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)

Intravenous injection of NG-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor, elevated mean blood pressure by 29.0 +/- 4.9 mm Hg and decreased heart rate by 40.7 +/- 5.6 beats per minute in anesthetized Japanese monkeys (n = 6), whereas NG-nitro-D-arginine was without effect. After pretreatment with pentolinium, the magnitude of the pressure elevation by L-NA was significantly less than that after pretreatment with phentol-amine. The reduced blood pressure by either of the pretreatment drugs was compensated to control levels by a continuous infusion of angiotensin II before L-NA administration. Isolated monkey distal mesenteric arteries (150 to 200 microns OD) without endothelium responded to nerve stimulation by nicotine with a contraction, which was abolished by prazosin alone or in combination with alpha, beta-methylene ATP. In the strips thus treated and contracted with prostaglandin F2 alpha, nicotine caused a relaxation that L-NA abolished. L-NA but not NG-nitro-D-arginine reversed the inhibition. Histochemical staining of NADPH diaphorase, considered to be identical to nitric oxide synthase in neuronal tissues, demonstrated that positively stained nerve fibers were consistently present in the adventitia of monkey distal mesenteric arteries and arterioles. These results strongly suggest that nitroxidergic vasodilator nerves innervate peripheral small arteries and arterioles in the monkey and that these nerves participate in the regulation of systemic blood pressure. High blood pressure caused by nitric oxide synthase inhibitors is associated with an elimination of nitroxidergic nerve function together with an impairment of the basal release of nitric oxide from the endothelium.
Hypertension 1996 Sep
PMID:Neural mechanism of pressor action of nitric oxide synthase inhibitor in anesthetized monkeys. 879 14

Aortic clamp-induced hypertension has long been implicated in the cardiovascular mortality and morbidity following infrarenal aortic operations. We studied the physiologic mechanisms leading to clamp-induced hypertension. Mean arterial pressure (MAP), cardiac output, heart rate, and left ventricular pressure were measured in alpha-chloralose-anesthetized dogs. Animals received alpha, beta, both alpha and beta, or no adrenergic blockade (n = 3, 4, 12 and 7, respectively). The infrarenal aorta was clamped following ligation of the infrarenal collateral vessels (lumbar, circumflex iliac, and tail arteries). Statistical analysis used paired t tests within groups, and ANOVA and unpaired t tests between groups, with Bonferroni's correction as indicated. Following placement of the clamp, MAP increased immediately in all groups, with magnitude of the increase related to the extent of adrenergic blockade. MAP increased 5.6 +/- 0.8 mm Hg with no blockade (P = 0.0005), 6.7 +/- 0.8 mm Hg with alpha blockade (P = 0.0153), 15 +/- 3.1 mm Hg with beta blockade (P = 0.0163), and 16.7 +/- 1.3 mm Hg with combined alpha and beta blockade (P < 0.0001). The increase in MAP immediately following infrarenal aortic clamping was most pronounced with combined alpha and beta blockade. We suggest that acute intraoperative hypertension associated with infrarenal aortic clamping is caused by the attenuation of compensatory baroreceptor reflex mechanisms.
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PMID:Infrarenal aortic clamp hypertension is exacerbated by baroreceptor blockade. 881 20

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 mumol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 100 mumol/L; an ecto-5'-nucleotidase inhibitor), and 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSPX, 100 mumol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5'-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10(-4) mol/L) and 8-bromo-cAMP (10(-4) mol/L) on fetal calf serum-induced DNA synthesis ([3H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A2 adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5'-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
Hypertension 1996 Nov
PMID:Cyclic AMP-adenosine pathway inhibits vascular smooth muscle cell growth. 890 21

In 1963 Liddle et al. described a disorder that simulated primary aldosteronism, characterized by severe hypertension and hypokalemia but with negligible secretion of aldosterone. They theoried that this was a disorder in which the renal tubules transport ions with such abnormal facility that the end result simulates that of a mineralcorticoid excess. Later, it was postulated that this disorder could be related to the abnormality of amiloride sensitive Na channel. The activity of amiloride-sensitive Na channels constitutes the rate limiting step for Na reabsorption in Na transporting epithelia. Recently, the primary sequence of the rat amiloride-sensitive epithelial Na+ channel (rENaC) was determined by functional expression cloning and shown to be composed of three homologous subunits: alpha, beta, and gamma. Its expression of all three subunits in Xenopus oocytes markedly increased the magnitude of these currents. Analysis of subjects with Liddle's syndrome demonstrates the mutation of carboxy-terminal domain in alpha, beta, and gamma subunits. The mutations are either premature termination, frameshift mutation, or missense mutations.
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PMID:[Liddle syndrome]. 890 41

Alcohol acutely causes vasodilation and hypotension in Orientals. To study the mechanisms responsible for the alcohol-induced blood pressure (BP) reduction, we examined levels of various vasoactive hormones after a single intake of alcohol in twelve Japanese men with mild hypertension. On the alcohol intake day, they consumed 1 ml/kg of alcohol with an evening meal, while on the control day they took an isocaloric control drink. BP and vasoactive hormone levels were determined before and 2 h after intake of the alcohol or the control drink. BP after alcohol ingestion was significantly lower than that before drinking or on the control day. This alcohol-induced hypotension was associated with significant increases in heart rate, plasma catecholamines and plasma renin activity (PRA). The changes in heart rate and plasma noradrenaline were inversely related to the changes in BP. Plasma levels of vasopressin and insulin were lower in the alcohol period than in the control period, but these changes were not correlated with the changes in BP. Levels of aldosterone, cortisol, atrial natriuretic peptide, prostaglandin (PG) E2, 6-keto-PGF1 alpha, beta-endorphin, and cyclic GMP were not significantly different between the alcohol and the control periods. These results suggest that changes in pressor hormones may not contribute to the acute hypotensive effect of alcohol, and that the sympathetic nervous system is activated by the BP reduction. The levels of the depressor hormones measured also appear to play no role in alcohol-induced hypotension.
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PMID:Pressor and depressor hormones during alcohol-induced blood pressure reduction in hypertensive patients. 895 4

The epithelial amiloride-sensitive sodium channel (ENaC) controls transepithelial Na+ movement in Na(+)-transporting epithelia and is associated with Liddle syndrome, an autosomal dominant form of salt-sensitive hypertension. Detailed analysis of ENaC channel properties and the functional consequences of mutations causing Liddle syndrome has been, so far, limited by lack of a method allowing specific and quantitative detection of cell-surface-expressed ENaC. We have developed a quantitative assay based on the binding of 125I-labeled M2 anti-FLAG monoclonal antibody (M2Ab*) directed against a FLAG reporter epitope introduced in the extracellular loop of each of the alpha, beta, and gamma ENaC subunits. Insertion of the FLAG epitope into ENaC sequences did not change its functional and pharmacological properties. The binding specificity and affinity (Kd = 3 nM) allowed us to correlate in individual Xenopus oocytes the macroscopic amiloride-sensitive sodium current (INa) with the number of ENaC wild-type and mutant subunits expressed at the cell surface. These experiments demonstrate that: (i) only heteromultimeric channels made of alpha, beta, and gamma ENaC subunits are maximally and efficiently expressed at the cell surface; (ii) the overall ENaC open probability is one order of magnitude lower than previously observed in single-channel recordings; (iii) the mutation causing Liddle syndrome (beta R564stop) enhances channel activity by two mechanisms, i.e., by increasing ENaC cell surface expression and by changing channel open probability. This quantitative approach provides new insights on the molecular mechanisms underlying one form of salt-sensitive hypertension.
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PMID:Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach. 898 18

The amiloride-sensitive, epithelial sodium channel (ENaC) is composed of at least three subunits (alpha, beta, and gamma). This study demonstrates that the ENaC beta subunit gene is expressed in human B cell lines, peripheral blood lymphocytes, and lymph node at the mRNA level. Further, this study shows that both wild-type and mutated alleles of the ENaC beta subunit gene are transcribed in human B lymphocytes derived from an individual affected with Liddle's syndrome, an autosomal dominant form of human hypertension.
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PMID:Expression of the amiloride-sensitive sodium channel beta subunit gene in human B lymphocytes. 901 57

Epithelial Na+ channels are expressed widely in absorptive epithelia such as the renal collecting duct and the colon and play a critical role in fluid and electrolyte homeostasis. Recent studies have shown that these channels interact via PY motifs in the C terminals of their alpha, beta, and gamma subunits with the WW domains of the ubiquitin-protein ligase Nedd4. Mutation or deletion of these PY motifs (as occurs, for example, in the heritable form of hypertension known as Liddle's syndrome) leads to increased Na+ channel activity. Thus, binding of Nedd4 by the PY motifs would appear to be part of a physiological control system for down-regulation of Na+ channel activity. The nature of this control system is, however, unknown. In the present paper, we show that Nedd4 mediates the ubiquitin-dependent down-regulation of Na+ channel activity in response to increased intracellular Na+. We further show that Nedd4 operates downstream of Go in this feedback pathway. We find, however, that Nedd4 is not involved in the feedback control of Na+ channels by intracellular anions. Finally, we show that Nedd4 has no influence on Na+ channel activity when the Na+ and anion feedback systems are inactive. We conclude that Nedd4 normally mediates feedback control of epithelial Na+ channels by intracellular Na+, and we suggest that the increased Na+ channel activity observed in Liddle's syndrome is attributable to the loss of this regulatory feedback system.
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PMID:Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. 961 57

Liddle's syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the beta or gamma subunit of the epithelial sodium channel. Systematic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the alpha, beta, or gamma subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of the beta subunit have been reported to cause Liddle's syndrome. We sequenced the C-termini of the beta and gamma subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle's syndrome and found a new missense mutation in the PY motif of the beta subunit, P615S. Expression studies with P615S mutant in Xenopus oocytes resulted in an about 3-fold increase in the amiloride-sensitive sodium current compared to the wild type (p = 0.001). These findings provide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.
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PMID:A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. 962 62

The epithelial Na+ channel (ENaC) complex is composed of three homologous subunits: alpha, beta and gamma. Mutations in ENaC subunits can increase the number of channels on the cell surface, causing a hereditary form of hypertension called Liddle's syndrome, or can decrease channel activity, causing pseudohypoaldosteronism type I, a salt-wasting disease of infancy. To investigate surface expression, we studied ENaC subunits expressed in COS-7 and HEK293 cells. Using surface biotinylation and protease sensitivity, we found that when individual ENaC subunits are expressed alone, they traffic to the cell surface. The subunits are glycosylated with high-mannose oligosaccharides, but seem to have the carbohydrate removed before they reach the cell surface. Moreover, subunits form a complex that cannot be disrupted by several non-ionic detergents. The pattern of glycosylation and detergent solubility/insolubility persists when the N-teminal and C-terminal cytoplasmic regions of ENaC are removed. With co-expression of all three ENaC subunits, the insoluble complex is the predominant species. These results show that ENaC and its family members are unique in their trafficking, biochemical characteristics and post-translational modifications.
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PMID:Cell surface expression and biosynthesis of epithelial Na+ channels. 984 84


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