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

Nitric oxide may act at autonomic sites in the brain to regulate arterial blood pressure. Our goal was to determine whether gene expressions of the brain isoform of nitric oxide synthase and of the beta subunit of soluble guanylyl cyclase, the target of nitric oxide, were altered in discrete autonomic brain regions after induction of hypertension in rats. The two-kidney, one clip model was used to induce hypertension, and measurements were made 3 and 6 weeks after the left renal artery was clipped. Only experimental rats with blood pressures elevated by at least 25 mm Hg were used. Total RNA was purified from microdissected tissue blocks containing hypothalamus, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Changes in nitric oxide synthase and guanylyl cyclase mRNA were semiquantified in each region by use of reverse transcription-polymerase chain reactions in which known concentrations of deletion mutants of the two genes were coamplified as internal standards. Compared with controls, significant decreases and increases in nitric oxide synthase mRNA were found in the hypothalamus (x 2.2) and caudal ventrolateral medulla (x 6.4), respectively, of hypertensive rats 3 weeks after clipping. These alterations were reversed in hypertensive rats at 6 weeks; levels increased (x 4.6) in the hypothalamus and decreased (x 5.5) in the caudal ventrolateral medulla. Changes in guanylyl cyclase expression paralleled those for nitric oxide synthase in some but not all areas at both time points.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Jul
PMID:Gene expression of brain nitric oxide synthase and soluble guanylyl cyclase in hypothalamus and medulla of two-kidney, one clip hypertensive rats. 754 80

To investigate the potential mechanisms by which indigo carmine produces hypertension, we tested the hypothesis that indigo carmine inhibits endothelium-dependent vasodilation and determined the possible site of the inhibition (endothelium versus smooth muscle). Using isolated rat thoracic aortic rings that were precontracted with phenylephrine, we examined vasodilatory responses to acetylcholine, histamine, and Ca2+ ionophore A23187 (in endothelium-intact rings) and sodium nitroprusside and isoproterenol (in endothelium-denuded rings) in the presence and absence of indigo carmine. In addition, the effects of methylene blue on the acetylcholine- and sodium nitroprusside-induced vasodilation were compared with those of indigo carmine. Indigo carmine (10(-6), 10(-5), and 10(-4) mol/L) significantly inhibited receptor- and non-receptor-mediated endothelium-dependent vasorelaxation. Indigo carmine (10(-4) mol/L) also inhibited endothelium-independent vasorelaxation induced by sodium nitroprusside (an activator of vascular smooth muscle soluble guanylyl cyclase), although to a lesser extent than vasodilation from acetylcholine, histamine, and Ca2+ ionophore A23187. In contrast, indigo carmine (10(-4) mol/L) had no effect on the vasodilation induced by isoproterenol (an activator of adenylyl cyclase), indicating that indigo carmine selectively inhibits nitric oxide-mediated responses. Methylene blue, a known inhibitor of soluble guanylyl cyclase, inhibited both acetylcholine- and sodium nitroprusside-induced vasorelaxation. The inhibition was also greater in the acetylcholine- than the sodium nitroprusside-induced vasodilation. These results suggest that indigo carmine, like methylene blue, may inhibit endothelium-dependent relaxation by a mechanism that involves two levels. The major action of indigo carmine appears to be at the level of nitric oxide generation and/or release from the endothelial cell. In addition, indigo carmine appears to inhibit vascular smooth muscle guanylyl cyclase. Thus, indigo carmine may elevate blood pressure by interfering with these nitric oxide-mediated vasodilatory mechanisms.
Hypertension 1996 Feb
PMID:Indigo carmine inhibits endothelium-dependent and -independent vasodilation. 856 45

Effects of a novel soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were characterized on guanylyl cyclase activity in cytosolic fraction of COS-7 cells overexpressing the alpha 1 and beta 1 subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn2+ or Mn(2+)-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 mumol/L) reduced deta nonoate-stimulated cGMP production in COS-7 cells overexpressing soluble guanylyl cyclase and in rat aortic vascular smooth muscle cells. ODQ did not inhibit particulate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxidize deta nonoate-donated NO in the presence of cells at physiological pH. Therefore, ODQ is a selective inhibitor of soluble guanylyl cyclase. Using ODQ in isolated aortic ring preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with NO. Phenylephrine (100 nmol/L)-precontracted, isolated rat aortas were relaxed in a concentration-dependent manner by deta nonoate (0.01 to 100 mumol/L) and nitroglycerin (0.01 to 300 mumol/L). ODQ (10 mumol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimakalim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.
Hypertension 1997 Jan
PMID:Selective guanylyl cyclase inhibitor reverses nitric oxide-induced vasorelaxation. 903 11

Although carbon monoxide (CO) has been suggested to be involved in the regulation of cardiovascular function through activation of soluble guanylyl cyclase, the pathophysiological significance in hypertension remains unknown. We therefore examined the effects of heme oxygenase (HO) inhibitor zinc protoporphyrin IX (ZnPP-IX) on blood pressure and determined HO mRNA expression level in various tissues in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and Wistar Kyoto rats (WKY/Izm). Although ZnPP-IX significantly increased systolic blood pressure in both strains, the increment of blood pressure was larger in SHR-SP/Izm than in WKY/Izm. An essentially similar increase of blood pressure was demonstrated even in the ganglion blocker-pretreated rats. Constitutive type HO-2 mRNA levels in the aorta and kidney and inducible type HO-1 mRNA levels in the cardiac ventricle were significantly increased in SHR-SP/Izm compared with WKY/Izm. Clearly these results indicate the importance of the endogenous HO/CO system in the peripheral tissues in genetically hypertensive rats.
 ...
PMID:Roles of heme oxygenase/carbon monoxide system in genetically hypertensive rats. 942 13

Activation of a soluble guanylyl cyclase plays an important role in nitric oxide (NO)-induced vasodilation. Recently, we have reported that NO increases the calcium-activated potassium (K(Ca)) channel activity in vascular smooth muscle cells from coronary arteries. The present study examined the role of the soluble guanylyl cyclase in the control of basal activity of the K(Ca) channels and in mediating NO-induced activation of the K(Ca) channels in vascular smooth muscle cells, using a selective inhibitor of this enzyme, 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ). In the cell-attached patch-clamp mode, addition of ODQ into the bath solution (10 micromol/L) decreased the K(Ca) channel activity by 59% and attenuated activation of the channels induced by the NO donor, deta nonoate, by 70%. ODQ had no effect on 8-bromo-cGMP-induced activation of the K(Ca) channels. Deta nonoate produced a concentration-dependent relaxation of precontracted coronary arteries. When ODQ was added to the bath, the deta nonoate-induced relaxations were inhibited. The IC50 for deta nonoate was decreased by about 25-fold and the maximal effect of deta nonoate was reduced by about 60%. A specific K(Ca) channel inhibitor, iberiotoxin, decreased deta nonoate-induced vasodilation but to a lesser extent than ODQ. However, ODQ was without effect on the vasodilation induced by a prostacyclin analog, iloprost, and by adenosine. These results indicate that a soluble guanylyl cyclase and cGMP play an important role in the control of the K(Ca) channel activity in coronary arterial smooth muscle cells. K(Ca) channel activation participates in the NO-induced vasodilation in coronary circulation.
Hypertension 1998 Jan
PMID:Effect of selective inhibition of soluble guanylyl cyclase on the K(Ca) channel activity in coronary artery smooth muscle. 945 20

Despite its well-documented importance, the mechanism for nitric oxide (NO) transport in vivo is still unclear. In particular, the effect of hemoglobin-NO interaction and the range of NO action have not been characterized in the microcirculation, where blood flow is optimally regulated. Using a mathematical model and experimental data on NO production and degradation rates, we investigated factors that determine the effective diffusion distance of NO in the microcirculation. This distance is defined as the distance within which NO concentration is greater than the equilibrium dissociation constant (0.25 microM) of soluble guanylyl cyclase, the target enzyme for NO action. We found that the size of the vessel is an important factor in determining the effective diffusion distance of NO. In approximately 30- to 100-micron-ID microvessels the luminal NO concentrations and the abluminal effective diffusion distance are maximal. Furthermore, the model suggests that if the NO-erythrocyte reaction rate is as fast as the rate reported for the in vitro NO-hemoglobin reaction, the NO concentration in the vascular smooth muscle will be insufficient to stimulate smooth muscle guanylyl cyclase effectively. In addition, the existence of an erythrocyte-free layer near the vascular wall is important in determining the effective NO diffusion distance. These results suggest that 1) the range of NO action may exhibit significant spatial heterogeneity in vivo, depending on the size of the vessel and the local chemistry of NO degradation, 2) the NO binding/ reaction constant with hemoglobin in the red blood cell may be much smaller than that with free hemoglobin, and 3) the microcirculation is the optimal site for NO to exert its regulatory function. Because NO exhibits vasodilatory function and antiatherogenic activity, the high NO concentration and its long effective range in the microcirculation may serve as intrinsic factors to prevent the development of systemic hypertension and atherosclerotic pathology in microvessels.
 ...
PMID:Effective diffusion distance of nitric oxide in the microcirculation. 961 83

The nitric oxide (NO) signaling system, consisting of NO synthases, soluble guanylyl cyclase, and cGMP, plays a prominent role in salt handling and regulation of blood pressure. Soluble guanylyl cyclases are heme-containing heterodimers (alpha/beta). The alpha1/beta1 isoform has greater NO sensitivity than the alpha1/beta2. It has recently been shown that expression of the beta subunits is altered in the kidney of the Dahl salt-sensitive rat, ie, the beta1 subunit is decreased and the beta2 subunit increased. However, whether soluble guanylyl cyclase is linked to salt sensitivity is not known. In the present study, we investigated linkage of guanylyl cyclase genes to blood pressure. Alpha1 and beta1 gene loci for soluble guanylyl cyclase were mapped to rat chromosome 2, and the beta2 gene locus was mapped to rat chromosome 5 using fluorescent in situ metaphase hybridization. By use of a rat radiation hybrid panel, the gene loci were then further mapped with respect to known quantitative trait locus markers of salt-sensitive hypertension in the Dahl rat on chromosomes 2 and 5. Genes for alpha1 and beta1 were closely linked by two-point analysis to Na+,K+-ATPase alpha1 isoform (LOD of 15.1 and 14.0, respectively) and calmodulin-dependent protein kinase II-delta loci (LOD of 14.3 and 12.9, respectively), which have been previously shown to flank a quantitative trait locus for blood pressure in the Dahl rat. The alpha1 and beta1 genes were closely linked (LOD of 11.3; theta, 0.4). The beta2 gene locus was closely linked to the endothelin-2 (ET-2) locus (LOD of 13.0), which has been shown to cosegregate with blood pressure. We conclude that soluble guanylyl cyclase subunit loci, ie, alpha1, beta1, and beta2, are good candidates for genes controlling salt-sensitive hypertension in the Dahl rat.
Hypertension 1998 Jul
PMID:Genetic mapping of soluble guanylyl cyclase genes: implications for linkage to blood pressure in the Dahl rat. 967 52

Dilator responses, superoxide anion-production, endothelial nitric oxide (NO) synthase and soluble guanylyl cyclase expression were determined in aortic rings from Wistar rats treated for 5 weeks either with the NO synthase inhibitor NG-nitro-L-arginine-methylester (L-NAME), L-NAME plus hydralazine or placebo. In the L-NAME-treated group, acetylcholine-induced relaxation was significantly attenuated whereas it was nearly normal in the L-NAME/hydralazine group. This difference was even more pronounced following inhibition of the endogenous superoxide dismutase using diethyldithiocarbamate. Aortic superoxide production was significantly elevated in both L-NAME-treated groups and hydralazine had no acute effect on superoxide formation. Expression of endothelial NO synthase was similar in all three groups whereas the attenuated soluble guanylyl cyclase expression in rats treated with L-NAME was nearly normalised by concomitant hydralazine treatment. These results demonstrate that in NO-deficient hypertension hydralazine treatment improves vasodilator responses but not the increased superoxide production.
 ...
PMID:Hydralazine prevents endothelial dysfunction, but not the increase in superoxide production in nitric oxide-deficient hypertension. 986 34

Endothelial dysfunction, as observed in hypertension and atherosclerosis, is associated with a reduction in the bioavailability of endothelium-derived nitric oxide (NO). We tested the hypothesis that alterations in the soluble guanylyl cyclase (sGC) pathway may also contribute to the pathogenesis of hypertension. Therefore, we investigated the expression and activity of sGC in young (6 weeks) and aging (17 months) spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY). Endothelium-independent relaxation of aortic rings in response to the sGC activator YC-1 was attenuated in SHR, and expression of both alpha(1) and beta(1) subunits of heterodimeric sGC and the basal contents of cGMP were reduced specifically in SHR aorta. Moreover, mRNA expression of the cGMP receptor and effector protein cGMP-dependent protein kinase type Ialpha (cGKIalpha) was also reduced. Interestingly, downregulation of both sGC and cGKIalpha expression was observed in young, ie, normotensive SHR, whereas impairment of the endothelium-independent relaxation was found only in aging SHR. Accordingly, similar cGMP levels were reached in response to YC-1 in young SHR and young WKY, suggesting a compensatory increased sensitivity or effectiveness of the sGC pathway in young SHR. In aging SHR, however, increased sensitivity to YC-1 no longer compensated for the impairment of endothelium-independent relaxation, suggesting that other mechanisms were involved. In fact, endothelium-independent relaxations were partially restored by superoxide dismutase, suggesting a pathophysiological role of superoxide production, particularly at later disease stages. Thus, tissue-specific downregulation of components of the sGC/cGMP pathway is an early event in the pathogenesis of hypertension.
 ...
PMID:Downregulation of soluble guanylyl cyclase in young and aging spontaneously hypertensive rats. 1048 56

We analyzed the influence of aging and genetic hypertension on the function and expression of soluble guanylyl cyclase (sGC) in the aortas of prehypertensive and old spontaneously hypertensive rats (SHR) as well as in age-matched normotensive Wistar-Kyoto rats (WKY). The expression of heterodimeric sGC (alpha(1) and beta(1)) was assessed at the mRNA and protein level, and its function was assessed by the relaxant responses of phenylephrine-contracted endothelium-denuded aortic rings to the nitric oxide (NO) donor sodium nitroprusside. The vasodilator potency of sodium nitroprusside was significantly reduced (P<0.05) with age (3- to 6-fold increase in the EC(50) in old WKY and SHR compared with their young counterparts) as well as with hypertension (3-fold increase in old SHR compared with age-matched WKY), whereas the vasodilator potency of sodium nitroprusside did not differ between young SHR and WKY. A similar influence of aging and hypertension on NO-stimulated GC activity was revealed at the GC expression level: Whereas the beta(1) protein content was similar in young rats of both strains, old WKY exhibited 60% lower and old SHR exhibited 80% lower beta(1) subunit protein compared with young rats (P<0.05). Moreover, the abundance of alpha(1) and beta(1) mRNA (assessed by reverse transcriptase-polymerase chain reaction) was similar in young rats but was 2.5-fold (alpha(1)) and 4.3-fold (beta(1)) lower in old SHR compared with old WKY. In conclusion, our findings show that both aging and hypertension decrease sGC expression and its NO-dependent activation in aortic tissue. Downregulation of sGC may therefore contribute to arterial dysfunction in senescence and chronic hypertension.
Hypertension 2000 Jan
PMID:Aging and chronic hypertension decrease expression of rat aortic soluble guanylyl cyclase. 1064 73


1 2 3 4 5 6 7 8 9 10 Next >>