Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endogenously produced nitric oxide (NO) modulates nitrovasodilator-induced relaxation. We investigated the underlying mechanism in wild-type (WT) mice and endothelial NO synthase knockout (eNOS(-/-)) mice to determine whether a chronic lack of endothelial NO alters the soluble guanylyl cyclase (sGC) pathway. In aortic segments from eNOS(-/-) mice, the vasodilator sensitivity to sodium nitroprusside (SNP) was significantly greater than that in WT mice. There was no difference in sensitivity to the G-kinase I activator 8-para-chlorophenylthio-cGMP or to cromakalim. N(omega)-Nitro-L-arginine had no effect on the SNP-induced relaxation in eNOS(-/-) but increased the sensitivity in WT mice so it was no longer different than that of eNOS(-/-). Basal cGMP levels in aortic rings were significantly lower in eNOS(-/-) mice than in WT mice. SNP (300 nmol/L) induced a significantly greater cGMP accumulation in eNOS(-/-) mice than in WT mice. The maximal SNP-induced (10 micromol/L) increase in cGMP was similar in both strains. SNP-stimulated sGC activity was significantly greater in eNOS(-/-) mice than in WT mice. Incubation of aortic segments from WT mice with N(omega)-nitro-L-arginine increased sGC activity, an effect prevented by coincubation with SNP (10 micromol/L). The aortic expressions of the sGC alpha1 and beta1 subunits in WT and eNOS(-/-) mice were identical as determined with Western blot analysis. These data suggest that chronic exposure to endothelium-derived NO, as well as acute exposure to nitrovasodilator-derived NO, desensitizes sGC to activation by NO but does not alter sGC expression. Both the acute cessation of endothelial NO formation in WT mice and the chronic deficiency of NO in eNOS(-/-) mice restore the NO sensitivity of sGC and enhance vascular smooth muscle relaxation in response to nitrovasodilator agents.
Hypertension 2000 Jan
PMID:Increased nitrovasodilator sensitivity in endothelial nitric oxide synthase knockout mice: role of soluble guanylyl cyclase. 1064 3

We used YC-1 as a pharmacological tool to investigate the short-term blood pressure effects of NO-independent activation of sGC in normotensive and hypertensive rats. Four groups of normotensive Wistar-Kyoto rats were treated by i.v. injection with vehicle (V), YC-1 (YC-1), sodium nitroprusside (SNP), or YC-1 and SNP (YC-1+SNP). Hypertension was induced in four additional groups of WKY rats by 3 weeks of oral treatment with L-NAME. These animals were investigated with the same protocol as the normotensive animals: L-NAME/V, L-NAME/YC-1, L-NAME/SNP, L-NAME/YC-1+SNP. YC-1 lowered mean arterial blood pressure (MAP) in normotensive and hypertensive animals similarly to SNP alone (P<0.05, respectively). The combination of YC-1 with SNP caused a strong decrease of MAP in both the hypertensive and normotensive animals (P<0.05, respectively). SNP with YC-1 also induced a pronounced cyclic GMP increase in the aorta. This study shows for the first time the blood pressure lowering potential of bimodal targeting of the NO-sGC-system.
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PMID:Acute blood pressure effects of YC-1-induced activation of soluble guanylyl cyclase in normotensive and hypertensive rats. 1080 55

Adrenomedullin, which was discovered as a vasodilating peptide, has been reported to be produced in various organs, in which adrenomedullin regulates not only vascular tone but also cell proliferation and differentiation in an autocrine/paracrine manner. We evaluated the effect of adrenomedullin on endothelial cell apoptosis. Human umbilical vein endothelial cells underwent apoptosis when cultured in serum-free medium. Treatment with adrenomedullin reduced the number of cells with pyknotic nuclei (Hoechst 33258 staining) and inhibited cell death (dimethylthiazol-diphenyltetrazolium bromide assay) in a dose-dependent manner. The administration of adrenomedullin did not alter the expression levels of Bcl-2 family proteins. Experiments with analogs of cAMP or a cAMP-elevating agonist demonstrated that elevation of the intracellular cAMP concentration does not mediate the antiapoptotic effect of adrenomedullin. The coadministration of N-nitro-L-arginine methyl ester (2 mmol/L), an inhibitor of nitric oxide synthase, abrogated the effect of adrenomedullin. Lower doses of sodium nitroprusside (1 to 10 micromol/L), a nitric oxide donor, mimicked the antiapoptotic effect of adrenomedullin. The antiapoptotic effect of sodium nitroprusside was not attenuated by the inhibition of soluble guanylyl cyclase with 1 micromol/L oxadiazolo-quinoxalin-1-one nor could apoptosis be inhibited by the incubation of human umbilical vein endothelial cells with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analog. These results indicate that adrenomedullin and nitric oxide inhibit endothelial cell apoptosis via a cGMP-independent mechanism.
Hypertension 2000 Jul
PMID:Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cyclic GMP-independent mechanism. 1090 17

Soluble guanylyl cyclase activity and its stimulation by diethylamineNONOate was measured in aortae from hypertensive TGR(mREN2)27 rats (TGR) and Sprague-Dawley controls. Superoxide dismutase was added in vitro to evaluate the contribution of oxidative breakdown of nitric oxide (NO) by superoxide anions. Expression of soluble guanylyl cyclase was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Basal and stimulated soluble guanylyl cyclase activity was significantly reduced in TGR rats, addition of superoxide dismutase had no effect. Expression of soluble guanylyl cyclase subunits was not different between strains. The independent contribution of hypertension and the overactive renin-angiotensin system to soluble guanylyl cyclase subsensitivity was assessed after normalization of TGR's blood pressure by the Ca(2+)-channel blocker amlodipine or the angiotensin converting enzyme-inhibitor enalapril. Soluble guanylyl cyclase activity in TGR was slightly increased by amlodipine and almost completely restored by enalapril. In conclusion, TGR showed desensitized vascular soluble guanylyl cyclase, depending on their overactive renin-angiotensin system.
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PMID:Contribution of the renin-angiotensin system to subsensitivity of soluble guanylyl cyclase in TGR(mREN2)27 rats. 1096 40

The objective of this study was to test the hypothesis that renal interstitial (RI) cGMP is natriuretic in vivo. In conscious rats (n=8), urinary sodium excretion (U(Na)V) was significantly greater on days 3 and 4 of RI infusion of cGMP (1.17+/-0.14 and 1.61+/-0.11 mmol/24 h, respectively) than during vehicle infusion (0.56+/-0.15 and 0.70+/-0.17 mmol/24 h, respectively) (P<0.01). Similarly, U(Na)V was greater on days 3 and 4 of RI infusion of 8-bromo-cGMP (2.15+/-0.42 and 2.16+/-0.1 mmol/24 h, respectively). Protein kinase G inhibitor Rp-8-pCPT-cGMPS reduced cGMP-induced and 8-bromo-cGMP-induced U(Na)V to control levels. Acute RI infusion of L-arginine (L-Arg, 40 mg. kg(-1). min(-1)), but not D-arginine, caused an increase in U(Na)V from 1.65+/-0.11 to 4.07+/-0.1 micromol/30 min (P<0.01). This increase was blocked by RI infusion of N(G)-nitro-L-arginine methyl ester (100 ng. kg(-1). min(-1)) by the phosphodiesterase (PDE II) activator 5,6DMcBIMP (0.01 micromol/microL), by PDE II (0.03 U. kg(-1). min(-1)) itself, or by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo-[4,2-alpha]quinoxalin-1-one (ODQ, 0.12 mg. kg(-1). min(-1)). The PDE II activator also blocked L-Arg-stimulated cGMP levels. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 0.12 micromol. L(-1). kg(-1). min(-1)) increased U(Na)V from 1.65+/-0.11 to 2.93+/-0.08 micromol/30 min (P<0.01), and this response was blocked completely by ODQ. Renal arterial but not RI administration of the heat-stable enterotoxin of Escherichia coli induced natriuresis. RA infusion of cGMP (3 microg/min) increased U(Na)V, renal blood flow (RBF), and glomerular filtration rate (GFR). Renal cortical interstitial cGMP infusion increased U(Na)V with no effect on total RBF, renal cortical blood flow, or GFR. Similarly, the natriuretic actions of renal interstitial L-Arg or SNAP were not accompanied by any change in RBF or GFR. Medullary cGMP infusion had no effect on U(Na)V, total RBF, or medullary blood flow. Texas red-labeled cGMP infused via the RI space was distributed exclusively to cortical renal tubular cells. The results demonstrate that RI cGMP inhibits renal tubular sodium absorption via protein kinase G independently of hemodynamic changes. These observations indicate that the cortical interstitial compartment provides a potentially important domain for cell-to-cell signaling within the kidney.
Hypertension 2001 Sep
PMID:Renal interstitial cGMP mediates natriuresis by direct tubule mechanism. 1156 96

NO acting through soluble guanylyl cyclase and cGMP formation is a negative regulator of cardiomyocyte hypertrophy. Downstream targets mediating the inhibitory effects of NO/cGMP on cardiomyocyte hypertrophy have not been elucidated. In addition to its antihypertrophic effects, NO promotes apoptosis in cardiomyocytes, presumably through cGMP-independent pathways. We investigated the role of cGMP-dependent protein kinase (PKG) in the antihypertrophic and proapoptotic effects of NO. Incubation of neonatal rat cardiomyocytes with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) (250 micromol/L) or the PKG-selective cGMP analog 8-pCPT-cGMP (500 micromol/L) activated endogenous PKG type I, as shown by the site-specific phosphorylation of vasodilator-stimulated phosphoprotein, a well-characterized PKG substrate. SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) modestly attenuated the hypertrophic response to alpha(1)-adrenergic stimulation with phenylephrine. Although a high concentration of SNAP (1000 micromol/L) promoted apoptosis in cardiomyocytes, as evidenced by the formation of histone-associated DNA fragments, antihypertrophic concentrations of SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) did not promote cell death. Because chronic activation downregulated endogenous PKG I, we explored whether gene transfer of PKG I would enhance the sensitivity of cardiomyocytes to the antihypertrophic effects of NO/cGMP. Indeed, after adenoviral overexpression of PKG Ibeta, SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) completely suppressed the hypertrophic response to alpha(1)-adrenergic stimulation. As observed in noninfected cells, SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) did not promote apoptosis in cardiomyocytes overexpressing PKG Ibeta. Moreover, overexpression of PKG Ibeta did not enhance the proapoptotic effects of 1000 micromol/L SNAP, implying PKG-independent effects of NO on apoptosis. Endogenous PKG I mediates antihypertrophic but not proapoptotic effects of NO in a cell culture model of cardiomyocyte hypertrophy. Adenoviral gene transfer of PKG I selectively enhances the antihypertrophic effects of NO without increasing the susceptibility to apoptosis.
Hypertension 2002 Jan
PMID:Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects of nitric oxide in cardiomyocytes. 1179 84

BAY 41-8543 is a novel non-NO-based stimulator of sGC. This study investigates the acute effects of BAY 41-8543 on haemodynamics in anaesthetized rats and dogs, its long-term effects in conscious hypertension rat models and its antiplatelet effects. In anaesthetized dogs, intravenous injections of BAY 41-8543 (3 - 100 microg kg(-1)) caused a dose-dependent decrease in blood pressure and cardiac oxygen consumption as well as an increase in coronary blood flow and heart rate. In anaesthetized normotensive rats, BAY 41-8543 produced a dose-dependent and long-lasting blood pressure lowering effect after intravenous (3 - 300 microg kg(-1)) and oral (0.1 - 1 mg kg(-1)) administration. A dose-dependent and long-lasting decrease in blood pressure was also observed in conscious spontaneously hypertensive rats with a threshold dose of 0.1 mg kg(-1) p.o. After 3 mg kg(-1) the antihypertensive effect lasted for nearly 24 h. After multiple dosages, BAY 41-8543 did not develop tachyphylaxis in SHR. BAY 41-8543 prolonged the rat tail bleeding time and reduced thrombosis in the FeCl(3) thrombosis model after oral administration. In a low NO, high renin rat model of hypertension, BAY 41-8543 prevented the increase in blood pressure evoked by L-NAME and reveals a kidney protective effect. In this model, the overall beneficial effects of BAY 41-8543 manifested as both antiplatelet effect and vasodilatation were reflected in a significant reduction in mortality. The pharmacological profile of BAY 41-8543 suggests therefore that this compound has the potential to be an important research tool for in vivo investigations in the sGC/cGMP field and it also has the potential of being a unique clinical utility for treatment of cardiovascular diseases.
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PMID:Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. 1181 69

Type 2 diabetes mellitus is frequently associated with arterial hypertension. The mechanisms involved in this association are not known in detail, but endothelial dysfunction and a blunted vascular response to endogenous vasodilators are thought to play a role. In the present study we investigated the in vitro activity of vascular and renal soluble guanylyl cyclase in type 2 diabetic Goto-Kakizaki rats aged 5, 15, and 30 weeks, in comparison with age-matched Wistar controls. Blood pressure was monitored by radiotelemetry, and serum glucose and insulin concentrations were measured by standard assays. Goto-Kakizaki rats of all age groups had serum glucose concentrations significantly higher than those of corresponding Wistar controls. Serum insulin was unchanged until 15 weeks of age and was elevated in the 30-week-old diabetic rats. Blood pressure in Goto-Kakizaki rats was significantly higher than that in Wistar controls, and heart rate was significantly lower. Mesenteric arteries of diabetic rats showed a blunted relaxation in response to acetylcholine and sodium nitroprusside. In aortic tissue from Wistar rats an age-dependent increase was found in nitric oxide-stimulated cGMP formation, which was absent in the diabetic animals. Moreover, the maximum activity of soluble guanylyl cyclase was significantly lower in Goto-Kakizaki rats in all age groups studied. In renal tissue no differences were found between diabetic and control rats, except at 30 weeks of age when Goto-Kakizaki rats showed a significant reduction in basal and stimulated guanylyl cyclase activity. In conclusion, the present study shows a persistent reduction in vascular nitric oxide-sensitive guanylyl cyclase in Goto-Kakizaki rats, which occurred shortly after weaning and may contribute to the elevation in blood pressure in this strain of genetically diabetic rats.
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PMID:Dysfunction of soluble guanylyl cyclase in aorta and kidney of Goto-Kakizaki rats: influence of age and diabetic state. 1182 39

Preeclampsia (PE) is a leading cause of maternal hypertension in pregnancy, fetal growth restriction, premature birth, and fetal and maternal mortality (1). Activation and dysfunction of the maternal and fetal endothelium in PE may be the consequence of increased oxidative stress associated with circulating lipid peroxides (2-4), and in cases of severe maternal hypertension, uterine and umbilical artery waveforms are abnormal (5). We have investigated PE-associated abnormalities in the regulation of intracellular Ca2+ ([Ca2+]i) and cyclic guanosine monophosphate (cGMP) production (index of nitric oxide [NO]) in human fetal umbilical vein endothelial cells. Basal [Ca2+]i was slightly elevated in PE cells, whereas agonist-stimulated Ca2+ entry was reduced in cells from PE compared with normal term or age-matched preterm pregnancies. Furthermore, PE cells exhibited a decreased permeability to Ba2+ but an increased permeability to Mn2+ and Gd3+, suggesting that PE is associated with phenotypic alterations in fetal endothelial cation channel(s). Basal and histamine-stimulated cGMP levels were elevated in PE compared with preterm or normal cells, implying an increased NO production in PE. However, immunoblots for endothelial NO synthase (eNOS) and soluble guanylyl cyclase (sGC) revealed reduced eNOS expression in PE and preterm cells, with negligible changes in sGC levels. This study provides important and novel insights into abnormalities of fetal endothelial cells isolated from women with PE, reveal ing an altered cation membrane permeability and activity of eNOS-sGC pathway. As these changes are sustained in culture in vitro, this may reflect long-term "programming" of the fetal cardiovascular system.
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PMID:Preeclampsia is associated with altered Ca2+ regulation and NO production in human fetal venous endothelial cells. 1192 25

The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3'5'-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 micromol/L) against Ang II (1 micromol/L)-induced [3H]phenylalanine incorporation was abolished by the soluble guanylyl cyclase inhibitor [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 micromol/L). In Langendorff-perfused rat hearts, Ang II (10 nmol/L)-induced increases in [3H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 micromol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 micromol/L, a B2-kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart.
Hypertension 2002 Oct
PMID:Acute antihypertrophic actions of bradykinin in the rat heart: importance of cyclic GMP. 1236 53


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