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)

Functional modifications, such as a reduction in hormonal response, which occur in the cardiovascular system in hypertension, are reflected at the cellular level by anomalies in cyclic nucleotide and other messenger systems. To distinguish between primary and adaptive abnormalities, we pursued three research strategies. (i) Investigations on various models of hypertension. To be considered a primary defect, an abnormality should also be present in other genetically hypertensive models. Indeed, we have confirmed the occurrence of cellular hyperplasia in the heart of spontaneously hypertensive rats (SHR) as well as in spontaneously hypertensive mice (SHM). An increase of calmodulin levels in the heart and kidney is also observed in both the SHR and SHM. (ii) Studies on the evolution of hypertension with age. In humans, a decrease of cAMP levels in response to beta-adrenergic stimulation in older patients is contrasted with an excess in younger subjects. In the SHR, protein kinase activity of the heart is lower in the prehypertensive stages, whereas this defect appears much later in the aorta. (iii) Experiments on anomalies in newborns and cultured cells. The heart and kidney in the SHR exhibit significant hyperplasia at birth, and an abnormal growth continues in tissue culture. We hope that these strategies will eventually help to provide biochemical and functional markers for genetic analysis of factors which may be involved in the pathogenesis of hypertension.
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PMID:Primary versus secondary events in hypertension. 298 25

Nisoldipine is a calcium antagonist that specifically blocks the slow or voltage-dependent calcium channel up to the highest concentrations. This mode of action has been confirmed in pharmacological studies on isolated organs, electrophysiological and binding studies, and by the measurement of transmembrane calcium transport. As with other dihydropyridine calcium antagonists, an interaction with intracellular calcium reservoirs and calmodulin seems to be of minor importance. The drug exhibits higher potency, longer duration of action, and a higher binding affinity in vitro and in vivo than nifedipine. In contrast to its vasodilating and spasmolytic activity, its negative inotropic effect occurs in vitro only after higher concentrations than after nifedipine. In whole animals a secondary positive inotropic effect occurs regularly owing to sympathetic counter-regulation. The influence of nisoldipine on cardiac stimulus formation and conduction is also very slight in anesthetized animals, and is completely eliminated in awake animals and humans by counter-regulation up to very high doses. The cardiac anti-ischemic action of nisoldipine has been demonstrated in various ischemia models and is probably based predominantly on its afterload-reducing properties in addition to its spasmolytic effect on the coronary arteries. Various other suspected effects, for which there are isolated indications, e.g., inhibition of thromboxane synthesis, preload reduction, interaction with the transport of adenosine, and normalization of the sarcolemmal Na+, K(+)-ATPase activity, are probably of subordinate importance. Its antihypertensive effect is explained primarily by lowering of the peripheral resistance. There are, however, some indications that nisoldipine exerts certain effects over and above pure vasodilation. The prevention of postischemic calcium overloading in the renal tubule epithelium and the natriuretic effect are probably of importance in the therapeutic action. Clinically, nisoldipine was found more potent and prolonged in its action in comparison with nifedipine. In comparative studies, nisoldipine, 10 mg once a day, was found equieffective with nifedipine 10 mg three times or 20 mg twice a day in angina or hypertension, respectively.
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PMID:The pharmacology of nisoldipine. 315 74

Previous studies showed that erythrocytes from the Milan hypertensive strain of rats (MHS) are smaller and have a faster Na-K cotransport when compared with their normotensive controls (MNS). These characteristics are determined within the stem cell, are genetically associated with hypertension and are similar to other renal tubular cell abnormalities more directly involved in the development of hypertension in MHS. The difference in volume is maintained in ghost membranes, while the difference in transport is abolished in inside-out vesicles. Ghosts and cytoskeletons contain a 105-kilodalton protein already characterized by immunoblotting. This protein has been identified with erythrocyte adducin by several criteria, including binding to calmodulin and protein kinase C, phosphorylation and full immunological cross-reactivity with human adducin. Since only MHS rats immunized with MNS erythrocyte cytoskeletons produce anti-adducin antibodies, we suggest an immunogenic structural difference in adducin from the two strains, and an involvement of this difference in the alteration of Na-K cotransport observed.
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PMID:Characterization of erythrocyte adducin from the Milan hypertensive strain of rats. 324 Dec

This study was designed to investigate the role of protein kinase C and calmodulin in adrenergic transmission in hypertension. In isolated mesenteric vasculature prepared from spontaneously hypertensive rats (SHR, Okamoto and Aoki strain) and age-matched Wistar-Kyoto rats (WKY), we examined the effects of protein kinase C inhibitor (H-7) and calmodulin antagonist (W-7) on pressor responses and noradrenaline release from the vascular adrenergic neurons. Endogenous noradrenaline release and vasoconstrictor responses evoked by periarterial nerve stimulation were significantly enhanced in SHR compared to those in age-matched WKY. Protein kinase C inhibitor H-7 and the calmodulin antagonist W-7 inhibited the stimulation-evoked noradrenaline release and pressor responses, respectively, in a dose-dependent manner. Further, these inhibitory effects of H-7 and W-7 were greater in SHR than in WKY. These results demonstrate that noradrenaline release and vascular responsiveness are increased in the mesenteric vasculatures of SHR. The marked reduction in noradrenaline release and pressor responses induced by H-7 and W-7 in SHR suggests the presence of enhanced protein kinase C-dependent and calmodulin-dependent regulation of adrenergic neurotransmission, which may contribute to the calcium abnormalities in this model of hypertension.
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PMID:Protein kinase C-dependent and calmodulin-dependent regulation of neurotransmitter release and vascular responsiveness in spontaneously hypertensive rats. 324 Dec 55

Several alterations in membrane transport systems are observed in rat and human hypertension. Na+ flux changes are numerous, and cellular homeostasis to Na+ loading is impaired. Transmembrane Ca2+ movements are also numerous but clearly defined by a reduction in Ca2+ binders, a hypersensitivity of membrane phospholipase C, possible increased Ca2+ leak and reduced sensitivity of the Ca2+-pump to calmodulin. The resulting Ca2+ increase within arterial cells can be responsible for increased contractility and tone, leading to hypertension. These functional alterations in membrane transport can be secondary to a few well-defined membrane defects of genetic origin or to a diffuse structural perturbation in membranes involving lipid changes.
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PMID:Cell membrane in hypertension. 328 57

Using fluorescent calcium indicator quin2, we studied intracellular free calcium concentration in platelets that have a number of features similar to vascular smooth muscle cells. Intracellular free calcium concentration in platelets of male SHR was significantly higher at 4, 11 and 28 weeks old compared with age-matched male WKY. However, no significant difference was observed in platelets cytosolic free calcium level of DOCA-salt hypertensive and two-kidney, one clip hypertensive rats in the chronic stage. Cardiac Ca++ channels were estimated by means of radioligand binding method with [3H]-nimodipine. No significant changes were observed in the concentration and affinity of cardiac Ca++ channel in SHR, DOCA-salt hypertensive and two-kidney, one clip hypertensive rats. Calmodulin levels in mesenteric arteries of SHR were significantly decreased in comparison with those of WKY. However no significant differences were observed in DOCA-salt hypertensive rats in the chronic stage. These results indicate that the increase in intracellular free calcium concentration of SHR is not the secondary change caused by high blood pressure. It is impossible to detect the ratio of the three states (open, resting and inactivated) of Ca++ channel. Therefore, there remains a possibility of the changes in the ratio of the states of Ca++ channel. The observed abnormalities of Ca++ regulation may contribute to the pathogenesis of hypertension.
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PMID:Intracellular free calcium concentration, Ca++ channel and calmodulin level in experimental hypertension in rats. 343 Jun 91

Whether maintenance of normal calcium homeostasis can afford protection against the development of hypertension in humans has emerged as a controversial area of both clinical and basic cardiovascular disease research. The data that have provoked this debate are derived from epidemiological reports, human studies, animal investigations, and cellular research. Ten published reports have identified an association between greater dietary calcium consumption and lower blood pressure in humans. In both humans and experimental animals with hypertension, several end-organ defects have been identified that are consistent with an inability to maintain external calcium balance. With the provision of supplemental dietary calcium, both humans and experimental models with high blood pressure have reduced their blood pressure. A variety of membrane-associated defects of Ca2+-ATPase-dependent calcium transport have been identified in cells derived from multiple organs of both the hypertensive animal and human. These abnormalities of cellular calcium handling could account for the failure of the hypertensive subject to appropriately defend its calcium balance. More important, they provide a theoretical mechanism by which calcium, interacting with calmodulin, might favorably modify vascular smooth muscle function and, thereby, peripheral vascular resistance.
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PMID:Metabolic considerations and cellular mechanism related to calcium's antihypertensive effects. 353 38

Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with food admixed, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)-1- piperazinyl]methyl)isoquinoline (Ro 22-4839), a novel cerebral circulation improver, for a period of 15 weeks starting from 5 weeks of age at an average daily dose of 30.6 or 66.0 mg/kg. As compared with normotensive Wistar Kyoto rats, SHRSP in the control group rapidly developed severe hypertension (244 mmHg at the end of the experiments) accompanied with deterioration of cardiovascular parameters including left ventricular hypertrophy, reduction in pumping ability and increase in peripheral vascular tone. At 20 weeks of age (i.e. at the end of experiments), 75% of SHRSP developed stroke signs and concomitant cerebral edema evidenced by the increases in water and sodium contents in the brain. These stroke symptoms were accompanied with a profound externalized shape change of erythrocytes after in vitro treatment with Ca2+ and ionophore A23187, an increased plasma level of thiobarbituric acid reacting substance (TBARS), a measure of lipid peroxides, and a decreased sensitivity of platelets to ADP. The long-term treatment with Ro 22-4839 prevented the progress of stroke and cerebral edema, although the deteriorated cardiovascular parameters were not prevented by the treatment. This compound was also found to prevent the hypersusceptibility of erythrocyte membrane to Ca2+-ionophore and Ca2+, the hypoaggregability of platelets and the elevated plasma TBARS in SHRSP. These results indicate that the beneficial effects of Ro 22-4839 in SHRSP may be attributable to its calmodulin antagonistic and anti-lipid peroxidative actions but not to its hypotensive action.
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PMID:Preventive effects of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)- 1-piperazinyl]methyl)isoquinoline on stroke symptoms in stroke-prone spontaneously hypertensive rats. 367 71

Calcium ion (Ca++) serves an important role as an activation messenger; it initiates or regulates key cellular processes including contraction in the heart and vascular smooth muscle. Ca++ acts as both an electrical and a chemical signal. Upon entering the cell, the positively charged Ca++ carries an inward (depolarizing) current that contributes to pacemaker activity in the sinoatrial node and to atrioventricular conduction. Ca++ also binds to anionic surfaces of cell membranes and to anionic groups of both extracellular and intracellular proteins. The intracellular calcium-binding proteins include troponin and calmodulin, which when bound to Ca++ initiate contraction in cardiac and smooth muscles, respectively. Calcium channel blockers inhibit the entry of calcium into the cell, and thus prevent calcium from gaining access to the high-affinity, intracellular calcium-binding proteins. Verapamil and diltiazem decrease myocardial contractility and inhibit smooth muscle tone, while the dihydropyridines are mainly vasodilators. All of these drugs can play an important role in the treatment of hypertension.
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PMID:Mechanisms of action and differences in calcium channel blockers. 376 7

To investigate the Ca-sensitivity of the erythrocyte membrane in hypertension, the changes of the osmotic fragility of erythrocytes by Ca-loading and the effects of Ca-channel blockers or calmodulin-antagonist were observed in patients with essential hypertension. Erythrocytes were obtained from untreated patients with essential hypertension and age-matched normotensive subjects. Treatment of erythrocytes with Ca-ionophore A23187 and Ca in bathing medium caused the reduction of the osmotic fragility of erythrocytes dose-dependently on Ca-concentration. The degree in alteration of the osmotic fragility of erythrocytes was greater in essential hypertension than that in normotensive controls. In addition, Ca-induced changes of erythrocyte osmotic fragility was inversely correlated with the plasma renin activity in essential hypertension. In the presence of Ca-antagonists (verapamil, diltiazem) or calmodulin-antagonist (trifluoperazine), the reduction of the osmotic fragility of erythrocytes by Ca-loading was inhibited, and the differences of the osmotic fragility of erythrocytes between the hypertensives and the normotensive controls were abolished by these drugs. These results suggest that the greater changes of the osmotic fragility of the erythrocytes by Ca-loading in essential hypertension might be due to the abnormality of Ca-handling of the cell membranes causing an increase in the intracellular Ca concentration, contributing at least partially to the pathogenesis of hypertension.
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PMID:Enhanced calcium-sensitivity of erythrocytes in hypertension--calcium-induced changes of erythrocyte osmotic fragility in essential hypertension. 382 May 28


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