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)

Labetalol was given to women with hypertension of pregnancy in their last trimester to study its acute effect on circulation and metabolism. Seven women were given 50 mg labetalol i v. There was a significant decrease of blood pressure from a mean of 143/101 +/- 4/2 (SEM) to 127/88 +/- 5/2 mm Hg. Maternal heart rate fell significantly from 77 +/- 5 to 68 +/- 3 beats per min. These changes persisted during a three-hour observation period. The hypotensive response was accompanied by a significant increase in plasma noradrenaline from 1.54 +/- 0.16 to 2.37 +/- 0.41 nmol/l, suggesting sympathetic activation. Plasma cyclic AMP, which is increased by beta 2-adrenoceptor stimulation, was significantly elevated after labetalol. This supports the hypothesis of partial beta-agonist activity of labetalol. Lipid metabolism, as judged from measurements of plasma FFA, glycerol and 3-hydroxybuturic acid, showed little change. The acute effect of labetalol on uteroplacental blood flow was determined in eight women with pregnancy hypertension using a gammacamera on line with a computer. 0.5 mCi indium-113m was given i v before and 30 min after labetalol was administered i v in a dose of 1 mg per kg body weight. After the injections of indium-113m, serial scintigrams were recorded during 10 s periods for 240 s. By computerized summation of the scintigrams, an image was obtained in which the placenta could be outlined for time-activity analysis of the isotope accumulation curve. From this curve a uteroplacental blood flow index could be calculated. Labetalol induced a significant drop of mean arterial blood pressure from 114 +/- mm Hg to 100 +/- 3 mm Hg after 30 min in this group of women. However, the uteroplacental blood flow index did not change. As we have earlier shown with this technique that uteroplacental blood flow can be severely impaired in hypertension of pregnancy, the finding of substained uteroplacental blood flow simultaneously with a decrease in blood pressure should be of clinical importance. Taken together with other studies of clinical effects, these results indicate that labetalol is useful in the treatment of hypertension of pregnancy.
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PMID:Labetalol, a combined alpha- and beta-blocker, in hypertension of pregnancy. 696 61

Kallikrein is present in the renal tubule near the macula densa, and it has recently been shown to activate inactive renin in human plasma. We recently showed that kallikrein was a potent stimulus of renin release and increased renin secretion in a dose-dependent fashion. To study its effect on renal renin release, we superfused rat renal cortical slices with purified rat urinary kallikrein. Kallikrein-stimulated renin release was completely abolished by trasylol and by amiloride, but was not affected by soybean trypsin inhibitor. Indomethacin did not block kallikrein action, indicating that kallikrein's effect is not mediated via kinin generation and prostaglandins. Kallikrein-stimulated renin release was not blocked by propranolol, trasylol did not block isoproterenol, and dibutyryl cyclic AMP stimulated renin release, indicating that kallikrein may not play a role in the beta-adrenergic mechanism of renin release. There was no demonstrable acid-activatable or kallikrein activatable renin in the superfusate, suggesting that all of the renin release was in the active form. Cathepsin D and plasmin also stimulated renin release from kidney slices in pH 6.0 buffer, whereas trypsin and pepsin did not. Our results support the hypothesis that kallikrein may play a role in the secretion of renin by the kidney. Other proteases can also release renin from the kidney.
Hypertension
PMID:Direct action of kallikrein and other proteases on the renin-angiotensin system. 702 11

1 Seven women with hypertension of pregnancy were given the combined alpha- and beta-adrenoceptor blocking drug labetalol (50 mg i.v.) in their last trimester. Acute effects were studied for 3 h after administration. 2 Systolic and diastolic blood pressures were significantly reduced from 143 +/- 4 (s.e. mean) to 127 +/- 5 mmHg and from 101 +/- 2 to 88 +/- 2 mmHg, respectively. Maternal heart rate fell significantly from 77 +/- 5 to 68 +/- 3 beats/min. The changes remained during the 3 h of observation. Foetal heart rate was not affected. No side-effects were encountered. 3 Plasma noradrenaline increased significantly from 1.54 +/- 0.16 to a peak value of 2.37 +/- 0.41 nmol/l suggesting sympathetic activation following labetalol. Plasma adrenaline levels were essentially unchanged. Plasma glucose, insulin and C-peptide showed only minor changes. No major effects on lipid metabolism were seen except a significant fall of nonesterified fatty acids at 60 min. Plasma cyclic AMP increased significantly throughout the observation period, perhaps indicating beta-adrenoceptor agonist activity of labetalol. 4 The effectiveness of labetalol as an acute hypertensive agent together with apparent absence of metabolic disturbances and other side-effects makes it an interesting drug for the treatment of hypertension during pregnancy.
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PMID:Circulatory and metabolic effects of a combined alpha- and beta-adrenoceptor blocker (labetalol) in hypertension of pregnancy. 729 64

Two siblings with congenital Cushing's syndrome due to bilateral nodular adrenal hyperplasia are described. The older, a boy, presented with severe hypertension and died soon after subtotal adrenalectomy. His sister, who had clitoral enlargement and showed persistent hyponatraemia, had a two-stage total adrenalectomy and is still alive. Investigations in the second case showed grossly elevated urinary cortisol metabolites, 17-oxosteroids and 3 beta-hydroxy-5-ene-steroids. These were not suppressed by dexamethasone, and plasma ACTH was undetectable, indicating that the disorder was not due to excessive ACTH secretion. Cell culture studies on the resected adrenals failed to demonstrate an abnormal pattern of steroid synthesis in vitro, and normal trophic responses were obtained with 1-24 ACTH and monobutyryl cyclic AMP. No stimulation of steroid synthesis was obtained with a range of polypeptide hormones, and the cause of the adrenal hyperplasia remains unknown.
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PMID:Familial congenital Cushing's syndrome due to bilateral nodular adrenal hyperplasia. 730 79

Defining the mechanisms regulating the proliferation of vascular smooth muscle is necessary to better understand the pathogenesis of atherosclerosis and hypertension. In the present investigation, we examined the effects of incubation with forskolin or isoproterenol on the proliferation of cultured rat aortic smooth muscle cells. Forskolin, a direct activator of adenylate cyclase, and isoproterenol, a beta-adrenergic agonist, increased intracellular cyclic AMP levels in a concentration-dependent manner, subsequent to a 5-min exposure. Isobutylmethylxanthine at 100 microM attenuated epidermal growth factor stimulated DNA synthesis by 35% without affecting intracellular cyclic AMP levels. Forskolin dose-dependently augmented this inhibition. In contrast, a 24-h exposure of cells to isoproterenol resulted in a biphasic effect on growth factor stimulated thymidine incorporation. Both forskolin and isoproterenol attenuated thymidine incorporation to the same degree up to 12 h poststimulation, the onset of S phase. By 16 h poststimulation, [3H]thymidine incorporation in smooth muscle cells treated with isoproterenol was significantly enhanced by 50%, whereas forskolin treatment continued to attenuate DNA synthesis by 40%. Somewhat surprisingly, this disparity in effect on DNA synthesis was evident in spite of heterologous desensitization to rechallenge by either forskolin or isoproterenol subsequent to a 24-h incubation with either drug. These results suggest that the isoproterenol enhancement of epidermal growth factor stimulated DNA synthesis in rat aortic smooth muscle cells may be cyclic AMP independent.
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PMID:Forskolin and isoproterenol effect discrete responses on epidermal growth factor induced DNA synthesis in aortic smooth muscle cells. 751 81

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

beta-Adrenoceptor antagonists such as propranolol and atenolol ameliorate the symptoms of human hyperthyroidism. We wished to define whether the cardiac changes of hyperthyroidism are attenuated by treatment with the beta-adrenoceptor antagonist atenolol. Rats were treated with triiodothyronine (T3) [1 mg/kg/day subcutaneously (s.c.) for 14 days] together with oral atenolol (100 mg/day on days 8-14); physiological parameters, inotropic and chronotropic responses in isolated cardiac tissues to compounds that increase intracellular cyclic AMP, and ventricular beta 1- and beta 2-adrenoceptors were measured. Administration of T3 produced marked hyperthyroidism, leading to increased metabolism, cardiac hypertrophy, tachycardia, hypertension, marked decrease in or loss of positive inotropic responses to calcium chloride, norepinephrine (NE), forskolin, and theophylline and increased ventricular beta 1- and beta 2-adrenoceptor density. Atenolol treatment of hyperthyroid rats attenuated the increases in heart rate (HR), rectal temperature, and O2 consumption but did not alter cardiac hypertrophy, hypertension, decreased positive inotropic responses or increased beta-adrenoceptor density. We conclude that beta-adrenoceptor antagonists produce only limited changes in hyperthyroidism-induced cardiovascular responses; furthermore, beta-adrenoceptor antagonists are unlikely to attenuate the cardiovascular risk factors of hyperthyroidism.
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PMID:Beta-adrenoceptor antagonism and the hyperthyroid rat heart. 752 70

Nitric oxide (NO) is an important molecular messenger accounting for endothelium-derived relaxing factor. Recently, NO synthase (NOS) from cultured endothelial cells has been purified and molecularly cloned. To evaluate the effect of phosphorylation by protein kinase C (PKC) and cyclic AMP-dependent protein kinase (PKA) on endothelial constitutive NOS catalytic activity, we incubated purified endothelial NOS with PKC or PKA. Endothelial NOS was stoichiometrically phosphorylated by PKC and PKA. In intact bovine aortic endothelial cells (BAECs), NOS was phosphorylated by stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA). NOS activity measured by the conversion of [3H]arginine to [3H]citrulline in homogenates of BAECs treated with TPA or phorbol 12,13-dibutyrate was reduced by 30%, whereas dibutylyl cyclic AMP did not affect NOS activity. Moreover, we measured NO release from cultured BAECs by a chemiluminescence method to examine the effect of PKC and PKA on endothelial NOS activity. In cultured BAECs, ATP gamma S and A23187 induced NO release in time- and dose-dependent manners. Phorbol esters such as TPA and phorbol 12,13-dibutyrate dose dependently inhibited NO release stimulated by A23187 as well as ATP gamma S. Reduction of NO release by TPA was almost completely prevented by pretreatment with staurosporine, an inhibitor of PKC. NO release by A23187 was increased in PKC-downregulated BAECs. In contrast, dibutylyl cyclic AMP or 8-bromo cyclic GMP had no effect on NO release from BAECs induced by A23187 or ATP gamma S. These results indicate that phosphorylation of NOS by PKC is associated with a reduction of its catalytic activity in vascular endothelial cells.
Hypertension 1995 Feb
PMID:Inhibition of endothelial nitric oxide synthase activity by protein kinase C. 753 Nov 74

To explore the mechanisms of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: -29 +/- 2% [SEM]; P < .01) and slightly increased the glomerular filtration rate and urinary sodium excretion (+108%; P < .05). These changes were associated with significant increases in urinary excretion of cyclic AMP (+54%; P < .05). Adrenomedullin decreased renal vascular resistance (10(-7) mol/L adrenomedullin: -41 +/- 2%; P < .001) and increased release of nitric oxide (+5.1 +/- 0.7 fmol/min per gram kidney weight; P < .001) in the isolated kidney. This increase in nitric oxide release was abolished by the inhibitor NG-monomethyl-L-arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate-salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10(-7) mol/L adrenomedullin: +0.8 +/- 0.2 fmol/min per gram kidney weight; P < .01 versus control) and renal vasodilation (-28 +/- 6%; P < .05). Videomicroscopic analysis revealed that adrenomedullin increased the diameters of both afferent and efferent arterioles (3 nmol/kg: +11%; P < .05). Thus, adrenomedullin-induced renal vasodilation is partially endothelium dependent and is attenuated in deoxycorticosterone acetate-salt hypertension, probably due to endothelial damage.
Hypertension 1995 Apr
PMID:Mechanisms of adrenomedullin-induced vasodilation in the rat kidney. 772 34

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


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