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

Studies on the rats with genetically-controlled hypertension (spontaneously hypertensive rats, SHR) in which myocardiopathy had been produced by isoproterenol (ISP) administration (2 X 80 mg/kg sc daily for two days) have shown that the myocardiopathy results in a fall of the activity of adenylate cyclase (AC) lasting from the second to the fourth day after administration of ISP, while the activity of phosphodiesterase (PDE) remained unchanged. In vitro, ISP (10(-7)-10(-4)M), Mg2+ (4-25nM), GTP (10(-6)-10(-5)M) and GTP (10(-5)M) given in combination with ISP (10(-6)-10(-5)M) elevated the AC activity in the cardiac muscle of SHR similarly in controls and the rats with ISP-induced myocardiopathy. The results indicate that the depression of AC activity in the cardiac muscle of SHR following ISP-induced myocardiopathy is a result of reduction of the number of AC molecules rather than a consequence of the structural damage of AC.
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PMID:The activity of adenylate cyclase and phosphodiesterase in the isoproterenol-damaged cardiac muscle of spontaneously hypertensive rats. 631 39

In a plant producing vinyl chloride by the emulsion method 200 workers who were exposed to vinyl chloride for 1 to 25 yr (mean 14), 58 (i.e. 29%) were free of complaints and nervous disturbances. An astheno-autonomic syndrome was found in 54 (i.e. 27%) and in 88 (i.e. 44%) in combination with positive neurological findings, i.e. pyramidal syndromes (in 52), cerebellar disturbances (in 38), trigeminal neuropathy (in 24) and extrapyramidal symptoms (in 3), in various combinations - pyramidal + cerebellar in 12, trigeminal + pyramidal in 7, trigeminal + cerebellar in 5. Headaches (48%), nervousness (26%), decrease in physical strength (16%), loss of memory (14%), sleeping disturbances and somnolence were the most frequent complaints. Scleroderma-like skin changes were found in ten subjects, but only six of them had any neurological disturbances. Occupational exposure to vinyl chloride was lower in workers without neurological findings. Frequency of the arterial hypertension was the same in both groups, whereas acroparesthesias, Raynaud's syndrome, and increased gamma GTP serum activity were significantly more frequent in workers with neurological disturbances. Sixty-two per cent of the neurologically positive group and only 24% of the negative group reported euphoric or narcotic states after exposure. This probably indicates episodic exposures to high concentrations of vinyl chloride. This difference points to a possibility that neurological disturbances may be related to short exposures to peak concentrations. The neurological injury may be both a direct neurotoxic effect of vinyl chloride and secondary to vascular disorders.
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PMID:Vinyl chloride disease-neurological disturbances. 662 5

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

Guanylate cyclase-A, the receptor for atrial natriuretic factor, contains a protein kinase-like domain and a catalytic domain in the intracellular region. To investigate the active site (the catalytic cavity) of guanylate cyclase-A, we amplified the catalytic domain plus three amino acids from the kinase-like domain of guanylate cyclase-A (GC-c) with polymerase chain reaction (PCR) and expressed it in Escherichia coli. During the screening of the PCR-cloned gene products with guanylate cyclase assay, a mutant that lacks enzyme activity was identified. Results of cDNA sequencing revealed that Leu 817 was replaced by an Arg residue in the mutated protein. The mutated GC-c bound to GTP-agarose as well as the wild-type protein, indicating that the binding capability of mutated GC-c to GTP is not significantly affected by the Arg substitution. Gel-filtration column chromatography showed that, like the wild-type GC-c, the mutated protein also formed a high-molecular-weight complex. Since mutation of Leu 817 to Arg abolishes the catalytic activity, Leu 817 is likely located near the active site of guanylate cyclase-A. These results demonstrate that the carboxyl fragment of guanylate cyclase-A is an ideal system for studying the active site of guanylate cyclase-A.
Hypertension 1995 Apr
PMID:Mutational inactivation of the catalytic domain of guanylate cyclase-A receptor. 772 18

Angiotensin II type 1 (AT1) receptors have been identified in a wide variety of tissues, including the kidney, liver, adrenal gland, cardiovascular system, and brain. AT1 receptors also mediate complex signaling mechanisms that elicit a diversity of specific physiological effects. The rat AT1A receptor has seven transmembrane domains and couples with three distinct G proteins: Gq, Gi, and Go. But it is unknown which domains of AT1A couple with and activate each type of G protein. To identify the domains responsible for the activation of various types of G protein, we studied the effect of five different synthetic peptides representing different domains of cytosolic segments of the rat AT1A receptor on the binding of the 35S-labeled stable analogue of GTP, GTP gamma S. Peptides P-3, which is located in the N-terminal region of the putative third intracellular loop of AT1A (residues 216 through 230), and P-5 (residues 306 through 320), corresponding to the N-terminal region of the C-terminal tail, were found to activate purified Gi1, Gi2, and Go proteins. These results indicate that not only the third cytosolic loop but also the C-terminal cytosolic domain of AT1A is important for Gi1, Gi2, and Go protein coupling and activation.
Hypertension 1995 Apr
PMID:Mapping of G protein coupling sites of the angiotensin II type 1 receptor. 772 23

Adenosine triphosphate (ATP), a co-transmitter in sympathetic nerves and released from platelets, has recently been shown to stimulate growth of vascular smooth muscle cells. It might therefore contribute to the development of vascular hypertrophy seen in hypertension and atherosclerosis. We aimed at characterising the receptor mediating this mitogenic effect in rat aorta smooth muscle cells. The potency of agonists indicates a P2 purinoceptor since ATP > or = ADP >> AMP, adenosine. The P2x-receptor subtype, which is responsible for ATP induced vasoconstriction in rat aorta, does not mediate the mitogenic effect since alpha, beta-methyleneATP had no effect and beta, gamma-methyleneATP had lower potency than ATP. The P2Y-receptor subtype was excluded since the selective agonist 2-methylthioATP had weak effect with lower potency than ATP. When we studied the involvement of other nucleotides similar effects were seen of the purines ATP, GTP and ITP; also the pyrimidine UTP had powerful mitogenic effects (Emax = 52% of ATP) with similar potency. Nucleotides with fewer phosphate groups showed a stepwise fall in mitogenic effect. This indicates involvement of a nucleotide-receptor (P2U). Ap4A were of equal potency and effect as ATP. There was strong correlation between the mitogenic effects of the nucleotides and analogues with both 45Ca(2+)-influx and inositol phosphate (IP) production, indicating that they may participate in mediating the mitogenic response. This is the first study describing the potencies for the mitogenic effects of the selective ATP-analogues and other nucleotides in vascular smooth muscle cells. The receptor characterisation indicates a nucleotide-receptor similar to the receptor which stimulates 45Ca(2+)-influx and inositol phosphate-formation in rat aorta smooth muscle cells. Substances related to ATP such as GTP, ITP, UTP and Ap4A which also can be released extracellularly in vivo stimulate mitogenesis of rat aorta smooth muscle cells through the same receptor.
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PMID:Characterisation of an ATP receptor mediating mitogenesis in vascular smooth muscle cells. 778 5

The association of obesity and hypertension is well documented, and the combination is important as a coronary risk factor, but its non-pharmacological management is very difficult. Japanese hypertensive obese subjects (HO, n = 95) selected from 321 non-medicated obese subjects with a body mass index > 25 kg/m2 were characterized by the clinical features of significant diaphragmatic elevation, higher heart rate (HR), fasting blood glucose (FBS), total cholesterol (Tch), uric acid and gamma GTP values and lower vital capacity (VC) compared to those of normotensive-obese subjects (NO, n = 226) (p < 0.01). During a diet therapy program (about 1,200 kcal/day) for HO (n = 55), 25 subjects were treated with a non-drug-dependent pulse-synchronized transpercutaneous electric abdominal muscle stimulator (PEM) (ca. 30,000 muscle contractions/day) for 4 weeks. These subjects showed significant improvement with reduction in body weight (9.4%, 7.4 kg), intra-abdominal visceral fat (VF) CT scan area (29%), abdominal subcutaneous area (10%) at the level of the umbilicus, blood pressure (BP), HR, FBS, gamma GTP, Tch, plasma norepinephrine, plasma renin activity and plasma insulin, an increase of VC and lowering of the diaphragm (p < 0.05). The reductions in weight, BP, FBS and Tch in the diet group (n = 30, 1,200 kcal/day for 4 weeks) were smaller than those in the PEM-diet group (p < 0.05). The Japanese hypertensive obese patients had complications of many other coronary risk factors, and the reduction in weight and VF with PEM-diet therapy seems to be effective for improving these risk factors.
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PMID:Improvement of multiple coronary risk factors in obese hypertensives by reduction of intra-abdominal visceral fat. 789 17

Cardiac beta-adrenergic signal transduction was examined in chronic portal vein-stenosed rats. Basal tension and maximum rate of tension development were significantly depressed in left ventricular papillary muscles (0.21 +/- 0.03 N/cm2 and 8.2 +/- 1.7 N.s-1.cm-2, respectively) compared with sham-operated controls (0.51 +/- 0.05 N/cm2 and 19.9 +/- 4.4 N.s-1.cm-2, respectively). The positive inotropic response to isoproterenol was also attenuated. Adenosine 3',5'-cyclic monophosphate formation was decreased significantly when GTP (-41.9%), isoproterenol with GTP (-45.3%), or guanosine 5'-O-(3-thiotriphosphate) (-52.4%) was used to stimulate adenylyl cyclase, but not when Mn2+ or forskolin was used. Beta-Adrenoceptor density (sham operated 24.6 +/- 2.0 fmol/mg; portal vein stenosed 26.4 +/- 2.1 fmol/mg) and the apparent dissociation constant (sham operated 0.26 +/- 0.04 nM; portal vein stenosed 0.29 +/- 0.04 nM) were unaffected. Portal venous hypertension did not alter beta-adrenergic receptor affinity for isoproterenol. However, it was necessary for isoproterenol to occupy three times the number of receptors in papillary muscles from stenosed animals to produce an equal increase in force generation. These data suggest that although portal vein stenosis does not alter cardiac beta-adrenoceptor density or affinity for ligands, transduction of the signal between the receptor and adenylyl cyclase is adversely influenced and may be responsible for the diminished responsiveness of beta-adrenoceptors in the myocardium.
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PMID:Cardiac beta-adrenoceptor-effector coupling in portal vein-stenosed rats. 790 Aug 2

The Ca2+ responsiveness of vascular smooth muscle myofilaments is not unique: it is increased during neuro-humoral activation and decreased during beta-adrenergic stimulation. In this study we tested whether an augmented Ca2+ responsiveness of smooth muscle myofilaments may contribute to the increased coronary tone observed in hypertension using beta-escin-permeabilized coronary arteries from 3-mo-old stroke-prone spontaneously hypertensive rats (SHRSP) and their age matched normotensive reference strain (WKY rats). In intact coronary arteries, the response to 5-hydroxytryptamine (5-HT) but not to KCl was larger in SHRSP than in WKY rats. In beta-escin permeabilized coronary arteries in which the receptor effector coupling is still intact, 5-HT enhanced force at constant submaximal (Ca2+) (pCa 6.38) to a greater extent in SHRSP. The Ca2+ sensitizing effect of 5-HT was mimicked by GTP gamma S (0.01-10 microM); again this effect was larger in SHRSP. In the absence of 5-HT or GTP gamma S the Ca2+ force relation was similar in both groups. Forskolin induced relaxation at constant submaximal (Ca2+). This desensitizing effect was smaller in SHRSP than in WKY rats. In conclusion, this study shows that intracellular signalling pathways involved in modulating the Ca2+ responsiveness of coronary smooth muscle myofilaments are altered in the genetically hypertensive animals favoring a hypercontractile state in the coronary circulation.
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PMID:Augmented agonist-induced Ca(2+)-sensitization of coronary artery contraction in genetically hypertensive rats. Evidence for altered signal transduction in the coronary smooth muscle cells. 792 15

Enhanced sodium reabsorption by the kidney has a significant role in the development of genetic hypertension. In the spontaneously hypertensive rat (SHR) model of genetic hypertension, the enhanced sodium reabsorption likely arises from abnormal hormonal regulation of tubular transport. Since hormonal signaling pathways are coupled frequently via GTP binding proteins, one explanation for hormonal abnormalities in SHR would be a defect in a GTP binding protein or proteins. Recent work has suggested that the regulation of Na+,K(+)-ATPase activity by cholera toxin-sensitive GTP binding proteins is abnormal in SHR. The purpose of the present studies was to clone the alpha S-subunit, which is the subunit ADP ribosylated by cholera toxin, of GS protein to determine whether it is abnormal in SHR. Reverse transcription-polymerase chain reaction was able to detect mRNA for alpha S in both Wistar-Kyoto (WKY) rats and SHR. Northern analysis indicated that equivalent amounts of alpha S mRNA were present in WKY rats and SHR. S1 nuclease analysis demonstrated that there was no difference in the amount of alpha S short and long forms between WKY rats and SHR. Subcloning and sequencing of polymerase chain reaction products from WKY rats and SHR indicated that the alpha S forms present in renal cortex were identical. ADP ribosylation studies with cholera toxin demonstrated the presence of equivalent amounts of alpha S protein in WKY rats and SHR. Taken together, these results suggest that the abnormal regulation of Na+,K(+)-ATPase activity by a cholera toxin-sensitive pathway in SHR does not arise from a defect in the alpha S subunit.
Hypertension 1994 Nov
PMID:Cloning of the alpha-subunit of GS protein from spontaneously hypertensive rats. 796 19


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