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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired beta-adrenergic-mediated vasodilation and reduced lymphocyte beta-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin-mediated [32P]ADP ribosylation and, in hypertensive subjects, with alpha s-specific and beta-subunit antisera, and (3) inhibitory G proteins by pertussis toxin-mediated [32P]ADP ribosylation and, in older subjects, with alpha i,1,2- and beta-subunit-specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride-stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride-stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin-mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin-mediated labeling was not altered; however, pertussis toxin-mediated labelling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins.
Hypertension 1995 Nov
PMID:G protein alterations in hypertension and aging. 759 Oct 10

Nitric oxide stimulates endogenous ADP-ribosylation of cytosolic and membrane-bound proteins. Endogenous ADP-ribosyltransferases modify several intracellular proteins including the heterotrimeric GTP-binding proteins (G proteins). ADP-ribosylation of G proteins in vascular smooth muscle leads to increased activation of adenylate cyclase and decreased activation of phospholipase C leading to vasodilation. We hypothesize that in hypertension, chronically depressed endothelium-derived nitric oxide levels lead to decreased ADP-ribosylation of G proteins. This reduced ADP-ribosylation leads to vasoconstriction since activation of the G proteins by agonists is unopposed. Thus, disinhibition of G proteins, mediated by nitric oxide deficit, is responsible for the observed increased sensitivity to vasoconstrictor agonists in hypertension. This novel role for nitric oxide in hypertension will provide a new area of research for antihypertensive therapeutic intervention.
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PMID:Nitric oxide regulation of ADP-ribosylation of G proteins in hypertension. 760 67

Dopamine is an essential and indispensable catecholamine, which acts not only as a neurotransmitter in dopaminergic and noradrenergic sympathetic neurons but also as an autocrine/paracrine substance in non-neuronal tissues. The regulatory mechanism of dopamine synthesis in neuronal tissues seems to be different from that in non-neuronal tissues. Among receptors specifically bound to dopamine, five different receptors have already been cloned. Dopamine exhibits vasodilative and natriuretic effects by stimulating specific dopamine receptors located in renal tubular cells, blood vessels, etc. Physiological effects of dopamine appear to be protective against hypertension and sodium retention. Spontaneously hypertensive rats (SHR) are known to have an enhanced dopamine generation associated with the increased sympathetic nervous activity. A defect of renal D1-receptor-mediated coupling to adenylate cyclase has also been demonstrated in SHR. On the other hand, it has been reported that Dahl salt sensitive rats exhibit defective dopamine synthesis during high salt intake, which may be a definitive abnormality in this strain. The pathophysiological role of peripheral dopamine is essential hypertensive patients is still controversial. Considering the previous studies, it seems to be the case that essential hypertensive patients with increased sympathoadrenergic activity show enhanced dopaminergic discharge where dopamine may negatively modulate high blood pressure, and that stable essential hypertensive patients with salt-sensitivity and/or suppressed renin activity show insufficient dopamine synthesis in the kidney.
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PMID:Recent aspect of the role of peripheral dopamine and its receptors in the pathogenesis of hypertension. 764 68

Renovascular and renal excretory responses to intrarenally infused angiotensin II (Ang II) (1 and 3 ng/min, one dose per rat) were assessed in young (approximately 6 weeks of age) anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats acutely treated with captopril. Urinary excretion of cyclic adenosine monophosphate (cAMP) was also measured in these rats to examine whether Ang II has an enhanced ability to inhibit adenylate cyclase activity in SHR. Ang II (1 ng/min i.r.a.) significantly reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in SHR but not in WKY rats. At this dose, Ang II produced significant decreases in glomerular filtration rate (GFR), filtration fraction (FF), urine volume (UV) and urinary excretion of sodium (UNaV) and potassium (UkV) in SHR without altering any of these parameters in WKY rats. Ang II at either dose did not cause any increase in systemic blood pressure in either SHR or WKY rats. Ang II (3 ng/min i.r.a.) decreased RBF in both SHR and WKY rats to a similar extent. However, the higher dose of Ang II produced significant decrements in GFR, FF, UV, UNaV and fractional excretion of sodium in SHR but not in WKY rats. Also, Ang II at both the doses significantly decreased urinary cAMP excretion rate in SHR without affecting the same in WKY rats. These data demonstrate that, even during the developmental phase of hypertension, the SHR kidney is more responsive to Ang II as compared with the WKY rat kidney. Also, these results suggest that the ability of Ang II to inhibit renal adenylate cyclase activity in young SHR may be enhanced. The exaggerated renal reactivity to Ang II may be an important determinant of the development of hypertension in SHR.
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PMID:Angiotensin II: enhanced renal responsiveness in young genetically hypertensive rats. 775 79

This study examined the relationship between sleep apnea and beta 2-adrenergic receptor characteristics. Using standard polysomnography, individuals were classified as either apneic (n = 15) or mild to nonapneic (n = 15) according to their respiratory disturbance index (RDI). Subjects were similar in terms of sodium excretion and blood pressure. Apneic subjects showed a decrease in beta 2-adrenergic receptor sensitivity (p = 0.01) [as determined by isoproterenol-stimulated cyclic adenosine 5'-monophosphate (AMP) production in lymphocytes] and an increased binding affinity to the beta receptor antagonist [125I]iodopindolol (p < 0.001). beta receptor density was also diminished in apneics, but not significantly (p = 0.08). Forskolin-stimulated cyclic AMP was not significantly different between the groups, indicating a similarity in postreceptor Gs-adenylate cyclase activation. Across all subjects, RDI was negatively correlated with beta receptor sensitivity (r = -0.35, p = 0.05) and Kd (r = -0.54, p < 0.01) and positively correlated with systolic blood pressure (r = 0.37, p < 0.05). The findings indicate that sleep apnea is associated with a diminished beta 2-adrenergic receptor function but no change in postreceptor components and suggest a mechanism for the high comorbidity between sleep apnea and hypertension.
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PMID:Beta 2-adrenergic receptor characteristics in sleep apnea patients. 776 41

Adrenomedullin recently has been found to potently stimulate cAMP formation in cultured rat vascular smooth muscle cells (VSMCs). In the present study, we examined the effect of adrenomedullin on the production of a vasoconstrictive and growth-promoting peptide, endothelin-1, after stimulation with a clotting enzyme, thrombin, and a potent mitogen, platelet-derived growth factor (PDGF), in cultured rat VSMCs. Thrombin and PDGF stimulated endothelin-1 production in a dose-dependent manner. Rat adrenomedullin significantly inhibited thrombin- and PDGF-stimulated endothelin-1 production in a dose-dependent manner between 10(-7) and 10(-9) mol/L. Inhibition by rat adrenomedullin of thrombin- and PDGF-stimulated endothelin-1 production was paralleled by an increase in the cellular level of cAMP. Human adrenomedullin also inhibited thrombin- and PDGF-stimulated endothelin-1 production and increased cAMP levels. The addition of 8-bromo-cAMP, a cAMP analogue, reduced thrombin- and PDGF-induced endothelin-1 production. Furthermore, forskolin, a potent activator of adenylate cyclase, reduced thrombin- and PDGF-induced endothelin-1 production. In contrast, basal production of endothelin-1 was not altered by rat or human adrenomedullin. These results indicate that adrenomedullin inhibits not basal but thrombin- and PDGF-induced ET-1 production in cultured VSMCs probably through a cAMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may modulate vascular tone as a paracrine regulator partially through the inhibition of VSMC endothelin-1 production in some pathophysiological states.
Hypertension 1995 Jun
PMID:Inhibition of endothelin production by adrenomedullin in vascular smooth muscle cells. 776 61

We have previously reported a defect in the coupling of the renal dopamine-1 receptor (D1) to adenylate cyclase (AC) in the proximal convoluted tubule (PCT) of the spontaneously hypertensive rat (Okamoto-Aoki strain). To determine if this defect is present in another model of hypertension, we microdissected PCTs from Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats on low- or high-NaCl diet. The ability of two selective D1 agonists, fenoldopam and SND-919-C12, and forskolin to stimulate AC activity in PCT was determined in each of the four groups of rats. Fenoldopam (10(-7) M) and SND-919-C12 (10(-6) M) failed to stimulate AC activity in the PCT of DSS rats whether on a low- or high-NaCl diet. In DSR rats, however, both fenoldopam and SND-919-C12 stimulated AC activity by 289-320% and 220-270%, respectively, whether on a low- or high-NaCl intake. Forskolin (10(-5) M), which directly stimulates AC activity, increased AC activity in all four groups. These studies show that in DSS rats the D1 receptor in the PCT fails to respond to D1 agonists. This defect is not a consequence of the hypertension because it was present in the DSS rats on a low-salt diet and before blood pressure elevation.
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PMID:Dopamine-1 receptors in the proximal convoluted tubule of Dahl rats: defective coupling to adenylate cyclase. 784 Mar 26

This study examined the effects of ethnicity and hypertension on beta 2-adrenergic receptors and on plasma catecholamines in a group of 77 unmedicated mildly hypertensive and normotensive men. Black hypertensive subjects had the most sensitive and white hypertensive subjects the least sensitive beta-receptors (as assessed by isoproterenol-stimulated cyclic AMP in lymphocytes [P = .02]). In contrast, postreceptor adenylate cyclase activation (as assessed by forskolin stimulation) was similar among groups. As with beta-receptor sensitivity, black hypertensive subjects had the highest beta-receptor density and white hypertensive subjects the lowest (P = .03). Blacks demonstrated lower plasma epinephrine values compared with whites (P = .03). Across all subjects, plasma epinephrine was negatively correlated with beta-receptor density (r = -.26, P < .05) and sensitivity (r = -.25, P < .05). There were no group differences in binding affinity to the beta-antagonist iodopindolol. The findings support the notion of increased beta-adrenergic receptors in hypertension in blacks.
Hypertension 1995 Jan
PMID:Racial differences in epinephrine and beta 2-adrenergic receptors. 784 60

It is well-known that atherosclerotic change and hypertension are common manifestations in patients with glucocorticoid excess. We previously reported that pituitary adenylate cyclase activating polypeptide (PACAP), prostaglandin E2 (PGE2) and carbacyclin, a stable analog of prostacyclin, have suppressive effects on vasopressin-induced DNA synthesis of rat aortic smooth muscle cells through cAMP production (Murase et al., J. Hypertens., 10 (1992) 1505; Oiso et al., Biochem. Cell. Biol., 71 (1993) 156). In the present study, we investigated the effect of glucocorticoid on cAMP production induced by PACAP, PGE2 and carbacyclin in aortic smooth muscle cells. The pretreatment with dexamethasone significantly inhibited cAMP accumulation induced by these vasoactive agents in a dose dependent manner in the range between 10 pM and 10 nM. These inhibitory effects of dexamethasone were dependent on the time of pretreatment up to 8 h. Dexamethasone inhibited cAMP accumulation induced by NaF, a GTP-binding protein activator, and forskolin which directly activates adenylate cyclase. Moreover, forskolin-induced adenylate cyclase activity was significantly reduced in membranes prepared from the cells treated with dexamethasone. These results strongly suggest that glucocorticoid inhibits cAMP production induced by vasoactive agents in primary cultured rat aortic smooth muscle cells and the inhibitory effect is exerted at the level of adenylate cyclase.
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PMID:Glucocorticoid inhibits cAMP production induced by vasoactive agents in aortic smooth muscle cells. 785 72

Lymphocytes are widely used as a model for the cardiovascular beta-adrenoceptor-adenylate cyclase system. We evaluated the role of this system in the pathogenesis of hypertension by studying lymphocytes obtained from patients with essential hypertension. Untreated hypertensive patients and normotensive control subjects were studied. The number and affinity of the beta-adrenoceptors were measured by a radioligand binding method with 125I-cyanopindolol. The responses of cyclic adenosine monophosphate (cAMP) to isoproterenol, cholera toxin, and forskolin were also determined. The concentration and affinity of beta-adrenoceptors did not differ significantly in the two groups, nor was a significant difference found in the basal level of cAMP. The effects of isoproterenol on the accumulation of cAMP were reduced in the lymphocytes from the hypertensive compared with the normotensive subjects. There was no significant difference in the effect of forskolin on cAMP accumulation in the two groups. These results indicate that the activity of the stimulatory nucleotide binding regulatory protein (Gs-protein) is reduced in lymphocytes from patients with essential hypertension. This defect of Gs-protein in the lymphocytes may represent a defect of Gs-protein in the cardiovascular system in such patients.
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PMID:Deficient activity of stimulatory nucleotide-binding regulatory protein in lymphocytes from patients with essential hypertension. 798 61


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