Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RhoA is commonly activated in the aorta in various hypertensive models, indicating that RhoA seems to be a molecular switch in hypertension. The molecular mechanisms for RhoA activation in stroke-prone spontaneously hypertensive rats (SHRSP) were here investigated using cultured aortic smooth muscle cells (VSMC). The level of the active form of RhoA was higher in VSMC from SHRSP than in those from Wistar-Kyoto rats (WKY). The phosphorylation level of myosin phosphatase target subunit 1 (MYPT1) at the inhibitory site was also significantly higher in SHRSP, and the phosphorylation levels in both VSMCs were strongly inhibited to a similar extent by treatment with Y-27632, a Rho-kinase inhibitor. The expression levels of RhoA/Rho-kinase related molecules, namely RhoA, Rho-kinase, MYPT1, CPI-17 (inhibitory phosphoprotein for myosin phosphatase) and myosin light chain kinase, were not different between SHRSP and WKY. Valsartan, an angiotensin II (Ang II)- type 1 receptor antagonist, selectively and significantly reduced the RhoA activation in VSMC from SHRSP. The expression levels of the Rho GDP-dissociation inhibitor (RhoGDI) and leukemia-associated Rho-specific guanine nucleotide exchange factor (RhoGEF) did not differ between SHRSP and WKY. In cyclic nucleotide signaling, cyclic GMP (cGMP)-dependent protein kinase Ialpha (cGKIalpha) was significantly downregulated in SHRSP cells, although there were no changes in the expression levels of guanylate cyclase beta and cyclic AMP (cAMP)-dependent protein kinase or the intracellular contents of cGMP and cAMP between the two rat models. These results suggest that the possible mechanisms underlying RhoA activation in VSMC from SHRSP are autocrine/paracrine regulation by Ang II and/or cGKIalpha downregulation.
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PMID:RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. 1512 84

We have studied the effects of exogenous human recombinant Vasostatin-1 (VS-1), Vasostatin-2 (VS-2) and the human Chromogranin A (CGA) 7-57 synthetic peptides on the mechanical performance of the isolated and perfused working eel (Anguilla anguilla) heart. Under basal conditions, the three peptides decreased stroke volume (SV) and stroke work (SW), thus exerting negative inotropism. The VS-1-mediated negative inotropism was abolished by exposure to inhibitors of either Gi/o protein (pertussis toxin; PTx) or M1 muscarinic receptors (Pirenzepine) or calcium (Lantanum and Diltiazem) and potassium (Ba2+, 4-aminopyridine, tetraethylammonium, glibenclamide) channels, while it required an intact endocardial endothelium (EE). Using NG-monomethyl-L-arginine (L-NMMA) as an inhibitor of nitric oxide (NO) synthase (NOS), and hemoglobin as a NO scavenger, we demonstrated the obligatory role of NO signaling in mediating the vasostatin response. Pretreatment with either a specific inhibitor of soluble guanylate cyclase (GC) 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), or the inhibitor of the cGMP-activated protein kinase (PKG) KT5823, abolished the VS-1-mediated inotropism, indicating the cGMP-PKG component as a crucial target of NO signaling. Of note, VS-1 was effective in counteracting the adrenergic (Isoproterenol and Phenylephrine)-mediated positive inotropism. These findings provide the first evidence that vasostatins exert cardiotropic action in fish, thus suggesting their long evolutionary history as well as their species-specific mechanisms of action.
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PMID:Influence of vasostatins, the chromogranin A-derived peptides, on the working heart of the eel (Anguilla anguilla): negative inotropy and mechanism of action. 1547 32

Nitric oxide (NO) is a molecule with pleiotropic effects in different tissues. NO is synthesized by NO synthases (NOS), a family with four major types: endothelial, neuronal, inducible and mitochondrial. They can be found in almost all the tissues and they can even co-exist in the same tissue. NO is a well-known vasorelaxant agent, but it works as a neurotransmitter when produced by neurons and is also involved in defense functions when it is produced by immune and glial cells. NO is thermodynamically unstable and tends to react with other molecules, resulting in the oxidation, nitrosylation or nitration of proteins, with the concomitant effects on many cellular mechanisms. NO intracellular signaling involves the activation of guanylate cyclase but it also interacts with MAPKs, apoptosis-related proteins, and mitochondrial respiratory chain or anti-proliferative molecules. It also plays a role in post-translational modification of proteins and protein degradation by the proteasome. However, under pathophysiological conditions NO has damaging effects. In disorders involving oxidative stress, such as Alzheimer's disease, stroke and Parkinson's disease, NO increases cell damage through the formation of highly reactive peroxynitrite. The paradox of beneficial and damaging effects of NO will be discussed in this review.
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PMID:The physiology and pathophysiology of nitric oxide in the brain. 1611 21

Carbon monoxide (CO) generated through the reaction of heme oxygenase (HO) has attracted great interest in regulation of hepatobiliary homeostasis. The gas generated by HO-2 in the hepatic parenchyma can modestly activate soluble guanylate cyclase (sGC) expressed in hepatic stellate cells in a paracrine manner and thereby constitutively relax sinusoids. Kupffer cells express HO-1, the inducible isozyme, even under normal unstimulated conditions and constitutes approximately 30% of the total HO activity in this organ. Upon exposure to a variety of stressors such as cytokines, endotoxin, hypoxia and oxidative stress, the liver induces HO-1 and over-produces CO. The stress-inducible CO has been shown to guarantee ample blood supply during detoxification of heme and thus to play a protective role in the liver. However, molecular mechanisms by which CO serves as a protectant for hepatocytes, the cells expressing little sGC, remain to be solved. Previous observation suggested that CO modulates intracellular calcium mobilization through inhibiting cytochrome P-450 activities and thereby maintain stroke volume of bile canalicular contraction in cultured hepatocytes. CO also stimulates mrp2-dependent excretion of bilirubin-IXalpha and helps heme catabolism. Although a direct molecular target responsible for the latter event remains unknown, such properties of CO could support xenobiotic metabolism through its actions on sinusoidal hemodynamics and hepatobiliary systems.
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PMID:Carbon monoxide as a guardian against hepatobiliary dysfunction. 1634 98

Hemolysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemolysis and its effects on nitric oxide (NO) biology and further examination of the subphenotypes of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemolysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasodilatation. When plasma hemoglobin liberated from intravascularly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodilation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be linked to the intensity of hemolysis. Hemolysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemolytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials.
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PMID:Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. 1708 51

Neuroendocrine regulation of cardiac function involves a population of three types of beta-adrenoceptors (ARs). In various mammalian species, beta1- and beta2-AR stimulation produces an increase in contractility; whereas beta3-AR activation mediates negative inotropic effects. At the moment, nothing is known about the physiological role of beta3-AR in fish. Using an isolated working heart preparation, we show that a beta3-AR selective agonist BRL(37344) (0.1-100 nmol l(-1)) elicits a dose-dependent negative inotropism in the freshwater eel Anguilla anguilla. This effect was insensitive to the beta1/beta2-AR inhibitor nadolol (10 mumol l(-1)), but was blocked by the beta3-AR-specific antagonist SR(59230) (10 nmol l(-1)). The analysis of the percentage of stroke work (SW) variations, in terms of EC(50) values, induced by BRL(37344) alone (10 nmol l(-1)), and in presence of SR(59230) (10 nmol l(-1)), indicated a competitive antagonism of SR(59230). In addition to the classic positive inotropism, the non-specific beta agonist isoproterenol (100 nmol l(-1)) induced, in 30% of the preparations, a negative inotropic effect that was abrogated by pre-treatment with SR(59230), pointing to a beta3-mediated pathway. The BRL(37344)-induced negative inotropic effect was abolished by exposure to a G(i/o) proteins inhibitor pertussis toxin (PTx; 0.01 nmol l(-1)), suggesting a G(i/o)-dependent mechanism. Using L-N5(l-imino-ethyl)ornithine (L-NIO; 10 mumol l(-1)), as a nitric oxide (NO) synthase (NOS) blocker and haemoglobin (Hb; 1 mumol l(-1)), as a NO scavenger, we demonstrated that NO signalling is involved in the BRL(37344)-induced response. Pre-treatment with either an inhibitor of soluble guanylate cyclase (GC) 1H-(1,2,4) oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ; 10 mumol l(-1)), or an inhibitor of the cGMP-activated protein kinase (PKG) KT(5823) (100 nmol l(-1)), abolished the beta3-dependent negative inotropism, indicating the cGMP-PKG component as a crucial target of NO signalling. Taken together, our findings provide functional evidence for the presence of beta3-like adrenoceptors in the eel Anguilla anguilla heart identifying, for the first time in a working fish heart, the beta3-AR-dependent negative inotropy discovered in mammals.
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PMID:Beta3-adrenoceptor in the eel (Anguilla anguilla) heart: negative inotropy and NO-cGMP-dependent mechanism. 1714 85

1. The present study was designed to characterize the effects of salt on vasorelaxation via the nitric oxide (NO)/cGMP pathway in stroke-prone spontaneously hypertensive rats (SHRSP), which are highly salt sensitive. 2. Male 8-week-old SHRSP were given 1% NaCl solution as drinking water for 4 weeks, whereas control animals were given water only. 3. In aortic rings from salt-loaded SHRSP, relaxations in response to acetylcholine and sodium nitroprusside were significantly impaired compared with those in the control. In the presence of zaprinast, a cGMP-specific cyclic nucleotide phosphodiesterase (PDE)-5 inhibitor, the cGMP levels induced by these drugs were significantly reduced by salt loading, but remained unchanged in the absence of zaprinast. The protein levels of endothelial NO synthase, soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase (PKG) remained unchanged with salt loading, but those of PDE-5 decreased significantly and those of phosphorylated PKG tended to decrease, although the change was not statistically significant. Salt loading significantly impaired the relaxation in response to 8-bromo-cGMP. 4. These results indicate that, in aortas from SHRSP, salt loading causes impairment of relaxation in response to NO, which may be due to a decrease in cGMP production by sGC and impairment of the relaxation pathway downstream of cGMP, which, in turn, probably causes a decrease in PKG activity. Reduced PDE-5 protein expression may act, in part, as a compensatory response to impairment of cGMP-mediated relaxation.
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PMID:Impaired effect of salt loading on nitric oxide-mediated relaxation in aortas from stroke-prone spontaneously hypertensive rats. 1720 35

Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H(2)S) is the third gaseous mediator in mammals. H(2)S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B(6)) as a cofactor. H(2)S stimulates ATP-sensitive potassium channels (K(ATP)) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H(2)S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also, attenuating their physiological functions, like nitric oxide does. In contrast to NO and CO, H(2)S does not stimulate soluble guanylate cyclase. H(2)S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H(2)S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. Exogenous H(2)S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs. On the other hand, excessive production of H(2)S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states.
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PMID:Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. 1737 2

Biotin is a member of the vitamin B-complex family. Biotin deficiency has been associated with hyperglycaemia and insulin resistance in animals and humans. In the present study, we investigated the pharmacological effects of biotin on hypertension in the stroke-prone spontaneously hypertensive rat (SHRSP) strain. We observed that long-term administration of biotin decreased systolic blood pressure in the SHRSP strain; also, a single dose of biotin immediately decreased systolic blood pressure in this strain. Pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole [4,3-alpha]quinoxalin-1-one abolished the hypotensive action of biotin in the SHRSP strain, while pretreatment with the NO synthase inhibitor NG-nitro-l-arginine methyl ester had no effect on the action of biotin. Biotin reduced coronary arterial thickening and the incidence of stroke in the SHRSP strain. These results suggest that the pharmacological dose of biotin decreased the blood pressure of the SHRSP via an NO-independent direct activation of soluble guanylate cyclase. Our findings reveal the beneficial effects of biotin on hypertension and the incidence of stroke.
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PMID:Antihypertensive effect of biotin in stroke-prone spontaneously hypertensive rats. 1817 28

The catecholamine release-inhibitory catestatin [Cts; human chromogranin (Cg) A(352-372), bovine CgA(344-364)] is a vasoreactive and anti-hypertensive peptide derived from CgA. Using the isolated avascular frog heart as a bioassay, in which the interactions between the endocardial endothelium and the subjacent myocardium can be studied without the confounding effects of the vascular endothelium, we tested the direct cardiotropic effects of bovine Cts and its interaction with beta-adrenergic (isoproterenol, ISO) and endothelin-1 (ET-1) signaling. Cts dose-dependently decreased stroke volume and stroke work, with a threshold concentration of 11 nM, approaching the in vivo level of the peptide. Cts reduced contractility by inhibiting phosphorylation of phospholamban (PLN). Furthermore, the Cts effect was abolished by pretreatment with either nitric oxide synthase (N(G)-monomethyl-l-arginine) or guanylate cyclase (ODQ) inhibitors, or an ET(B) receptor (ET(BR)) antagonist (BQ-788). Cts also noncompetitively inhibited the positive inotropic action of ISO. In addition, Cts inhibited the positive inotropic effect of ET-1, mediated by ET(A) receptors, and did not alter the negative inotropic ET-1 influence mediated by ET(BR). Cts action through ET(BR) was further suggested when, in the presence of BQ-788, Cts failed to inhibit the positive inotropism of both ISO and ET-1 stimulation and PLN phosphorylation. We concluded that the cardiotropic actions of Cts, including the beta-adrenergic and ET-1 antagonistic effects, support a novel role of this peptide as an autocrine-paracrine modulator of cardiac function, particularly when the stressed heart becomes a preferential target of both adrenergic and ET-1 stimuli.
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PMID:Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart. 1846 47


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