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)

This study was undertaken in order to investigate the newly discovered spontaneously hypertensive rat (SHR)-specific restriction fragment length polymorphism (RFLP) at the genomic locus of (poly)phosphoinositide-specific phospholipase C (PLC)-delta at a DNA sequence level. Our aim was to clone the PLC-delta complimentary DNA (cDNA) from SHR and analyse the genomic DNA obtained from two hypertensive rat strains such as SHR and its stroke-prone substrain (SHR-SP) and three normotensive rat strains such as Sprague-Dawley, Donryu and Wistar-Kyoto (WKY) by preparing an aortic cDNA library of SHR, hybridization cloning of PLC-delta cDNA and an analysis of the genomic DNA by polymerase chain reaction. By digesting with restriction enzyme XhoI, we discovered an RFLP band displaying only in SHR and SHR-SP, not in Sprague-Dawley, Donryu and WKY rats. DNA sequencing of PLC-delta cDNA cloned from an aortic cDNA library of SHR revealed a total of three SHR-specific point mutations, two of which resulted in amino acid substitutions. The first point mutation (A to T) was detected at the XhoI site, changing a threonine(ACG) to a serine(TCG), and the second point mutation (A to G) was discovered in the vicinity of the first one, changing an isoleucine(ATA) to a methionine(ATG). This is the first demonstration of the mutations in the SHR genome changing amino acid sequences. These amino acid substitutions, situated in the putative catalytic X domain of PLC-delta, may be the major cause of the augmented PLC activity observed in the SHR, possibly leading to hypertension-related phenonemoma such as abnormal calcium homeostasis and increased intracellular calcium ion concentrations.
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PMID:Phospholipase C-delta gene of the spontaneously hypertensive rat harbors point mutations causing amino acid substitutions in a catalytic domain. 168 14

Membrane phospholipase C (PLC) activation is induced by the interaction of numerous vasoactive hormones and growth factors with their receptors. Two products are liberated: inositol triphosphate (IP3) and diacyglycerol (DG). The first product liberates intracellular calcium from its stores in the sarcoplasmic reticulum and the second one activates a phosphokinase, which triggers a transmembrane Na+/H+ exchange. A cascade of metabolic events secondary to these chemical changes impinges on the expression of nuclear proto-oncogenes, which determines cell growth. Studies conducted in spontaneously hypertensive rats (SHRs) have shown that PLC is hyperreactive to various agonists and that the phenomenon is present within a variety of cells, fibroblasts, platelets, and myocytes. Therefore, it is likely that hypertension in SHRs is characterized by a diffuse and intrinsic cellular defect that cannot be considered a consequence of the hemodynamic changes of hypertension. On the one hand, enhanced intracellular calcium mobilization may play a role in arterial tone and contraction whereas, on the other hand, enhanced activation of proto-oncogenes, myc, fos, and jun, may be involved in the mechanisms of arteriosclerosis. The pattern of an evolution towards arterial cell proliferation with acquisition of a secretory phenotype with collagen production was indeed observed in cultured cells from the arterial wall.
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PMID:Hypertension and atherosclerosis. 169 95

Endothelial cells can produce contracting factors; endothelin, a 21-amino acid peptide that can control local vascular tone, is the most potent of these factors. Of the three isoforms of endothelin, endothelial cells appear to release primarily endothelin-1. The peptide is formed from its precursor big endothelin via the activity of the endothelin converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and the calcium ionophore A23187. In vascular smooth muscle cells, endothelin binds to a specific receptor that activates phospholipase C and leads to the formation of inositol trisphosphate, diacylglycerol, and increased intracellular calcium levels. In certain blood vessels, the endothelin receptor is linked to a voltage-operated calcium channel via a Gi protein. This may explain why calcium antagonists inhibit endothelin-induced contractions only in certain blood vessels. In the human forearm circulation, calcium antagonists of different classes prevent endothelin-induced contractions. In hypertension, the circulating endothelin levels appear to be normal, whereas the vascular sensitivity to the peptide is reduced in most vascular tissues, but normal and enhanced responses have also been reported. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are augmented, a phenomenon that may be related to an increased formation of the peptide induced by modified forms of low-density lipoproteins.
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PMID:Endothelin. 172 99

It is reported that a defect in dopamine-1 (DA-1) receptor adenylate cyclase coupling in the proximal convoluted tubule in the spontaneously hypertensive rat may contribute to the diminished natriuretic response to DA-1 receptor agonists. Since the tubular DA-1 receptor is also coupled to phospholipase C, and both of these cellular signaling processes are involved in DA-1 receptor-mediated diuresis and natriuresis, it is important to know whether a similar defect is also present in DA-1 receptor-coupled phospholipase C pathway. The present study was therefore designed to determine the functional status of DA-1 receptor-phospholipase C coupling system of adult spontaneously hypertensive rats using a renal cortical slice preparation. In addition, the renal response to exogenously administered dopamine (1 microgram/kg/min i.v.) was also determined. We found that basal phospholipase C activity was significantly higher in hypertensive rats than in age-matched Wistar-Kyoto rats (7.36 +/- 0.32% versus 5.61 +/- 0.27%, p less than 0.05). However, compared with the normotensive controls, dopamine-induced increases in phospholipase C activity were significantly attenuated in the preparations of hypertensive rats in a concentration-dependent manner (13 +/- 6% versus 38 +/- 6% for 1 mM dopamine, p less than 0.05; 49 +/- 6% versus 71 +/- 9% for 3 mM dopamine, p less than 0.05; 50 +/- 16% versus 106 +/- 22%, p less than 0.05 for 10 mM dopamine).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jan
PMID:Diminished phospholipase C activation by dopamine in spontaneously hypertensive rats. 173 Apr 34

Essential hypertension is primarily hereditary. The property inherited is present in all cells but because of adaptation and differentiation it is particularly prominent in systemic vascular smooth muscle. This inherited property is manifested functionally as increased reactivity to vasoactive substances, such as (-)noradrenaline and angiotensin II. This abnormal function is present before the onset of hypertension. Vascular hypertrophy and hyperplasia are not only caused by hyperactivity of the smooth muscle and by the hypertension itself but are also trophic effect of the agonists, especially noradrenaline. The only two proteins in vascular smooth muscle which can produce both contractile and trophic effects are the guanosine triphosphate binding protein (Gs) and phospholipase C. Phospholipase C has already been demonstrated to be abnormally active in response to agonists in the spontaneously hypertensive rat and in human essential hypertension. The Gs protein is less likely to be critically abnormal since it is active in the vascular smooth muscle relaxation cascade as well as in contraction. None of the other proteins involved in vascular smooth muscle contraction or relaxation affect both contractile reactivity and cellular growth. There are many secondary effects dependent upon the phospholipase C abnormality such as calcium (Ca2+) cellular content, Ca2+ Mg2+ ATPase pump effects and possibly Ca2+ Na+ exchange. There are also many secondary effects impinging on the phospholipase C abnormality including changes in noradrenaline and angiotensin II metabolism. Present antihypertensive therapy is directed largely at secondary factors dependent upon or influencing the primary phospholipase C cascade. The path is now open for a more direct and basic diagnostic and therapeutic attack.
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PMID:The aetiology of essential hypertension. 177 Apr 74

Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.
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PMID:Tyrphostins inhibit PDGF-induced DNA synthesis and associated early events in smooth muscle cells. 185 Jan 95

The ability of angiotensin peptides to stimulate prostaglandin release and raise intracellular calcium levels by activating a phosphoinositide-specific phospholipase C was assessed in three human astrocytoma cell lines (CRTG3, STTG1, and WITG2). The addition of angiotensin II to CRTG3 cells resulted in a dose-dependent release of prostaglandin E2 and prostacyclin, the production of inositol 1,4,5-trisphosphate, and the mobilization of intracellular calcium. Angiotensin-(1-7), previously considered to be an inactive metabolite of angiotensin II, was as potent as angiotensin II for prostaglandin release but did not activate phospholipase C or mobilize intracellular calcium. In contrast, angiotensin-(2-8) caused only a slight increase in prostaglandin release, even though it was as effective as angiotensin II in augmenting inositol 1,4,5-trisphosphate production and calcium mobilization. Moreover, neither the release of prostaglandins in response to angiotensin II or angiotensin-(1-7) nor the mobilization of intracellular calcium in response to angiotensin II required extracellular calcium. Angiotensin II and angiotensin-(1-7) caused the release of prostaglandins from all three human astrocytoma cell lines, but changes in the level of intracellular calcium in response to angiotensin II only occurred in CRTG3 cells. Although previous studies have provided evidence for angiotensin receptor subtypes on the basis of selectivity of antagonists or signal transduction mechanisms, these data suggest that human astrocytes contain multiple angiotensin receptor subtypes on the basis of their response to different angiotensin heptapeptides--angiotensin-(1-7) and angiotensin-(2-8).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1991 Jul
PMID:Human astrocytes contain two distinct angiotensin receptor subtypes. 186 Jul 9

Release of endothelin-1, a novel potent vasoconstrictor peptide originally isolated from endothelial cells, from cultured bovine endothelial cells has been shown to be stimulated by arginine vasopressin and angiotensin II. To elucidate the cellular mechanism by which endothelin-1 is released by these vasoconstrictors, we tested the effects of several compounds on the agonist-induced endothelin-1 release and studied the changes of cytosolic free Ca2+ concentrations and phosphoinositide breakdown by these agonists in cultured bovine endothelial cells. Protein kinase C inhibitors (H-7, staurosporine), an intracellular Ca2+ chelator, and an inhibitor of phospholipase C (neomycin), all abolished the agonist-induced endothelin-1 release, whereas the Ca2+ channel blocker nicardipine was ineffective. Although synthetic 1,2-diglyceride (diolein) dose dependently stimulated endothelin-1 release, downregulation of protein kinase C after pretreatment with phorbol ester resulted in decreased effects to increase endothelin-1 release by the agonists. Both arginine vasopressin and angiotensin II induced immediate and transient increases in intracellular Ca2+ levels of fura-2-loaded endothelial cells as well as formation of inositol trisphosphate; the agonist-induced intracellular Ca2+ increases were not affected either by nicardipine or by chelating extracellular Ca2+. The arginine vasopressin- and angiotensin II-induced intracellular Ca2+ increases, inositol trisphosphate formation, and endothelin-1 release were completely abolished by V1-receptor antagonist and saralasin, respectively. It is concluded that arginine vasopressin and angiotensin II stimulate the release of endothelin-1 by a common mechanism, involving receptor-mediated mobilization of intracellular Ca2+ and activation of protein kinase C in endothelial cells.
Hypertension 1991 Aug
PMID:Cellular mechanism of endothelin-1 release by angiotensin and vasopressin. 190 4

When cultured in the presence of fetal calf serum, arterial smooth muscle cells from spontaneously hypertensive rats (SHR) proliferate more rapidly and are more numerous at confluency than cells from normotensive Wistar-Kyoto (WKY) animals. The phenomenon has been demonstrated in several laboratories but its molecular origin remains unclear. On the other hand phospholipase C activation and c-fos transcription are early events able to trigger cell mitosis. Therefore, the enhancement of inositol phosphates formation induced in SHR cells by various vasoactive agents and growth factors suggests that this enzyme might be implicated in the abnormal proliferation triggered by serum. In this case a unique molecular abnormality would be responsible for both arterial hypercontractility and dystrophy encountered in hypertension. In order to test this hypothesis we have compared DNA replication, phospholipase C activation, and c-jun and c-fos nuclear protooncogene transcriptions stimulated by fetal calf serum (FCS), vasoactive agents (angiotensin II and vasopressin), and epithelial growth factor (EGF) in SHR and WKY rat cells. The results obtained with these various agonists tested under the same experimental conditions confirm that the classical pathogenic diagram: (PLC hyperactivation----increase in c-fos transcription----enhanced cell proliferation) may apply to the action of vasoactive agents which are only slightly mitogenic on SHR cells, but not to the very important effect of fetal calf serum. Indeed, FCS stimulated inositol phosphate formation and c-jun and c-fos transcription, but none of these parameters was enhanced in SHR cells. Phospholipase C activation may exert some control upon DNA replication, as its partial inhibition by pertussis toxin coincided with an equivalent decrease in thymidine incorporation. It is, however, not absolutely required for the onset of DNA replication in aortic smooth muscle cells, as shown by the results obtained with EGF under the same experimental conditions. An abnormal molecular reaction different from PLC activation is therefore responsible for the enhanced proliferation of cultured SHR aortic smooth muscle cells, and several cell alterations may concur to the formation of the hypertensive arteriopathy.
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PMID:Hyperactivation of phospholipase C does not support the enhanced proliferation of aortic smooth muscle cells from spontaneously hypertensive rats. 193 Aug 47

Prostacyclin (PGI2) synthase is one of the key enzymes for vasodepressor PGI2 biosynthesis in the vascular wall. In this study, we attempted to define the alterations in PGI2 synthase and its role in the PGI2 generation in the vascular wall of deoxycorticosterone acetate (DOCA)-salt rats. The PGI2-generating capacity was enhanced significantly when DOCA-salt rats established hypertension, whereas the generation of other arachidonate metabolites, eg, PGE2, PGF2 alpha, and thromboxane, was unaltered. Moreover, the increase in PGI2 generation was associated with an increase in PGI2 synthase activity in the vascular wall. Indeed, the averaged PGI2 generating capacity was closely correlated to the averaged PGI2 synthase activity in DOCA-salt hypertensive rats and three lines of control rats. Incontrast, phospholipase C and phospholipase A2, both of which liberate arachidonate for PGI2 synthesis, were rather lowered in DOCA-salt hypertensive rats. These data clearly indicate that vascular PGI2 generation is increased in the development of DOCA-salt hypertension and that PGI2 synthase is mainly responsible for this enhancement. The increased PGI2 synthase may be relevant to the blood pressure elevation and is expected to have beneficial effects on the vascular protection in hypertension.
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PMID:Possible role of prostacyclin synthase in altered prostacyclin generation in DOCA-salt hypertensive rats. 193 Aug 48


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