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)

Fifteen patients with Bartter's syndrome (hyponatremic hypochloremic hypokalemic metabolic alkalosis) were compared with 15 healthy volunteers. Red blood cell Na+/H+ and Cl-/HCO3- exchanges were enhanced in all patients with Bartter's syndrome. In calciuric normomagnesemic patients, sensitive to nonsteroidal anti-inflammatory drugs (classic Bartter's syndrome), red blood cell Na+,K+,2Cl- cotransport was markedly reduced, calcium-dependent K+ permeability was moderately increased, and up to 60% of sodium permeability was represented by cAMP-activated fraction (presumably human analog of beta-isoform of Na+/H+ exchange). In noncalciuric hypomagnesemic patients insensitive to indomethacin (Gitelman's syndrome), Na+,K+,2Cl- cotransport was enhanced, Na+ permeability was increased due to calmodulin-dependent fraction, and calcium-dependent K+ permeability was markedly enhanced. A new subtype of Bartter-like syndrome ("variant Bartter's syndrome") has been described in which calciuria, hypomagnesemia, and insensitivity to nonsteroidal anti-inflammatory drugs were associated with decreased Na+,K+,2Cl- cotransport, enhanced calmodulin-activated fraction of Na+ influx, and reduced calcium-dependent K+ permeability.
Hypertension 1997 Dec
PMID:Membrane ion transport in Bartter's syndrome: evidence for a new syndrome subtype. 940 50

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

In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal regulated kinase (ERK) activity in a pertussis toxin insensitive manner. This ERK activation was abolished by the Gq-associated phospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca2+ chelation by BAPTA-AM or TMB-8 abolished Ang II induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca2+ ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21(Ras), which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca2+-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK and that Ang II markedly induced its activation in a Ca2+/calmodulin-sensitive manner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21(Ras). These findings demonstrate that in cardiac fibroblasts, Ang II induced Ras/ERK activation is dominantly regulated by Gq-coupled Ca2+/calmodulin signaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II induced Ras/ERK pathway.
Hypertension 1998 Oct
PMID:Role of calcium-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II induced Ras/ERK signaling. 977 61

We investigated the role of calcium/calmodulin-dependent protein kinases in the phosphorylation of cyclic AMP response element binding protein and subsequent induction of c-fos gene elicited by sustained hypertension in neurons of the nucleus tractus solitarii of anesthetized rats. Activation of glutamate receptors in the nucleus tractus solitarii significantly increased the number of neurons that were immunoreactive to phosphorylated cyclic AMP response element binding protein and Fos protein. Microinjection bilaterally into the nucleus tractus solitarii of the calcium/calmodulin-dependent protein kinase inhibitor, 1-[N,O-bis(5-isoquinolinesulfonyl-N-methyl-L-tyrosyl]-4-phenylpiperazine , appreciably blunted such an increase. This inhibitor also attenuated the augmented immunoreactivity for phosphorylated cyclic AMP response element binding protein or Fos protein in the same nucleus induced by sustained hypertension. These results were comparable to those observed after blockade of either N-methyl-D-aspartate or non-N-methyl-D-aspartate ionotropic glutamate receptors in the nucleus tractus solitarii. Reverse transcription-polymerase chain reaction further indicated that the calcium/calmodulin-dependent protein kinase blocker attenuated the expression of Fos protein induced by sustained hypertension in the nucleus tractus solitarii by suppressing the transcription of c-fos messenger RNA. The present results suggest that activation of calcium/calmodulin-dependent protein kinases may represent an important step in the cascade of intracellular events that leads to phosphorylation of cyclic AMP response element binding protein and subsequent induction of c-fos gene after activation of ionotropic glutamate receptors by baroceptive signals in the nucleus tractus solitarii.
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PMID:Role of calcium/calmodulin-dependent protein kinases in expression of Fos protein in the nucleus tractus solitarii after sustained hypertension. 1061 71

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
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PMID:Calcineurin blockade prevents cardiac mitogen-activated protein kinase activation and hypertrophy in renovascular hypertension. 1101 40

Hypertension, the result of a sustained increase in vascular peripheral resistance, is partly due to vascular remodeling and increased vasoconstrictor sensitivity. Stimulation of heterotrimeric G-protein-coupled receptors by various contractile agonists activates intracellular signaling molecules to result in an increase in cytosolic Ca++ and the subsequent phosphorylation of myosin light chain by Ca++/calmodulin-dependent myosin light chain kinase. Additionally, a portion of alpha-adrenergic, serotonergic, and endothelin-1-induced contraction is partially mediated by the calcium-independent activation of the small G-protein RhoA and of a downstream target, Rho-kinase. Isolated arteries from hypertensive animals have been shown to have an increased contractile sensitivity to various agonists and to exhibit evidence of remodeling. Recent data suggest that some of these vascular changes may be mediated by increased activity of RhoA/Rho-kinase, potentially introducing a novel therapeutic approach for the treatment of hypertension.
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PMID:RhoA/Rho-kinase, vascular changes, and hypertension. 1127 96

The changes of activities of myosin light chain kinase (MLCK) and Ca2+/CaM-PP in different arterial vessels from hypertensive and normotensive rats were studied. The results were as follows. The MLCK activity of different arteries of spontaneous hypertensive rats (SHR) was different with the order of aorta (A) >> caudal artery (CA) >> mesenteric artery (MA), while in WKY rats the order of activity among different arteries is A << CA and MA and MA Ca2+/CaM-PP is obviously higher than in SHR. In renal hypertensive rats the activities of Ca2+/CaM-PP in different arteries are not quite different from those of the Wistar rats. The above results suggest that higher activities of MLCK or/and lower activity might be related to vasocontraction and hypertension.
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PMID:[Changes of activities of MLCK and dephosphatase in different arterial vessels from hypertensive rats]. 1132 22

The aim of this study was to evaluate the proliferative behavior of vascular smooth muscle cells in primary culture (pC-SMC) and the endothelial nitric oxide synthase (eNOS) activity in the endothelial lining of the aorta of fructose-fed rats (FFR). This is an experimental model of syndrome X, a cluster of cardiovascular risk factors including hyperinsulinemia, insulin resistance, and hypertension that has been suggested to be of pathophysiologic importance for the development of atherosclerosis. Male Wistar rats were used: Control (n = 12) and FFR (n = 12). After receiving fructose in drinking water (10% w/v) during 8 weeks, biochemical parameters, systolic blood pressure (SBP) and relative heart weight (RHW) were determined. The proliferative effect of 10% fetal calf serum (FCS) was examined in aortic pC-SMC by [3H]thymidine incorporation and by cell counting. Ca2+/calmodulin-dependent NOS activity was estimated in aortic endothelial lining and in heart tissue homogenates by conversion of [3H]arginine into [3H]citrulline. Fructose-fed rats showed hyperinsulinemia (P = .0263), altered glucose tolerance test (P < .001), higher SBP (P < .0001), and RHW (P = .0145), compared to control rats. These animals also showed an increase of 10% FCS-induced [3H]thymidine incorporation (P < .0001) and cell number of aortic pC-SMC (P = .0049) and decreased eNOS activity in both aortic endothelium (P = .0147) and cardiac tissue (P < .0001). These data support the hypothesis that syndrome X is associated to changes in SMC proliferation and endothelial dysfunction, which could be involved in the onset or progression of the atherogenic process.
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PMID:Aortic smooth muscle cell proliferation and endothelial nitric oxide synthase activity in fructose-fed rats. 1172 13

The spontaneously hypertensive rat (SHR) exhibits not only hypertension but also behavioral hyperactivity which are not genetically linked. Two strains of rats, one hypertensive but normoactive (WKHT) and another, hyperactive but normotensive (WKHA), have been generated from SHR. We have reported that in renal proximal tubules, the linkage between D1-like receptors an adenylyl cyclase was impaired in SHR and WKHT but intact in WKHA. The impaired renal D1-like receptor function in the SHR was associated with increased phosphorylation of the D1 receptor, presumably caused by increased phosphorylation by G protein-coupled receptor kinases (GRK) or decreased dephosphorylation by protein phosphatase 2A. Because calmodulin kinase (CaMK) can regulate GRK activity, CaMK activity in renal cortical membranes of WKHA and WKHT were studied. We found that CaMK-dependent phosphorylation was two-fold higher in WKHA than in WKHT. In addition, serine phosphorylation of a 36 KDa and a 24 KDa protein was 5-fold and 3-fold greater in WKHA than in WKHT. We hypothesize that the increased CaMK activity in the renal cortical membrane may serve to inhibit GRK activity in WKHA and prevent the development of hypertension.
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PMID:Elevated renal cortical calmodulin-dependent protein kinase activity and blood pressure. 1206 59

Cardiac hypertrophy is induced by a variety of diseases, such as hypertension, valvular diseases, myocardial infarction, and endocrine disorders. Although cardiac hypertrophy may initially be a beneficial response that normalizes wall stress and maintains normal cardiac function, prolonged hypertrophy is a leading cause of heart failure and sudden death. A number of studies have elucidated molecules responsible for the development of cardiac hypertrophy, including the mitogen-activated protein (MAP) kinases pathway, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and calcium/calmodulin-dependent protein phosphatase calcineurin pathway. These molecules may be targets for therapies designed to prevent the progression of cardiac hypertrophy. Numerous studies have focused on characterization of the intracellular signal transduction molecules that promote cardiac hypertrophy in order to clarify the molecular mechanisms, but there have been only a few reports on the inhibitory regulators of hypertrophic response. Recently, several molecules have attracted much attention as endogenous inhibitory regulators of cardiac hypertrophy. Enhancement of these inhibitory regulators would also seem to be a potential approach for the pharmacological treatment of hypertrophy. In this review, we summarize the inhibitory molecules of cardiac hypertrophy.
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PMID:Inhibitory molecules in signal transduction pathways of cardiac hypertrophy. 1235 32


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