Reversal of two-kidney one clip renovascular hypertension in the rat.

Attempted correction of two-kidney, one clip Goldblatt hypertension in the rat was carried out by three techniques; removal of the constricting clip, removal of the ischemic kidney, and converting enzyme blockade by oral captopril. Since duration of hypertension is said to be a critical factor, groups of rats were studied after short term (less than 6 weeks from clipping) and chronic (greater than 4 months) hypertension. Blood pressure, sodium balance, and plasma renin concentration (PRC) were followed before and after these correcting procedures. In a control group of animals, removal of a loose renal artery clip did not influence blood pressure and only caused trivial postoperative retention of sodium. Unclipping, however, normalized blood pressure in both short-term and chronic hypertension. After a major postoperative fall, blood pressure returned to somewhat elevated levels after nephrectomy in animals with chronic (but not short-term) hypertension. Sodium balance became markedly positive with the fall in blood pressure of operated hypertensive animals and was significantly correlated with the fall in blood pressure of operated hypertensive animals and was significantly correlated with the fall in blood pressure in these four groups at 7 days (r = 0.43). Captopril also produced a fall in blood pressure at 24 hours, with a positive sodium balance, although the relationship between blood pressure fall and sodium balance did not reach statistical significance (r = 0.30). The PRC was elevated in all hypertensive groups, although individual values overlapped with values from normal rats and nonhypertensive rats with a loose renal artery clip. The PRC fell to normal or subnormal values after either operative procedure and stabilized for at least 2 months independently of whether blood pressure fell or not. It is concluded that neither sodium retention nor renin hypersecretion maintains blood pressure in this model. Also, the rapidity of the blood pressure fall is not consistent with a role for vascular hypertrophy. The greater efficacy of unclipping suggests that the revascularized kidney after this procedure exerts a vasodepressor function independent of sodium excretion or the renin-angiotensin system.

Surgical reversal of two-kidney one clip hypertension during inhibition of the renin-angiotensin system.

Conscious rats with two-kidney one clip Goldblatt hypertension had the constricting clip removed during continuous infusion of either dextrose, saralasin, or captopril. Other dextrose-infused animals underwent removal of the ischemic kidney or a sham procedure. Direct arterial blood pressure (BP) was recorded throughout the 15-hour preoperative and subsequent 24-hour postoperative period. Rats were studied in the "early" phase (1-3 weeks duration) or "chronic" phase (greater than 4 months) of hypertension. Animals subjected to a sham procedure returned to preoperative BP values. The BP of animals unclipped or nephrectomized did not return to previous hypertensive levels. Instead, a biphasic response was seen where BP partially recovered from an operative fall and then slowly declined to normal at 24 hours; this effect occurred in both stages of hypertension. At 24 hours, removal of the ischemic kidney was as effective as removal of the constricting clip in the correction of both early and chronic phase hypertension. Rats infused with saralasin or captopril demonstrated an acute (within 2 hours) and sustained fall in BP, but not to normotensive levels. This fall was significant in all animals (p less than 0.01) apart from chronic phase rats infused with saralasin where no significant fall was seen. Although animals infused with saralasin or captopril commenced at a lower preoperative BP, the biphasic pattern of response to unclipping was identical to that of dextrose-infused unclipped rats. Thus, sustained inhibition of the renin-angiotensin system did not modify the correction of hypertension produced by removal of the constricting clip, and the response to surgical correction did not appear to be entirely mediated by changes in the activity of the renin-angiotensin system, particularly in the chronic stage. Equally, the rapidity of correction is not consistent with a role of vascular hypertrophy.

Arterial wall uptake of renal renin and blood pressure control.

We have studied the contribution of circulating renin of renal origin to renin-like activity within the arterial wall and to blood pressure. Bolus injections of renin sufficient to elevate blood pressure by 44.7 mm Hg caused aortic renin to rise from 0.13 to 1.48 ng angiotensin I/100 mg/hr in nephrectomized rats. Elevation of aortic renin was still present at 6 hours, and this was associated with significant blood pressure elevation (p less than 0.05) which could be reversed by infusion of sarcosine, alanine, angiotensin II (saralasin). Prevention of the pressor effect by pretreatment with the converting enzyme inhibitor captopril did not reduce renin uptake. When kidneys were left in situ, although significant uptake of renin could be demonstrated 1 hour after injection, the increase at 3 hours was no longer significant (p greater than 0.05) and blood pressure returned to normal by 1 1/2 hours. This change in blood pressure may be related to the much more rapid clearance of circulating renin in the presence of normal kidneys or to other renal factors influencing the blood pressure response. The present studies demonstrate therefore that most of the renin-like activity within the aortic wall is derived from plasma renin and it seems probable that this component of the renin-angiotensin system plays an important role in blood pressure maintenance in the nephrectomized rats injected with renin. The relationship is less obvious in the presence of normal kidneys where additional influences may come into play.

Leukocyte ionized calcium and sodium content and blood pressure in humans.

The relationship between leukocyte ionized calcium concentration, sodium content, and blood pressure was studied in normotensive subjects with (n = 17) and without (n = 21) a family history of hypertension and in untreated patients with essential hypertension (n = 22). There was a highly significant correlation between intracellular ionized calcium and mean supine blood pressure (measured on the same occasion) in normal subjects with no family history of hypertension (r = +0.73, p less than 0.01). This relationship was lost in normal subjects with a family history of hypertension, and in hypertensive patients there was a nonsignificant negative correlation between intracellular ionized calcium and blood pressure (r = +0.08 and -0.31, respectively). Intracellular ionized calcium was similar in the normotensive groups (both, 126 +/- 7 nmol/L) and slightly but nonsignificantly elevated in hypertensive patients (143 +/- 10 nmol/L; p = 0.09). There was no correlation between intracellular ionized calcium and sodium content in any group (r less than 0.1). These results indicate that while leukocyte ionized calcium in normotensive subjects with no family history of hypertension may reflect smooth muscle contractility resulting in the positive correlation between leukocyte ionized calcium and blood pressure, this relationship is lost in hypertensive patients and subjects predisposed to hypertension. This may be due to an altered relationship between leukocyte and smooth muscle calcium handling in these subjects or to non-calcium-mediated influences on blood pressure.

Effect of cold pressor test-induced stress on leukocyte sodium transport and norepinephrine.

The effects of stress on leukocyte membrane sodium efflux rate constant and plasma norepinephrine levels were studied before and during cold pressor test in normotensive subjects with and without a family history of hypertension. After 20 minutes of supine rest, no significant differences in total, ouabain-resistant or ouabain-sensitive sodium efflux rate constants were apparent between the two groups. In normotensive subjects with no family history, there was no significant change in any efflux rate constant during cold pressor test, although there was a highly significant negative correlation between change in total efflux rate constant and change in norepinephrine levels (r = -0.82, p less than 0.01, n = 12). During cold pressor test in subjects with a family history of hypertension, there was a significant rise in the ouabain-resistant efflux rate constant (1.5 +/- 0.1 vs 1.0 +/- 0.1 hr-1; p less than 0.01, n = 10); this level was also significantly higher than that in control subjects (p less than 0.002). In this group, the ouabain-sensitive efflux rate constant fell slightly but not significantly (1.8 +/- 0.2 vs 2.1 +/- 0.2 hr-1; n = 10). These results suggest that stress in the form of a cold stimulus produces qualitative differences in leukocyte cation transport in normotensive offspring of hypertensive patients as compared with subjects without such a family history.

Changes in leucocyte sodium transport in normotensive relatives of hypertensive subjects. Dissociation from blood pressure.

It has been postulated that depressed membrane sodium transport is a necessary step in blood pressure elevation in essential hypertension. Accordingly, leucocyte sodium efflux-rate constants were estimated in 14 normotensive subjects who had one or more first-degree relatives with essential hypertension, and also in 14 matched control subjects with no such family history, before and after taking bendrofluazide for 7 days. Efflux rates in the controls did not change after the diuretic. However, in the relatives, mean total sodium efflux-rate constant was at first significantly depressed but later rose to normal with the diuretic. This was due almost entirely to an increase in glycoside-sensitive sodium pump activity. Blood pressure remained unchanged in both groups. Thus, assuming that perturbations in leucocytes reflect similar abnormalities in other cell lines, major changes in sodium transport in the normotensive individual without accompanying changes in blood pressure suggest that, while these changes may be a marker for later hypertension, they do not participate directly in blood pressure control.

Rat thymocyte sodium transport. Effects of changes in sodium balance and experimental hypertension.

The wide range of membrane electrolyte transport abnormalities associated with experimental, genetic, and essential hypertension may either reflect an underlying global change in the cell membrane or may be directly related to the underlying disturbance that causes hypertension or to changes in sodium balance. To investigate this further, we studied sodium transport and intracellular electrolyte composition in the thymocytes of normal rats undergoing salt loading or depletion, and in rats with renovascular, mineralocorticoid, or spontaneous hypertension compared to appropriate age-matched normotensive control rats. In normotensive rats, although there was no significant difference between the blood pressures at the two extremes of sodium balance, sodium loading caused a nonsignificant rise in sodium transport, whereas sodium depletion was associated with a significant fall in sodium transport and intracellular sodium. When cells from salt-loaded or normal animals were incubated in a medium containing their own serum, sodium transport was slightly stimulated in both, but there was no significant difference in the sodium efflux-rate constant of thymocytes obtained from rats on the normal as opposed to the high salt intake. Compared to normotensive rats, there was no significant change in the sodium efflux-rate constant in any of the hypertensive rat models studied. However, the sodium efflux-rate constant fell with age in both the spontaneously hypertensive and Wistar-Kyoto normotensive rats. The present studies show that dietary sodium intake and aging had considerable effects on rat thymocyte sodium transport, but neither of these changes was related to a change in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical renal medullectomy. Effect on urinary prostaglandin E2 and plasma renin in response to variations in sodium intake and in relation to blood pressure.

We have studied the possible vasodepressor role of the renal medulla by chemical medullectomy. Bromoethylamine hydrobromide (200 mg/kg) was injected to induce selective renal medullary necrosis in rats. The acute effects on sodium balance and long-term effects on blood pressure, plasma renin concentration (PRC) and urinary prostaglandin E2 (PGE2) were studied and compared with saline injected controls. There was an immediate and sustained increase in urine volume of low osmolality. Direct blood pressure in conscious free-moving animals was higher at 2 and 10 weeks after injection in medullary-damaged rats, although this was only significant at 10 weeks (136 +/- 3.3 vs 118 +/- 4.5 mm Hg, p less than 0.01). An initial negative sodium balance returned to normal by 7 days and rats with established medullary damage tolerated a wide range of sodium intakes. Although there was no evidence of sodium retention on the normal diet, with very high sodium loads some sodium retention was apparent since PRC was suppressed and body weight increased. Plasma creatinine and creatinine clearance were normal. PRC in rats with medullary damage was unchanged on normal diet and rose to similar levels as in control rats on low sodium intake. Urinary PGE2 was markedly reduced (148 +/- 54 vs 536 +/- 71 ng/day, p less than 0.01) in medullary damaged rats, consistent with the renal medulla being the major source of urinary PGE2. High salt intake increased urinary PGE2 in normal and proportionally in medullary damaged rats, whereas on a low sodium intake, urinary PGE2 was not different from that on the normal diet in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythrocyte calcium-stimulated, magnesium-activated adenosine 5'-triphosphatase activity in essential hypertension.

OBJECTIVE: The aim of this study was to investigate the basis of reduced erythrocyte calcium-stimulated, magnesium-activated adenosine 5' triphosphatase (Ca2+, Mg(2+)-ATPase) activity in essential hypertension. DESIGN: Experiments were performed to establish whether the reduced erythrocyte Ca2+, Mg(2+)-ATPase activity in patients with essential hypertension, when compared with age- and sex-matched normotensive control subjects, was due to changes in enzyme properties or to an altered membrane environment. METHODS: Erythrocyte membrane Ca2+, Mg(2+)-ATPase activity was determined by measuring ATP-dependent 45Ca2+ uptake in inside-out vesicles and calcium-dependent gamma-32P ATP hydrolysis in ghost membranes, prepared from the same sample of blood. Calcium-dependent gamma-32P ATP hydrolysis activity was also measured in detergent extracts of erythrocyte membranes. RESULTS: In the absence and presence of calmodulin, both ATP-dependent Ca2+ uptake and calcium-dependent ATP hydrolysis activities of erythrocyte membranes prepared from patients with essential hypertension were significantly reduced when compared with normotensive subjects. No difference in calmodulin affinity was observed between hypertensive and normotensive subjects, although the calcium dependence of calmodulin-independent Ca2+ uptake activity in inside-out vesicles was altered. No significant difference in calcium-dependent ATP hydrolysis activity was observed between hypertensive and normotensive preparations after detergent solubilization of erythrocyte membrane proteins. CONCLUSIONS: These results suggest that the number of Ca2+, Mg(2+)-ATPase units is similar in erythrocytes of hypertensive and normotensive subjects and that the reduced activity in the intact erythrocyte membrane of hypertensive patients is due to an altered membrane environment.

Effects of changes in sodium balance on leucocyte sodium transport: qualitative differences in normotensive offspring of hypertensives and matched controls.

To investigate the effects of changes in sodium balance on blood pressure and leucocyte sodium transport, normotensive first-degree relatives of hypertensive patients and control subjects were randomized to receive low- and high-salt diets for 2 weeks, separated by a wash-out period of 2 weeks. High-salt intake failed to alter blood pressure, whereas the low-salt diet produced significant falls in standing pressures in both groups. In the control subjects leucocyte sodium efflux was not changed by either manoeuvre, but in the relatives low-salt diet stimulated ouabain-insensitive sodium efflux rate constant. There was a significant qualitative difference in the pattern of response of total efflux rate constant to the two dietary periods between the two groups of subjects. These data are not compatible with the release of a humoral sodium pump inhibitor in response to sodium-induced volume expansion, and lend support to a disturbance of membrane permeability to sodium in subjects genetically prone to hypertension.

Nifedipine substituted for minoxidil in the treatment of refractory hypertension.

Nifedipine slow release tablets were substituted for minoxidil in the treatment of 13 patients with hypertension refractory to conventional therapy. In 12 patients substitution was associated with continuing control of blood pressure (BP), although 11 required maximum dose of 120 mg daily and one 80 mg daily. BP control remained satisfactory in nine patients for at least one year after substitution and in all, loop diuretics previously required with minoxidil to control fluid retention, were discontinued. Three patients (23%) however had to be withdrawn because of side effects; one within days of starting therapy and two after three months: one patient died after sustaining myocardial infarction. There was no evidence of deterioration in renal function in those patients continuing on nifedipine. This drug in combination with other antihypertensive agents provides an alternative approach to the management of patients with refractory hypertension, avoiding the severe side effects of the potent vasodilators.

Abnormalities of erythrocyte membrane fatty acid composition in human essential hypertension.

The fatty acid content of erythrocyte plasma membrane was estimated in cells of 17 untreated hypertensive patients, and compared to that of 16 control subjects matched for age, sex and weight. Mean linoleic acid (18:2) content was significantly lower in hypertensives than controls, whereas arachidonic acid (20:4) and oleic acid (18:1) were significantly higher. These results provide further evidence for an alteration in the physiochemical structure of the plasma membrane in cells of hypertensive patients and may be related to the multiple disturbances in erythrocyte ion fluxes which have been observed.

Effects of manipulation of sodium balance on erythrocyte sodium transport.

The effects of changing sodium balance on blood pressure (BP) and erythrocyte sodium transport were investigated in normotensive first-degree relatives of hypertensive patients and control subjects randomised to receive low and high salt diets for two weeks, separated by a two week washout period. Changing from high to low salt intake produced a significant fall in standing diastolic pressure (DBP) in control subjects but not in the offspring of hypertensive patients. In both groups erythrocyte sodium efflux was not changed significantly by either manoeuvre, but the relatives had a significantly higher ouabain insensitive sodium efflux rate constant on both the low and the high salt diet compared to the controls (P less than 0.05). These results are not in keeping with the hypothesis which suggests the release of a humoral sodium pump inhibitor in response to sodium loading but lend support to the view that there is a disturbance of membrane permeability to sodium in subjects genetically prone to hypertension.

The haemodynamic effects of intravenous nifedipine in normotensive and hypertensive subjects.

The antihypertensive effects of intravenous nifedipine, given by bolus and 2 hour infusion, were studied at two dose levels in seven hypertensive (mean BP 178/114 mmHg) and five age-matched normotensive controls (mean BP 128/81 mmHg). Nifedipine significantly reduced systolic and diastolic blood pressure in the hypertensive patients by approximately 20%, but not in the normotensive controls. Similar changes in heart rate and forearm blood flow were seen after bolus injection in both groups, but these were not sustained during infusion. Intravenous nifedipine may be a useful acute treatment for hypertensive emergencies.

Intravenous infusion of magnesium sulphate after acute myocardial infarction: effects on arrhythmias and mortality.

Two hundred patients with acute myocardial infarction were entered into a randomised double-blind trial where they received either intravenous magnesium sulphate or saline for 24 hours after admission to hospital. The incidence of ventricular arrhythmias necessitating treatment was reduced by more than half in the group receiving magnesium sulphate. There were two deaths in the group receiving magnesium sulphate and seven receiving saline placebo. Total cardiac events were significantly reduced in the magnesium treated group. These reductions cannot be attributed to differences in risk factors or therapy between the two groups, either before or during the period of study. These results suggest that magnesium administration reduces the incidence of serious tachyarrhythmias and death after acute myocardial infarction and that this simple regime warrants further study.

Renal vasodepressor mechanism: characterization by chemical medullectomy.

The features of hypertension produced in the rat by chemical medullectomy with 2-bromoethylamine hydrobromide are described. This procedure partially prevents the fall in blood pressure that occurs when the constriction is removed from the renal artery of rats with two-kidney one-clip Goldblatt hypertension. In normal rats, chemical medullectomy causes a moderate but consistent blood pressure elevation that is dose related and associated with elevation of peripheral resistance; the venous side of the circulation is normal. The hypertension is not associated with sodium retention or with activation of the renin angiotensin system. Although vasopressin levels are elevated, the rise is only modest, and blood pressure is not reduced by a vascular AVP antagonist. It is concluded that chemical medullectomy removes the source of a humoral substance that has been shown by other workers to carry out a vasodepressor role. The chemical medullectomy model therefore offers new insights into the renomedullary vasodepressor system.

Nifedipine infusion in acute myocardial infarction: experience in twelve patients.

Studies of nifedipine have not shown that it reduces myocardial infarct size in humans. These studies did not consider the pharmacokinetics and dynamics of nifedipine. Oral doses of nifedipine cause high plasma concentrations and possibly harmful hemodynamic changes. Intravenous nifedipine infusion can rapidly achieve and maintain a steady concentration without repeated hemodynamic upsets. We studied 24-h intravenous nifedipine infusion in 12 patients with acute myocardial infarct, starting within 6 (mean 4.0 +/- 0.7) h of onset of pain, to determine its safety, pharmacokinetics, and dynamics. An intravenous nifedipine bolus of 15 micrograms/kg was followed by an infusion of 0.9 mg/h for 24 h. After the bolus, pulse rate rose 12.5 +/- 8.0 p less than 0.01) and blood pressure fell (systolic by 20 +/- 34, p less than 0.05, and diastolic by 7.5 +/- 15.6, p less than 0.05). There were similar but lesser changes during the infusion. Myocardial oxygen requirements, as measured by the rate-pressure product, did not increase. The mean nifedipine concentration at steady state was 17.2 +/- 4.2 ng/ml and mean elimination T 1/2 3.57 +/- 2.70 h. Nifedipine was discontinued in 3 patients because of hypotension (SBP less than 90), rapid atrial fibrillation, and complete heart block in one patient each. Seven patients developed thrombophlebitis. Large studies of this preparation examining infarct size limitation and mortality are feasible, although in view of the problems of thrombophlebitis in peripheral veins, shorter infusion times or infusion via central lines would be more acceptable.

Treatment of familial hypercholesterolaemia. United Kingdom lipid clinics study of pravastatin and cholestyramine.

OBJECTIVE: To compare the efficacy and safety of cholestyramine, an anion exchange resin, and pravastatin, a new hydrophilic specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in the treatment of heterozygous familial hypercholesterolaemia. DESIGN: Double blind, double dummy, placebo controlled study with three parallel groups. SETTING: Six specialist lipid clinics in the United Kingdom. PATIENTS: 128 patients aged 18-70 with heterozygous familial hypercholesterolaemia diagnosed on strict biochemical and clinical findings. MAIN OUTCOME MEASURES: Total plasma cholesterol, triglyceride, and lipoprotein subfractions and biochemical and haematological safety parameters. RESULTS: Pravastatin (40 mg/day) led to a 25% reduction in total plasma cholesterol concentration and a reduction in low density lipoprotein cholesterol concentration of 30%. Cholestyramine (24 g/day) led to similar reductions in concentrations of total cholesterol (23%) and low density lipoprotein cholesterol (31%). No consistent changes occurred in high density lipoprotein cholesterol values with either compound. Plasma triglyceride concentrations showed a small rise (18%) on resin therapy. No serious adverse drug reactions occurred during the study. CONCLUSIONS: Pravastatin seems to be a highly effective, well tolerated drug for severe hypercholesterolaemia. Patients chosen for this study were recruited on the basis that they could tolerate a full dose of cholestyramine, and in this situation cholestyramine was also highly effective in lowering plasma low density lipoprotein cholesterol concentrations.

Membrane handling of calcium in essential hypertension.

Several abnormalities have been described in the blood-cell handling of calcium in patients with hypertension and rats with genetic hypertension. We have suggested elsewhere that the multiple abnormalities of monovalent and divalent ion handling by blood cells in hypertension, which are loosely and variably associated with blood pressure, reflect a global variability of cell membrane lipids. In the light of this suggestion we tested the relevance of decreased membrane binding of calcium by examining basal and maximal calcium binding in hypertensive patients and in normotensive subjects with and without a family history of hypertension. Calcium binding was reduced to a similar degree in both hypertensive subjects and those with a family history of hypertension. To examine the role of membrane lipids we examined calcium binding in relation to erythrocyte membrane composition, and found a negative correlation between the palmitic:linoleic acid ratio and calcium binding. This is consistent with the observation of a reduction in the unsaturated fatty acid, linoleic acid, in the erythrocyte membrane of hypertensive subjects, and this may therefore be of functional significance. In further studies, although there was no net difference in leucocyte cytosolic calcium between essential hypertensive subjects and normotensive controls, there was a positive relationship between leucocyte calcium and membrane palmitic:linoleic acid ratio only in normotensives. To test further the role of membrane lipids in calcium handling we administered linoleic acid (4 g daily safflower seed oil) to 13 normotensive volunteers in a double-blind crossover trial. Four weeks of administration of the linoleic acid produced a significant decrease in leucocyte calcium (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The role of vascular hypertrophy in early and chronic renovascular hypertension.

Pressor responsiveness to angiotensin II and noradrenaline have been examined using a blood perfused hind limb preparation in early and chronic renovascular hypertension before and after correction of the hypertension by removing the renal artery clip. Hypersensitivity was only partially developed in the early phase but markedly so in the chronic phase. After renal artery unclipping blood pressure returned to normal within 24 h despite the continued presence of enhanced vascular reactivity. When studied 60 days after unclipping, pressor responsiveness had returned to normal in both previously early and chronic hypertensive rats. These results suggest that hypersensitivity to pressor agents develops after hypertension has become established and as a consequence of structural vascular change in response to the raised blood pressure. Although these changes may play a role in the maintenance of blood pressure in chronic hypertension they are of little importance in the development of hypertension.