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)

Platelets provide an accessible and homogeneous cellular system for investigative studies on hypertension. Hypertension-associated abnormalities of cyclic adenosine 3',5'-monophosphate (AMP) metabolism were studied in human platelets. Platelets from hypertensive subjects had an enhanced cyclic AMP accumulation response to prostaglandin E1 (twofold increase in prostaglandin E1 sensitivity). The degree of adenylate cyclase activation in response to both prostaglandin E1 (receptor-mediated) and forskolin (non-receptor-mediated) was greater in hypertensive than normotensive subjects, and prostaglandin E1-stimulated and forskolin-stimulated adenylate cyclase activity correlated directly (r = 0.71, p less than 0.001, n = 26). This finding suggests that the catalytic subunit of the enzyme is the rate-limiting step of this hormonal information transduction. Platelets from hypertensive subjects were more sensitive to epinephrine-induced inhibition of the stimulatory effects of prostaglandin E1 on both cyclic AMP accumulation (fourfold) and activation of cyclic AMP-dependent protein kinase. These findings suggest that the enhanced cyclic AMP metabolic response to prostaglandin E1 in platelets from subjects with established essential hypertension may function as a negative feedback mechanism to protect the cells against calcium overload and to reduce their stimulated participation in hemostatic and thrombotic processes.
Hypertension 1986 Aug
PMID:Enhanced platelet cyclic AMP response to prostaglandin E1 in essential hypertension. 301 95

It has been well documented that vascular smooth muscle (VSM) reactivity, as well as calcium sensitivity in response to neurotransmitters is increased in a number of blood vessels in established hypertension. Regulation of VSM reactivity involves the interaction of neurotransmitters and blood-borne hormones with specific receptors on target cell membranes. This results in phospholipase-C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and the generation of two second messengers: inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG) both of which act synergistically to produce muscle contraction. We will summarize recent findings in this review which suggest that in essentially hypertensive patients and spontaneously hypertensive rats (SHR), the activation of phospholipase C in response to hormones is increased. Further, we will discuss how increases in phospholipase C activation via GTP-binding proteins may explain the observed increases in Ca2+ influx through potential- and receptor-operated Ca2+ channels, increased activation of protein kinase-C and increased [Ca2+]i in hormone-stimulated blood platelets and VSM cells in the hypertensive state. In addition to these defects, a decrease in the plasma membrane Ca2+ pump and Ca2+-binding proteins has been demonstrated in hypertension. Thus, it appears that the defect in Ca2+ metabolism in the hypertensive vessels is multifocal. All these defects in Ca2+ metabolism together may lead to an increase in peripheral vascular resistance with a concomitant increase in blood pressure.
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PMID:Calcium and abnormal reactivity of vascular smooth muscle in hypertension. 314 41

The activity of protein kinase C and A was studied in the erythrocytes of patients with essential hypertension (EH) and in spontaneously hypertensive rats (SHR, Okamoto-Aoki strain). Protein kinase C activity was also studied in the erythrocytes of patients with hypertension of renal origin. Protein kinase C activity in the lysate of erythrocytes of patients with EH and in SHR was found to be increased 1.6-2.0-fold as compared to that in normotensive controls. No notable differences in protein kinase A activity were observed between hypertensive and normotensive groups. In erythrocytes of patients with renal hypertension, no notable changes in protein kinase C activity were revealed.
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PMID:Activity of protein kinase C in erythrocytes in primary hypertension. 323 34

Calcium-activated phospholipid-dependent protein kinase (protein kinase C) and cyclic AMP-dependent protein kinase (protein kinase A) were measured in tissue extracts of aortas from 7-, 14- and 20-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Protein kinase C and protein kinase A activity was significantly higher in 14- and 20-week-old SHR. Furthermore, protein kinase C and protein kinase A activity in the aorta was positively correlated with systolic blood pressure. Since protein kinase A is known to relax vascular smooth muscle, the observed increase in its activity may represent a compensatory mechanism to offset further elevation of blood pressure in SHR. These results suggest that protein kinase C in the aorta may play a role in the maintenance of hypertension in SHR.
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PMID:Possible involvement of protein kinase C in the maintenance of hypertension in spontaneously hypertensive rats. 324 Nov 91

Cadmium (Cd) produces injurious effects on reproductive function and has been implicated in the pathogeneses of hypertension. The present article summarizes available data on alterations in the cyclic AMP system of testicular and prostatic tissue as well as in catecholamine metabolism in adrenal glands following exposure to Cd and subsequent withdrawal. Daily Cd (1 mg/kg IP) for 45 days decreased prostatic and testicular weights of mature male rats. In prostate, chronic treatment with Cd reduced cyclic AMP levels to 57% of normal values which appeared to be due to the decrease in adenylate cyclase activity since cyclic AMP metabolism by phosphodiesterase was not significantly altered. Cyclic AMP binding to prostatic protein kinase was increased following Cd administration as was the activity of the cyclic AMP-dependent form of protein kinase. In contrast to the prostate, testicular adenylate cyclase was stimulated by Cd treatment. However, the endogenous cyclic AMP levels remained unaffected since the increase in testicular adenylate cyclase was offset by a concomitant increase in the activity of phosphodiesterase. Although the activities of the cyclic AMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cyclic AMP to protein kinase from testes of Cd-treated rats was not affected. Discontinuation of treatment for 28 days in rats that had previously been given the heavy metal for 45 days resulted in at least a partial reversal of several of the cadmium-induced changes in cyclic AMP metabolism of the rat prostate and testes. However, the weight of the prostate glands remained essentially in the same range as that seen in the "treated group."Data suggest that cyclic AMP metabolism in both the primary and the secondary reproductive organs is altered following chronic Cd treatment and that some changes persist even 28 days following the termination of daily exposure to the heavy metal.Cd treatment also increased adrenal weights and augmented the levels of adrenal norepinephrine and epinephrine as well as the activity of tyrosine hydroxylase. Discontinuation of the heavy metal treatment for 28 days, in rats previously injected with Cd for 45 days, restored the activity of tyrosine hydroxylase as well as the amount of norepinephrine and epinephrine. In contrast, adrenal weights were restored only partially following withdrawal of Cd treatment. Evidence indicates that the changes in adrenal catecholamine metabolism may be the result of stress induced by chronic exposure to this heavy metal. In addition, some of the untoward effects such as hyperglycemia and arterial hypertension seen during Cd toxicity might be related to increased synthesis of epinephrine in adrenal glands.
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PMID:Testicular cyclic nucleotide and adrenal catecholamine metabolism following chronic exposure to cadmium. 611 36

In order to define the alteration of the function of the adrenergic system in hypertension, we studied directly the receptor-cyclase coupling protein (N protein), which is one of the components of the enzyme adenylate cyclase. N protein was determined in erythrocyte membranes of patients with essential hypertension and normal subjects, with a complementation assay in vitro. Fifteen normal subjects and 18 patients with essential hypertension (eight untreated and ten treated with beta-adrenoreceptor blocking drugs alone or in combination with other antihypertensive drugs), and two patients with pseudohypoparathyroidism type Ia (known to have deficient N protein activity), were studied. Erythrocyte N protein activities in the various groups expressed as percentages of the means +/- SD of normals were: normal subjects 100 + 13.7, untreated hypertensive 108.9 +/- 20.4, treated hypertensive 104.3 +/- 11.3 and pseudohypoparathyroidism type Ia 43%. The difference between N protein activity in the hypertensive patients and normals was not statistically significant. We suggest that the molecular basis for the altered sympathetic responsiveness in essential hypertension may reside in other components of the cyclic AMP protein kinase effector system.
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PMID:Receptor-cyclase coupling protein in erythrocytes of patients with essential hypertension. 614 35

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were compared for phosphorylation-dephosphorylation mechanism(s) in aorta, caudal artery, inferior vena cava, and right and left ventricles. Reduction of cAMP-induced phosphorylation of microsomes and cAMP-dependent protein kinase activity was significant in the aorta and caudal artery of SHR compared with WKY. These changes were not observed in the vena cava of SHR. Phosphoprotein phosphatase activity was significantly increased (p less than 0.05) in the soluble fraction of arterial smooth muscle. No changes were observed, however, in the myocardium or vein. Furthermore, the extent of phosphorylation, and Ca2+ uptake ability and the protein kinase activity in the soluble and the microsomal fractions were not reduced in the myocardium of SHR compared with WKY. These data suggest that phosphorylation-dephosphorylation mechanisms are altered in the microsomal fraction of the aorta and caudal artery of SHR, which may result in reduced Ca2+ uptake by the intracellular organelle. The changes observed could have a significant effect on vasodilatation of arteries in the hypertensive state. The lesion appears specific to the arterial smooth muscle in the cardiovascular tissues.
Hypertension
PMID:Possible role of phosphorylation-dephosphorylation in the regulation of calcium metabolism in cardiovascular tissues of SHR. 624 68

PTH causes dose dependent transient vasodilatation in various vascular beds, specifically renal, coeliac, coronary, but not osseous. It has an acute dose-dependent hypotensive effect in the intact animal which is not mediated by alpha- or beta-adrenergic, cholinergic or histaminergic mechanisms. Aortic medial smooth muscle cells respond to PTH with an increase of cAMP, cGMP and, presumably via protein kinase, with activation of phosphorylase B kinase. The acute vasodilatory effect of PTH is antagonised by indomethacin and diclofenac as well as by ouabain, suggesting that the membrane Na-K pump and prostaglandins are involved in PTH-induced vasodilatation. Parathyroidectomy and a high calcium diet attenuate the rise of arterial pressure in experimental hypertension, pointing to some permissive effect of PTH for development hypertension. This is most likely due to long term effects of PTH on vessel wall calcium content and exchange. This chronic effect of PTH may explain the high prevalence of hypertension in patients with primary hyperparathyroidism.
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PMID:Vascular effects of parathyroid hormone (PTH). 675 27

Parathyroid hormone (PTH) has been implicated in hypertension, but PTH infusion results in vasodilation. PTH activates adenylate cyclase in vascular smooth muscle, but little is known about the factors that regulate PTH receptor/adenylate cyclase coupling in vascular cells. To characterize hormone-receptor signaling, we measured cyclic AMP levels in rat arterial smooth muscle cells in culture exposed to PTH (bovine 1-34). PTH yielded time- and concentration-dependent increases in cyclic AMP levels. Compared with isoproterenol, PTH was more potent, with a threshold at 2 x 10(-9) versus 5 x 10(-8) mol/L and half maximal responses at 10(-8) versus 2.4 x 10(-7) mol/L. PTH-induced increases in cyclic AMP were independent of extracellular calcium, cyclooxygenase metabolites, phospholipase C, and protein kinase C because PTH-induced increases in cyclic AMP were not prevented by variations in extracellular calcium, indomethacin, angiotensin II, vasopressin, and protein kinase C activators or inhibitors. PTH/adenylate cyclase coupling was G protein-dependent because increases in cyclic AMP were prevented by preincubation with cholera toxin but not with pertussis toxin. Prolonged exposure to PTH resulted in time- and concentration-dependent homologous desensitization of cyclic AMP responses. Desensitization occurred proximal to G protein/adenylate cyclase because after prolonged PTH, responses to forskolin and cholera toxin remained intact. Desensitization was independent of protein kinase A and receptor sequestration because cyclic AMP responses remained after prolonged exposure to forskolin and pretreatment with phenylarsine oxide, colchicine, and cytochalasin D. We conclude that in vascular smooth muscle cells, PTH is coupled to adenylate cyclase through a cholera toxin-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Apr
PMID:Parathyroid hormone/adenylate cyclase coupling in vascular smooth muscle cells. 751 68

Nitric oxide (NO) is an important molecular messenger accounting for endothelium-derived relaxing factor. Recently, NO synthase (NOS) from cultured endothelial cells has been purified and molecularly cloned. To evaluate the effect of phosphorylation by protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA) on endothelial constitutive NOS catalytic activity, we incubated purified endothelial NOS with PKC or PKA. Endothelial NOS was stoichiometrically phosphorylated by PKC and PKA. In intact bovine aortic endothelial cells (BAECs), NOS was phosphorylated by stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA). NOS activity measured by the conversion of [3H]arginine to [3H]citrulline in homogenates of BAECs treated with TPA or phorbol 12,13-dibutyrate was reduced by 30%, whereas dibutylyl cyclic AMP did not affect NOS activity. Moreover, we measured NO release from cultured BAECs by a chemiluminescence method to examine the effect of PKC and PKA on endothelial NOS activity. In cultured BAECs, ATP gamma S and A23187 induced NO release in time- and dose-dependent manners. Phorbol esters such as TPA and phorbol 12,13-dibutyrate dose dependently inhibited NO release stimulated by A23187 as well as ATP gamma S. Reduction of NO release by TPA was almost completely prevented by pretreatment with staurosporine, an inhibitor of PKC. NO release by A23187 was increased in PKC-downregulated BAECs. In contrast, dibutylyl cyclic AMP or 8-bromo cyclic GMP had no effect on NO release from BAECs induced by A23187 or ATP gamma S. These results indicate that phosphorylation of NOS by PKC is associated with a reduction of its catalytic activity in vascular endothelial cells.
Hypertension 1995 Feb
PMID:Inhibition of endothelial nitric oxide synthase activity by protein kinase C. 753 Nov 74


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