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)

The relationship between lymph flow and intestinal secretion was studied in an isolated, vascularly perfused cat ileal preparation in which secretion was caused by three different means: 1) plasma dilution from a constant infusion of Tyrode solution (2.5 ml/min per kg), 2) elevation of intestinal venous pressure to 30 mmHg, and 3) exposure to cholera toxin. In the plasma-dilution group, lymph flow attained a peak value of 38 times control at 60-90 min following the onset of the infusion, after which time lymph flow progressively decreased. Concomitant to the rapid decrease in lymph flow was a rapid increase in intestinal secretion (filtration secretion). A similar pattern, i.e., a rapid increase in lymph flow followed by a progressive decrease in lymph flow and concomitant increase in filtration secretion, was observed in the venous hypertension group; however, peak lymph flow (20 X control) was observed within 10 min of the pertubation. No correlation between the onset of intestinal secretion and a decline in lymph flow was observed in the cholera toxin group.
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PMID:Interactions of intestinal lymph flow and secretion. 83 98

The effects of several 5-hydroxytryptamine (5-HT) receptor antagonists were tested in rats in vivo on the intestinal fluid secretion evoked by cholera toxin. Five receptor antagonists were used, namely 2-bromolysergic acid diethylamine (2-bromo-LSD), granisetron, ketanserin, methysergide and ondansetron. The drugs were used in doses that inhibited the arterial hypertension and/or bradycardia evoked by 5-HT given i.v. Granisetron and ondansetron markedly diminished cholera-toxin-evoked secretion, whereas ketanserin was without any effect. Methysergide also diminished cholera-toxin-induced fluid secretion particularly when the drug was given as an i.v. infusion. The results are considered in relation to the pathophysiology of cholera secretion and to the current views of receptor subtypes for 5-HT. It is proposed that the receptor involved is a 5-HT3 receptor, possibly also a receptor of the 5-HT1 type. Results from experiments in which 5-HT (20 mM) was placed in the intestinal lumen to evoke an intestinal secretion suggest that the 5-HT3 receptor is located in the villus tissue. It was also demonstrated that zimeldine, an inhibitor of presynaptic 5-HT reuptake, diminished choleraic secretion, an effect that may be ascribed to a 5-HT tachyphylaxis caused by an accumulation of 5-HT in a synaptic cleft.
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PMID:Actions of serotonin antagonists on cholera-toxin-induced intestinal fluid secretion. 135 26

We have previously shown that the stimulatory effects of guanine nucleotides, N-ethylcarboxamide-adenosine and other agonists on adenylate cyclase activity were diminished in aorta and heart sarcolemma of spontaneously hypertensive rats (SHR) [Anand-Srivastava (1988) Biochem. Pharmacol. 37, 3017-3022]. In the present studies, we have examined whether the decreased response of these agonists is due to the defective GTP-binding proteins (G-proteins) which couple the receptors to adenylate cyclase, and have therefore measured the levels of G-proteins in aorta and heart from SHR and their respective Wistar-Kyoto (WKY) controls by using pertussis toxin (PT)- and cholera toxin (CT)-catalysed ADP-ribosylations and immunoblotting techniques using specific antibodies against G-proteins. The labelling with [32P]NAD+ and PT identified a 40/41 kDa protein in heart and aorta from WKY and SHR and was significantly increased in the hearts (approximately 100%) and aorta (approximately 30-40%), from SHR as compared with WKY. Immunoblotting revealed an increase in the levels of the G-protein alpha-subunits Gi alpha-2 and Gi alpha-3 in heart and Gi alpha-2 in aorta, whereas no change in Go alpha was observed in heart from SHR and WKY. On the other hand, no differences were observed in CT labelling or immunoblotting of stimulatory G-protein (Gs) in heart and aorta from WKY and SHR. In addition, CT stimulated the adenylate cyclase activity in heart sarcolemma from WKY and SHR to a similar extent. These results were correlated with adenylate cyclase inhibition and stimulation by various hormones. Angiotensin II (AII), atrial natriuretic factor (ANF) and oxotremorine-mediated inhibition was found to be greater in SHR as compared with WKY, whereas the stimulatory effects of adrenaline, isoprenaline, dopamine and forskolin were diminished in SHR aorta as compared to WKY. These results indicate that regulatory protein G(i) is more expressed in SHR, which may be associated with the decreased responsiveness of stimulatory hormones and increased sensitivity of inhibitory hormones to stimulate/inhibit adenylate cyclase activity. It may thus be suggested that the enhanced G(i) activity may be one of the mechanisms responsible for the diminished vascular tone and impaired myocardial functions in hypertension.
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PMID:Enhanced expression of inhibitory guanine nucleotide regulatory protein in spontaneously hypertensive rats. Relationship to adenylate cyclase inhibition. 144 83

Systemic infusion of angiotensin II, a potent agonist, using doses that are initially subpressor, eventually produces sustained blood pressure elevation and reductions in glomerular capillary ultrafiltration coefficient characterized by enhanced signal transduction to angiotensin II and other agonists. In this setting, there is a significant increased affinity of angiotensin II binding to smooth muscle and glomerular mesangial receptors and enhanced sensitivity and magnitude of angiotensin II-induced decrements in cyclic AMP. Since G proteins are important modulators of binding and signal transduction, the present studies were designed to test the hypothesis that differences in the relative amounts of G proteins may be present and have accounted for differences observed. G proteins were identified and quantitated by isoelectric focusing/sodium dodecyl sulfate-polyacrylamide gel electrophoresis, radiolabeling in the presence of activated toxins with [gamma-32P]NAD+, immunoprecipitation, and immunoblotting. A 168% and 465% increase in pertussis toxin-catalyzed ADP ribosylation of alpha 40-41 was found in angiotensin II-treated groups over control groups for glomerular and mesenteric membranes, respectively. Immunoblotting revealed a 250% and 35% increase in the levels of the Gi isoforms alpha i-2 and alpha i-3, respectively, and a decrease of 53% in alpha i-1 from the angiotensin II-treated group. No differences were observed in cholera toxin labeling or immunoblotting of Gs. These results demonstrate multiple mechanisms whereby angiotensin-induced signal transduction can be modulated involving both the receptors and G proteins. These observed differences in G proteins in systemic and renal vasculature accompanying angiotensin II infusion suggest the possibility of a regulatory role in the pathophysiology of angiotensin II-induced hypertension and renal disease.
Hypertension 1992 Feb
PMID:Angiotensin II-induced changes in guanine nucleotide binding and regulatory proteins. 173 48

The effect of glucocorticoids on the dopamine (DA)-mediated cyclic adenosine monophosphate (cAMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from renal arteries of 14-week-old Wistar-Kyoto rats by explant method. Micromolar concentrations of dexamethasone (DEX) pretreatment for 48 hours potentiated DA-mediated response without any change of affinity constant. However, micromolar concentrations of aldosterone pretreatment for 48 hours had almost no effect on DA-mediated response. The DEX-induced facilitation began at 6 hours and reached maximum at 24 hours after DEX administration in a dose-dependent manner. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEX-treated cells was twofold higher than that in control cells. Treatment of VSMC with DEX increased cholera toxin-stimulated and forskolin-stimulated adenylate cyclase activity. However, pertussis toxin treatment did not augment or reduce the effect of DEX treatment. These results suggest that glucocorticoids increase DA-mediated cAMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis and that the activation of the catalytic unit may play some role in this facilitation.
Hypertension 1989 Jun
PMID:Glucocorticoids and dopamine-1 receptors on vascular smooth muscle cells. 247 57

The natriuretic effects of atrial peptide hormones have been attributed, at least in part, to their stimulation of guanylate cyclase activity in renal cell membranes. The effects of atrial natriuretic factor (ANF) on stimulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation were investigated in cloned human kidney tumor (hKT) cells and parent cells from a human renal tumor epithelial cell line (SK-NEP-1). Human ANF-(99-126) (10(-6)M) stimulated (p less than 0.001) cellular cGMP accumulation in a dose-dependent manner from a basal level of 0.26 +/- 0.04 to 3.73 +/- 0.81 pmol/mg protein/5 mi (mean +/- SEM, n = 13). ANF stimulation of cGMP accumulation was specific, in that high concentrations (10(-6)M) of atriopeptin I [rat ANF-(103-123)], angiotensin II, arginine vasopressin, and amiloride (10(-4)M) did not increase basal cGMP. Amiloride (10(-4)M) enhanced (p less than 0.01, n = 6) the ANF stimulation of cGMP accumulation (1.24 +/- 0.39 pmol/mg protein/5 min), particularly at low doses of ANF (10(-10)M) where stimulation by ANF without amiloride (0.34 +/- 0.08 pmol/mg protein/5 min) was barely distinguishable from a basal level (0.19 +/- 0.02 pmol/mg protein/5 min) of cGMP accumulation. The stimulatory effect of ANF (1.59 +/- 0.07 pmol/mg protein/5 min) was attenuated (0.75 +/- 0.06 pmol/mg protein/5 min, p less than 0.01, n = 6) by preincubation of the cells with pertussis toxin but not by cholera toxin. ANF (4.56 +/- 0.93 pmol/mg protein/5 min, n = 8) did not affect cAMP accumulation (4.32 +/- 0.98 pmol/mg protein/5 min) in hKT cells. This is the first report of an ANF responsive human renal cell line, and its use should facilitate investigation of ANF-receptor interactions.
Hypertension 1989 Jun
PMID:Atrial natriuretic factor effects on cyclic nucleotides in a human renal cell line. 256 5

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

Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired beta-adrenergic-mediated vasodilation and reduced lymphocyte beta-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin-mediated [32P]ADP ribosylation and, in hypertensive subjects, with alpha s-specific and beta-subunit antisera, and (3) inhibitory G proteins by pertussis toxin-mediated [32P]ADP ribosylation and, in older subjects, with alpha i,1,2- and beta-subunit-specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride-stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride-stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin-mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin-mediated labeling was not altered; however, pertussis toxin-mediated labelling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins.
Hypertension 1995 Nov
PMID:G protein alterations in hypertension and aging. 759 Oct 10

Regulation of HCO3- and Cl- absorption by arginine vasopressin (AVP) and prostaglandin E2 (PGE2) was examined in isolated, perfused medullary thick ascending limbs (MTAL) from 4- to 7-wk-old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. AVP inhibited HCO3- absorption by 50% at 10(-10) M and by 25% at 2 x 10(-12) M in MTAL from both WKY and SHR. Cholera toxin (10(-9) M) or forskolin (10(-6) M) in the bath also inhibited HCO3- absorption by 50% in the SHR. In MTAL from WKY, PGE2 (10(-6) M in the bath) increased HCO3- absorption from 7.1 +/- 0.4 to 12.0 +/- 0.4 pmol.min-1.mm-1 (P < 0.005) and decreased Cl- absorption from 65 +/- 7 to 47 +/- 6 pmol.min-1.mm-1 (P < 0.001) in the presence of 10(-10) M AVP. Under the same conditions, PGE2 had no effect on HCO3- or Cl- absorption in MTAL from SHR. PGE2 also reversed submaximal inhibition of HCO3- absorption by 2 x 10(-12) M AVP in WKY but not in SHR. With 10(-10) M AVP in the bath, phorbol 12-myristate 13-acetate (10(-6) M in the bath) increased HCO3- absorption from 6.6 +/- 0.5 to 12.3 +/- 0.4 pmol.min-1.mm-1 in MTAL from WKY and from 7.6 +/- 0.7 to 12.6 +/- 1.2 pmol.min-1.mm-1 in MTAL from SHR (P < 0.005). These results demonstrate that 1) the effects of PGE2 to stimulate HCO3- absorption and inhibit Cl- absorption in the presence of AVP are absent in MTAL from SHR, 2) the defect may involve an inability of PGE2 to stimulate protein kinase C, and 3) regulation of HCO3- absorption by AVP via adenosine 3',5'-cyclic monophosphate is similar in MTAL from WKY and SHR. The lack of PGE2 inhibition of NaCl absorption in the MTAL may contribute to renal salt retention during the development of hypertension in the SHR.
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PMID:Prostaglandin E2 regulation of ion transport is absent in medullary thick ascending limbs from SHR. 763 31

The development of hypertension in the spontaneously hypertensive rat (SHR) is associated with renal dysfunction and vasoconstriction. The kidneys of young SHRs exhibit exaggerated reactivity to angiotensin II (Ang-II) and attenuated responses to vasodilators that normally activate the cAMP signal to buffer hormone-induced vasoconstriction. The present study investigates the mechanism(s) responsible for this abnormality in activation of the cAMP second-messenger pathway in hypertensive animals. Renal vascular reactivity was assessed in 7-week-old anesthetized SHRs and normotensive Wistar-Kyoto rats. The animals were pretreated with indomethacin to block prostanoid production throughout an experiment. Ang-II was injected into the renal artery either alone or mixed with the vasodilator fenoldopam, a dopamine-receptor agonist. These two opposing vasoactive agents were administered before and during intrarenal infusion of NaF or cholera toxin, two activators of G proteins that stimulate cAMP production. The results show that Ang-II reduced renal blood flow by 45% in both strains. In Wistar-Kyoto rats, fenoldopam reduced the Ang-II-induced decrease in renal blood flow from -45% to -30%. This protective effect of fenoldopam was increased further during infusion of NaF or cholera toxin (-18% or -19% decrease in renal blood flow). In SHRs, fenoldopam failed to attenuate Ang II-mediated vasoconstriction (-45% vs. -44%). In contrast, fenoldopam effectively blunted the Ang-II-induced vasoconstriction when it was given concurrently with NaF or cholera toxin (-27 or -31% decrease in renal blood flow). These findings provide evidence for defective interaction between receptor coupling and activation of guanine nucleotide stimulatory factor proteins in the renal microcirculation of 7-week-old SHRs. Such a deficiency could play an important role in renal dysfunction associated with the development of genetic hypertension.
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PMID:Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension. 770 50


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