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

Anatagonists to angiotensin, catecholamines, aldosterone, and vasopressin have long been used to help determine agonist roles in hypertension. We here call attention to a possible extension of this approach to detect, evaluate, and treat vascular sodium transport defects in hypertension. Two basic types of transport defects have been identified in the blood vessels of hypertensive animals, increased sodium permeability and decreased sodium pump activity. Intravenous injection of 6-iodo-amiloride, a sodium channel blocker and vasodilator, produces an immediate and sustained decrease in blood pressure in two genetic models of hypertension characterized by increased permeability of the vascular smooth muscle cell membrane to sodium (Okamoto spontaneously hypertensive rat, Dahl salt sensitive rat), whereas it produces only a transient fall in arterial pressure in two renal models of hypertension having normal sodium permeability in vascular smooth muscle cells (reduced renal mass-saline rat, one-kidney, one clip rat). Canrenone, a metabolic product of spironolactone which can compete with oubain for binding to Na+,K+-ATPase at the digitalis receptor site, decreases blood pressure in a low renin, volume expanded model of hypertension which has been shown to have depressed sodium pump activity in arteries and increased sodium pump inhibitor in plasma (reduced renal mass-saline rat) but has no effect on blood pressure in a genetic model of hypertension which has been shown to have increased sodium pump activity secondary to increased sodium permeability (spontaneously hypertensive rat). Thus, a sodium channel blocker and a competitor to ouabain binding can detect and determine the functional significance of sodium transport defects in the blood vessels of intact hypertensive animals. Studies in red and white blood cells suggest that similar defects may exist in the blood vessels of hypertensive humans. Thus, this approach, probing for vascular transport defects in the intact animal, may ultimately also be useful in the clinical setting.
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PMID:Pharmacologic agents for the in vivo detection of vascular sodium transport defects in hypertension. 244 62

The current study tested the hypothesis that NaCl-sensitive hypertension may result from increased membrane sodium channel activity. The effect of 6-iodoamiloride, and analog of the sodium channel blocker amiloride, on mean arterial pressure (MAP) was examined in conscious, freely moving NaCl-sensitive spontaneously hypertensive rats (SHR-S) fed high (8%) or normal (1%) NaCl diets. SHR-S and age-matched NaCl-resistant SHR (SHR-R) and normotensive Wistar-Kyoto (WKY) control rats were studied at 9 weeks of age after 2 weeks on either high (8%) NaCl or control (1%) NaCl diets. 6-iodoamiloride was infused intravenously in doses of 0.38 or 0.76 mg/100 g body weight, and MAP and heart rate (HR) were monitored from a femoral arterial cannula for 2 hours. The 8% NaCl diet caused a significant elevation in MAP in SHR-S but not in SHR-R or WKY. Administration of 6-iodoamiloride (both doses) produced a significant, sustained decrease in MAP in both SHR-S and SHR-R. Maximal depressor responses to high dose 6-iodoamiloride were significantly enhanced in SHR-S fed 8% NaCl (31.2 +/- 3.7 mm Hg) compared to SHR-S fed 1% NaCl (14.8 +/- 2.4 mm Hg) or SHR-R fed either 8% or 1% NaCl diets (15.6 +/- 4.2 and 10.2 +/- 3.0 mm Hg, respectively). In contrast, feeding an 8% NaCl diet had no significant effect on the depressor responses to 6-iodoamiloride in either SHR-R or WKY rats. In WKY, these doses of 6-iodoamiloride had no significant effect on MAP in either diet group. 6-iodoamiloride had no significant effect on heart rate in any group. These results support the hypothesis that the exacerbation of hypertension in SHR-S fed a high NaCl diet may result from increased membrane sodium channel activity.
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PMID:Exaggerated depressor response to 6-iodoamiloride in NaCl-sensitive spontaneously hypertensive rats. 245 16

Amiloride (100-400 micrograms) injected intra-arterially into the dog forelimb perfused at constant flow produced a prompt but transient dose-dependent decrease in perfusion pressure. Intravenous injection lowered systemic arterial pressure, but effects were small and transient except in doses exceeding 10 mg. We tested 11 analogues of amiloride, 3 other diuretics, and a hypotensive imidazopyrazine for vasodilator activity in the dog forelimb and found one analogue, 6-iodo-amiloride, with twice the activity of amiloride. Intravenous injection of 3 mg of 6-iodo-amiloride promptly decreased systemic arterial pressure and forelimb perfusion pressure 65 and 47 mm Hg respectively. The decreases with 3 mg of amiloride were only 5 and 23 mm Hg respectively. Intravenous infusion of 17 to 77 mg of 6-iodo-amiloride produced diuresis, natriuresis, and antikaliuresis and, with the higher doses, hypotension. The latter occurred promptly on starting the infusion and was sustained for the duration of the infusion. Wistar rats responded to an intravenous infusion of 0.38 mg/100 g in 11 minutes in the same manner. In the spontaneously hypertensive rat, this same dose produced a large, sustained antihypertensive effect with little change in the urinary parameters. These studies indicate that 6-iodo-amiloride is a vasodilator and a vasodepressor as well as natriuretic and diuretic in the normal dog and rat and that it produces a sustained, large fall in blood pressure, independently of urinary effects, in the spontaneously hypertensive rat. These results suggest that 6-iodo-amiloride and other sodium channel blockers might be useful as vasodilatory antihypertensive agents, particularly in those types of hypertension characterized by increased vascular smooth muscle cell permeability to sodium.
Hypertension
PMID:Sodium channel blockers are vasodilator as well as natriuretic and diuretic agents. 258 96

We have previously shown that a 10-min intravenous infusion of 6-iodo-amiloride, an analogue of the sodium channel blocker amiloride, causes a sustained decrease in blood pressure in two genetic models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats. In contrast, the same infusion produced only a transient decrease in blood pressure in two renal models of hypertension, viz. one-kidney, one clip, and reduced renal mass-saline rats. With these findings, we suggested that 6-iodo-amiloride has potential both as a diagnostic probe and as a therapeutic agent in genetic models of hypertension. The aim of the present study was to examine the effectiveness of 6-iodo-amiloride as a long-term antihypertensive agent and determine the mechanism of its antihypertensive action. We administered 6-iodo-amiloride to SHR for 4 weeks in the drinking fluid (tap water). The treatment with 6-iodo-amiloride caused a significant decrease in blood pressure but had no effect on urine volume or urinary excretion of sodium and potassium. These data strongly suggest that 6-iodo-amiloride is an effective long-term antihypertensive agent in genetic types of hypertension.
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PMID:Sustained antihypertensive effect of chronic oral administration of 6-iodo-amiloride, a sodium channel blocker, in spontaneously hypertensive rats. 285 66

6-Iodoamiloride, an analogue of the sodium channel blocker amiloride, is a vasodilator-depressor, diuretic-natriuretic, and antikaliuretic agent. In these experiments we intravenously infused 6-iodamiloride (0.38 mg/100 g body weight) over a 10- to 11-minute period into rats with reduced renal mass-saline hypertension or one-kidney, one clip hypertension. The infusion produced a prompt but transient fall in blood pressure. These findings are in contrast to those in spontaneously hypertensive rats (SHR), in which the same infusion of 6-iodoamiloride produced a prompt, pronounced, and sustained fall in blood pressure. Studies from a number of laboratories suggest that vascular smooth muscle cells from the SHR have increased permeability to sodium whereas vascular smooth muscle cells from the other two models do not. Thus, 6-iodoamiloride may have potential both as a diagnostic probe and a therapeutic agent for hypertension characterized by increased vascular smooth muscle cell permeability to sodium.
Hypertension 1988 May
PMID:Effect of 6-iodoamiloride in various models of experimental hypertension. 336 78

Synaptic transmission and membrane properties of sympathetic neurons in superior cervical ganglia of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) were investigated in vitro by extracellular and intracellular recording. The sympathetic neurons of SHR showed an atypical loss of spike accommodation. The spike discharge was insensitive to the sodium channel blocker tetrodotoxin, but it was reversibly blocked by a variety of calcium antagonists. The loss of accommodation in the neurons of SHR was not due to a loss of M-current, a potassium current involved in controlling spike frequency adaptation in sympathetic neurons. Superfusion of ganglia of SHR with muscarine (10 microM), which suppresses M-current and leads to a loss of accommodation, potentiated the repetitive discharge. In the presence of muscarine the current-voltage curves in neurons of SHR and SD were shifted to similar extents. Resting membrane potentials of neurons of SHR and WKY were consistently depolarized as compared with neurons of SD. Synaptic efficacy through the ganglia of SHR, assessed by extracellular recordings of presynaptic and postsynaptic compound action potentials at 0.25 Hz stimulation, was elevated when compared with the ganglia of WKY, but was similar to that of the ganglia of SD. These results indicate that strain differences should be considered when attempting to attribute changes in sympathetic neuron membrane properties to hypertension. The sympathetic neurons of SHR appear to have lost their accommodative properties and might possess an exaggerated calcium conductance. This calcium conductance may explain the augmented calcium-dependent release of norepinephrine during sympathetic nerve stimulation in the SHR.
Hypertension
PMID:Loss of accommodation in sympathetic neurons from spontaneously hypertensive rats. 398 70

Sensitivity of blood pressure to dietary salt is a common feature in subjects with hypertension. These features are exemplified by the mendelian disorder, Liddle's syndrome, previously shown to arise from constitutive activation of the renal epithelial sodium channel due to mutation in the beta subunit of this channel. We now demonstrate that this disease can also result from a mutation truncating the carboxy terminus of the gamma subunit of this channel; this truncated subunit also activates channel activity. These findings demonstrate genetic heterogeneity of Liddle's syndrome, indicate independent roles of beta and gamma subunits in the negative regulation of channel activity, and identify a new gene in which mutation causes a salt-sensitive form of human hypertension.
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PMID:Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. 755 Mar 15

Hypertension is a common trait of multifactorial determination imparting an increased risk of myocardial infarction, stroke, and end-stage renal disease. The primary determinants of hypertension, as well as the factors which determine specific morbid sequelae, remain unknown in the vast majority of subjects. Knowledge that a large fraction of the interindividual variation in this trait is genetically determined motivates the application of genetic approaches to the identification of these primary determinants. Success in this effort will afford insights into pathophysiology, permit preclinical identification of subjects with specific inherited susceptibility, and provide opportunities to tailor therapy to specific underlying abnormalities. To date, mutations in three genes have been implicated in the pathogenesis of human hypertension: mutations resulting in ectopic expression of aldosterone synthase enzymatic activity cause a mendelian form of hypertension known as glucocorticoid-remediable aldosteronism; mutations in the beta subunit of the amiloride-sensitive epithelial sodium channel cause constitutive activation of this channel and the mendelian form of hypertension known as Liddle syndrome; finally, common variants at the angiotensinogen locus have been implicated in the pathogenesis of essential hypertension in Caucasian subjects, although the nature of the functional variants and their mechanism of action remain uncertain. These early findings demonstrate the feasibility and utility of the application of genetic analysis to dissection of this trait.
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PMID:Genetic determinants of human hypertension. 756 73

Liddle's syndrome, a rare cause of hypokalemic hypertension, is characterized by a renal tubular sodium channel defect resulting in excessive sodium absorption and concomitant potassium wasting. In this disorder, although the clinical manifestations resemble primary aldosteronism, serum and urine aldosterone are suppressed. The syndrome is transmitted in an autosomal dominant pattern. It has been reported previously in white and oriental populations but not in the black individuals. We identified four patients (two of whom are black) in our nephrology clinic, with severe hypokalemic hypertension not correctly diagnosed for several years. All patients underwent an extensive work-up for secondary hypertension because of persistent severe hypertension (average blood pressure, 210/130 mm Hg) despite high-dose multi-drug therapy. Primary aldosteronism was excluded because of low serum aldosterone. Cushing's syndrome, pheochromocytoma, renal artery stenosis, and enzymatic deficiencies of cortisol synthesis (11 beta-hydroxylase, 17 alpha-hydroxylase, 5 beta-reductase, and 11 beta-hydroxysteroid dehydrogenase) were ruled out with extensive endocrine and radiologic studies. Once the diagnosis of Liddle's syndrome was suspected, all patients were treated with either triamterene or ameloride, with resolution of hypokalemia and correction of hypertension occurring within 5 to 7 days. Our findings suggest that Liddle's syndrome can occur in the black population. Although the actual incidence of this syndrome remains unknown, it may be significantly more common than we are led to believe since it is inherited in a Mendelian pattern. Whether there is a subset of low-renin, salt-sensitive black hypertensive patients who have the same or similar sodium channel defect remains to be elucidated.
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PMID:Liddle's syndrome, an underrecognized entity: a report of four cases, including the first report in black individuals. 777 90

The basis of one type of inherited hypertension has been discovered-it is caused by mutations in the gene for the beta subunit of a renal sodium channel.
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PMID:Genetic hypertension. A direct link to salt. 778 Jul 35


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