-state ET-1 levels (fmol/mL) increased from 2.3 +/- 0.4 to 11.0 +/- 1.4 and 4.2 +/- 1.0 during crisis and post-crisis periods, respectively. There was no significant difference in plasma NOx levels. Cell-free Hb levels were significantly higher in sickle cell patients in all phases as compared to the control group, and especially during crisis cell-free Hb levels were elevated by 4-fold (209,000 +/- 31,000 vs. 46,000 +/- 5,300 ng/mL in steady-state). Conditioned medium from human pulmonary artery endothelial cells exposed to sickled erythrocytes prepared by deoxygenation induced contraction of aortic rings, and this effect was blocked by an ET(A) receptor antagonist. These findings indicate that ET-1 is the predominant contractile factor released by cultured endothelial cells upon exposure to deoxygenated sickled SS erythrocytes and ET-1-NO-NO scavenger balance is altered in favor of vasoconstriction during an acute episode in SCD.

Anemia, Sickle Cell↗
PubMed2004

Increaseed expression of mRNA for regulator of G protein signaling domain-containing Rho guanine nucleotide exchange factors in aorta from stroke-prone spontaneously hypertensive rats.

BACKGROUND: Rho guanine nucleotide exchange factors (RhoGEF) link activation of G protein-coupled receptors (GPCR) to RhoA/Rho-kinase signaling. This cellular signaling pathway regulates vascular tone and is implicated in hypertension. The RhoGEF, providing this coupling, contain the regulator of G protein signaling (RGS) domain. We hypothesized higher mRNA expression levels for these RhoGEF in aorta from stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: We measured mRNA expression by semiquantitative reverse transcriptase-polymerase chain reaction in the aorta of Wistar-Kyoto rats (WKY) and SHRSP. The protein expression level of p115RhoGEF was examined by Western Blot, too. RESULTS: Our results showed that mRNA for RGS domain containing RhoGEF is higher in SHRSP. CONCLUSION: The results of this study indicate that RhoGEF may contribute to increased activation of RhoA/Rho-kinase pathway in hypertension.

Animals↗
PubMed2004

Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid receptors.

Excess glucocorticoids result in decreased aortic dilation and expression of guanosine triphosphate (GTP) cyclohydrolase 1 (GTPCH1) messenger RNA (mRNA), the rate-limiting enzyme in the production of the nitric oxide synthase (NOS) cofactor tetrahydrobiopterin (BH4). It was hypothesized that this response is a genomic effect mediated through the glucocorticoid receptor (GR). Endothelium-intact rat aortas were incubated with dexamethasone (DEX; 1.3 x 10(-6) M) or vehicle for 2 or 6 hours and isometric force generation was measured. Maximum acetylcholine-induced relaxation in DEX-2hr aortas was not different compared with control values; however, acetylcholine-induced relaxations in DEX-6hr aortas were significantly decreased. Coincubation with sepiapterin (10(-4) M), which produces BH4 via a salvage pathway, restored relaxation in DEX-6hr aortas to that of controls. Coincubation with the GR antagonist mifepristone (10(-6) M) completely blocked the DEX-induced decrease in relaxation. Spironolactone (10(-5) M), a mineralocorticoid receptor antagonist, had no effect. GTPCH1 mRNA expression was significantly decreased in DEX-6hr aortas compared with control values. This was blocked by mifepristone; however, spironolactone and cycloheximide did not prevent the decrease of GTPCH1 by DEX. These results support the hypothesis that GTPCH1 downregulation by glucocorticoids is mediated through the GR and contributes to reduced endothelium-dependent relaxation.

Animals↗
PubMed2004

Sepiapterin decreases vasorelaxation in nitric oxide synthase inhibition-induced hypertension.

Exogenous BH4 (tetrahydrobiopterin) has been shown to improve endothelial function in cardiovascular disease; however, in the presence of elevated superoxide levels and decreased nitric oxide synthase (NOS) activity, BH4 may become autoxidized, resulting in reduced vasodilation. The authors tested the hypothesis that increasing BH4 will further reduce endothelium-dependent relaxation in aortas from rats made hypertensive by NOS inhibition. N omega-nitro-L-arginine (L-NNA, approximately 49 mg/kg/d) was administered in the rats' drinking water for 4 days. Systolic blood pressures, measured by tail-cuff technique, were significantly increased in L-NNA-treated rats. Endothelium-intact aortic segments were isolated and hung in organ chambers for the measurement of isometric force generation. Aortas from L-NNA-treated rats had decreased relaxation to acetylcholine compared with controls, and this was further decreased after incubation with sepiapterin. Superoxide dismutase (SOD) restored relaxation in aortas from L-NNA-treated rats to that of control. In addition, SOD or ascorbic acid reversed the sepiapterin-induced decrease in relaxation in aortas from L-NNA treated rats. Aortas from L-NNA-treated rats in the absence and presence of sepiapterin, and sepiapterin-treated control aortas, had increased dihydroethidium staining for superoxide compared with untreated controls. These results support the hypothesis that sepiapterin further reduces vasodilation in the presence of NOS inhibition and may be caused by BH4 autoxidation.

Animals↗
PubMed2004

Phenylalanine improves dilation and blood pressure in GTP cyclohydrolase inhibition-induced hypertensive rats.

GTP cyclohydrolase (GTPCH), the rate-limiting enzyme in the production of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), is partly regulated by the GTPCH feedback regulatory protein (GFRP). GFRP can inhibit GTPCH by end-product negative feedback, and L-phenylalanine (L-Phe) reverses this inhibition and increases BH4 biosynthesis in vitro. We hypothesized that L-Phe would increase endothelium-dependent relaxation and decrease blood pressure in rats made hypertensive by GTPCH inhibition. Di-amino-hydroxypyrimidine (DAHP, 10 mmol/L), a known inhibitor of GTPCH, was given with or without L-Phe or D-Phe (2 mmol/L) in the drinking water of rats for 3 days and blood pressure was measured via tail-cuff. Endothelium-intact aortic segments were hung in organ chambers for measurement of isometric force generation. Systolic blood pressure was increased significantly in DAHP-treated rats compared with controls. The addition of L-Phe attenuated the hypertensive effect, whereas D-Phe had no effect. Acetylcholine- and A23187-induced relaxation was decreased in aortas from DAHP-treated rats compared with controls, but was restored in aortas from DAHP+L-Phe-treated rats. Following NOS inhibition, sensitivity to sodium nitroprusside was increased in aortas from DAHP-treated rats, but restored in DAHP+L-Phe-treated rats. These results suggest that L-Phe can reverse GTPCH inhibition in vivo leading to increased vasodilation and decreased blood pressure.

Animals↗
PubMed2004

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta.

Evidence indicates that both the Rho/Rho kinase signaling pathway and reactive oxygen species (ROS) such as superoxide and H(2)O(2) are involved in the pathogenesis of hypertension. This study aimed to determine whether ROS-induced vascular contraction is mediated through activation of Rho/Rho kinase. Rat aortic rings (endothelium denuded) were isolated and placed in organ chambers for measurement of isometric force development. ROS were generated by a xanthine (X)-xanthine oxidase (XO) mixture. The antioxidants tempol (3 mM) and catalase (1,200 U/ml) or the XO inhibitor allopurinol (400 microM) significantly reduced X/XO-induced contraction. A Rho kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl-N-4-pyridil)cyclohexanecarboxamide dihydrochloride (Y-27632), decreased the contraction in a concentration-dependent manner; however, the Ca(2+)-independent protein kinase C inhibitor rottlerin did not have an effect on X/XO-induced contraction. Phosphorylation of the myosin light chain phosphatase target subunit (MYPT1) was increased by ROS, and preincubation with Y-27632 blocked this increased phosphorylation. Western blotting for cytosolic and membrane-bound fractions of Rho showed that Rho was increased in the membrane fraction by ROS, suggesting activation of Rho. These observations demonstrate that ROS-induced Ca(2+) sensitization is through activation of Rho and a subsequent increase in Rho kinase activity but not Ca(2+)-independent PKC.

Amides↗
PubMed2004

[Effect of topical application of a Rho-kinase inhibitor on the erectile response in rats].

OBJECTIVE: To investigate the effect of Rho-kinase inhibitor applied topically on the penile erection and systemic circulation of rats. METHODS: Y-27632 was applied to the surface of the tunica albuginea or to the penile skin of rats, and the changes of CCP/MAP were observed continuously. RESULTS: Both methods of drug administration resulted in a marked increase in the erectile response both with and without stimulation of the innervation of the penile vasculature. Some doses of the drug were also found to reduce systemic blood pressure. CONCLUSION: Inhibitors of Rho-kinase may represent a new and promising method of treatment for erectile dysfunction.

Amides↗
PubMed2003

Neuroprotection by tempol in a model of iron-induced oxidative stress in acute ischemic stroke.

Studies suggest iron exacerbates the damage caused by ischemic stroke. Our aim was to elucidate the effect of iron overload on infarct size after middle cerebral artery occlusion (MCAO) and to evaluate the efficacy of tempol, a superoxide dismutase mimetic, as a neuroprotective agent. Rats were administered iron +/- tempol before MCAO; control rats received saline. The middle cerebral artery was occluded for 24 h, and the size of the resultant infarct was assessed and expressed as the percentage of the hemisphere infracted (%HI). Iron treatment increased infarct size compared with control (51.83 +/- 3.55 vs. 27.56 +/- 3.28%HI iron treated vs. control, P = 0.01); pretreatment with tempol reversed this (51.83 +/- 3.55 vs. 26.09 +/- 9.57%HI iron treated vs. iron + tempol treated, P = 0.02). We hypothesized that reactive oxygen species (ROS) were responsible for the iron-induced damage. We measured ROS generated by exogenous iron in brain and peripheral vasculature from rats that had not undergone MCAO. There was no increase in ROS production in the brain of iron-treated rats or in brain slices incubated with iron citrate. However, ROS generation in carotid arteries incubated with iron citrate was significantly increased. ROS generation from the brain was assessed after MCAO by dihydroethidine staining; there was a dramatic increase in the ROS generation by the brain in the iron-treated rats compared with control 30 min after MCAO. We propose that iron-induced ROS generation in the cerebral vasculature adds to oxidative stress during an ischemic episode after the disruption of the blood-brain barrier.

Animals↗
PubMed2003

GTP cyclohydrolase 1 inhibition attenuates vasodilation and increases blood pressure in rats.

GTP cyclohydrolase 1 is the rate-limiting enzyme in production of tetrahydrobiopterin, a necessary cofactor for endothelial nitric oxide synthase. We tested the hypothesis that inhibition of tetrahydrobiopterin synthesis impairs endothelium-dependent relaxation and increase blood pressure in rats. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a GTP cyclohydrolase 1 inhibitor, was given in drinking water (approximately 120 mg.kg(-1).day(-1)) to male Sprague-Dawley rats for 3 days. Systolic blood pressures were measured (tail-cuff procedure) for 3 days before and each day during DAHP treatment. Blood pressure was significantly increased after DAHP treatment (122 +/- 2 vs. 154 +/- 3 mmHg before and after DAHP, respectively; P < 0.05). Endothelium-intact aortic segments from pentobarbital sodium-anesthetized rats were isolated and hung in organ chambers for measurement of isometric force generation. Aortas from DAHP-treated rats exhibited a decreased maximal relaxation to ACh compared with controls [% relaxation from phenylephrine (10-7 M)-induced contraction: DAHP 57 +/- 6% vs. control 79 +/- 4%; P < 0.05]. Relaxation responses to A-23187 were also decreased in aortas from DAHP-treated rats compared with controls. Incubation with sepiapterin (10-4 M, 1 h), which produces tetrahydrobiopterin via a salvage pathway, restored relaxation to ACh in aortas from DAHP-treated rats. Superoxide dismutase significantly increased ACh-induced relaxation in aortas from DAHP-treated rats, whereas catalase had no effect. Endothelium-independent relaxation to sodium nitroprusside in aortas from DAHP-treated rats was not different from control rats; however, nitric oxide synthase inhibition increased sensitivity to sodium nitroprusside in aortas from DAHP-treated rats. These results support the hypothesis that GTP cyclohydrolase 1 inhibition decreases relaxation and increases blood pressure in rats.

Animals↗
PubMed2003

Abnormal activation of Na+-K+ pump in aortas from rats with endotoxaemia.

A diminished reactivity to several vasoconstrictor agents is usually observed in blood vessels obtained from animals with endotoxic shock. The contractile state of vascular smooth muscle is influenced by the activity of the electrogenical sodium (Na(+)-K(+)) pump. Thus, we examined inhibitors and agonists of nitric oxide (NO)-guanosine 3':5'-cyclic monophosphate (cGMP) on contractions to phenylephrine (PE) and relaxations to potassium in isolated aortic segments from rats treated with bacterial endotoxin (lipopolysaccharide, LPS) for 6 h (i.e. to mimic a shock syndrome). Endotoxaemia for 6 h was associated with a severe hypotension and vascular hyporeactivity to noradrenaline and an increased plasma nitrate level in vivo. The PE-induced contraction was attenuated in aortic smooth muscle obtained from rats with endotoxic shock while the potassium-induced relaxation was greater in these preparations. Ouabain dose-dependently inhibited the potassium-induced relaxation in aortas from normal and endotoxaemic rats. 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one enhanced the PE-induced contraction in endotoxaemic rats only, whereas it attenuated the difference of potassium-induced relaxation between normal and endotoxaemic rats. In contrast, in aortas obtained from normal rats, 8-bromo-cGMP reduced the PE-induced contraction and enhanced the potassium-induced relaxation to the level as seen in endotoxaemic animals. In aortas obtained from endotoxaemic rats, methylene blue further restored the PE-induced contraction to the normal and abolished the difference of potassium-induced relaxation between normal and endotoxaemic rats. These results suggest that the Na(+)-K(+) pump in the vascular bed of animals with endotoxic shock is abnormally activated and this augmented activation is modulated by cGMP.

Animals↗