Cosegregation of the renin allele of the spontaneously hypertensive rat with an increase in blood pressure.

The spontaneously hypertensive rat (SHR) exhibits alterations in the renin-angiotensin-aldosterone system which are similar to those that characterize patients with "nonmodulating" hypertension, a common and highly heritable form of essential hypertension. Accordingly, we determined whether the inheritance of a DNA restriction fragment length polymorphism (RFLP) marking the renin gene of the SHR was associated with greater blood pressure than inheritance of a RFLP marking the renin gene of a normotensive control rat. In an F2 population derived from inbred SHR and inbred normotensive Lewis rats, we found the blood pressure in rats that inherited a single SHR renin allele to be significantly greater than that in rats that inherited only the Lewis renin allele. To the extent that the SHR provides a suitable model of "nonmodulating" hypertension, these findings raise the possibility that a structural alteration in the renin gene, or a closely linked gene, may be a pathogenetic determinant of increased blood pressure in one of the most common forms of essential hypertension in humans.     

Effect of sodium intake on brain angiotensin-converting enzyme activity in spontaneously hypertensive rat

The effect of sodium intake on angiotensin-converting enzyme activity in five areas of the brain (the cerebral cortex, midbrain, striatum, thalamus and hypothalamus) was studied in normotensive, spontaneously hypertensive and stroke-prone spontaneously hypertensive rats. The enzyme activity was significantly higher in the hypothalamus than in other areas of the brain of spontaneously hypertensive rats. Sodium intake resulted in a significant rise of the enzyme activity in the midbrain of spontaneously hypertensive rats and also in the midbrain and the striatum of stroke-prone spontaneously hypertensive rats. In normotensive rats, however, there was no significant difference in the enzyme activity in any area of brain between the control and the salt-treated group. It is likely therefore that a high circulating sodium level increases angiotensin-converting enzyme content of the brain in spontaneously hypertensive rats, and it is suggested that the increased converting-enzyme activity may play a role in development of hypertension induced by sodium loading.     

Arterial wall renin and renal venous renin in the hypertensive rat.

1. Infusion of sufficient renin to raise the blood pressure of normal rats to hypertensive levels resulted in increased renin in the arterial wall. 2. Arterial wall renin and renal venous renin were normal in younger spontaneously hypertensive rats, but in older spontaneously hypertensive rats arterial wall renin was significantly increased and renal venous renin was significantly decreased. 3. Arterial wall renin in rats with either acute or chronic two-kidney Goldblatt renal hypertension was significantly increased, whereas circulatory renin was elevated in the former, but depressed in the latter. 4. Arterial wall renin may play a role in the maintenance of acute and chronic renal hypertension and also perhaps of spontaneous hypertension of long duration in older rats.     

The renin-aldosterone system in exaggerated natriuresis of essential hypertension

1. The effect of intravenous loading with 500 ml of sodium chloride solution (50 g/l) on plasma renin concentration, plasma aldosterone concentration, urinary sodium excretion and mean blood pressure was studied in 15 young patients with mild essential hypertension and 10 healthy normotensive control subjects. 2. Plasma renin concentration and plasma aldosterone concentration were suppressed to the same degree during loading in both the hypertensive and normotensive groups. Urinary sodium excretion was significantly higher in the hypertensive patients than in the normotensive subjects. Mean blood pressure increased slightly in both groups. 3. Plasma renin concentration and plasma aldosterone concentration were significantly correlated in both groups before sodium loading. The increase in urinary sodium excretion was significantly correlated to the suppression of plasma aldosterone concentration in the hypertensive, but not in the normotensive, group. No correlation was found between changes in urinary sodium excretion and changes in plasma renin concentration or mean blood pressure. 4. The results indicate that the suppressibility of the renin-aldosterone system by hyperosmotic sodium chloride solution is normal in young patients with mild essential hypertension. It is suggested that the changes in plasma aldosterone concentration induced by sodium loading might be involved in the regulation of exaggerated natriuresis in essential hypertension.     

Sodium-potassium-adenosine triphosphatase in nephron segments of spontaneously hypertensive rats

Sodium pump activity of blood vessels has been reported to decrease in several animal models of hypertension. We studied sodium-potassium-adenosine triphosphatase (Na-K-ATPase) activity of renal tubular segments in 12-week-old spontaneously hypertensive rats and in age-matched Wistar-Kyoto normotensive rats. The enzyme activity of the individual nephron segments was determined by a microfluorometric assay in which ATP hydrolysis is coupled with NADH oxidation. In the spontaneously hypertensive rats, systolic blood pressure was significantly higher (181 +/- 3 mm Hg) than in the Wistar-Kyoto rats (134 +/- 2 mm Hg). However, there was no difference in mean Na-K-ATPase activity in any of the nephron segments from the spontaneously hypertensive compared with the Wistar-Kyoto group. It is concluded that Na-K-ATPase activity does not change in any of the nephron segments with spontaneous hypertension.     

Effect of potassium supplementation on blood pressure and vasodilator mechanisms in spontaneously hypertensive rats

1. Supplementation with 1% (w/v) KCl solution significantly attenuated the blood pressure rise with age normally observed in spontaneously hypertensive rats, resulting in a difference in blood pressure of 18 mmHg after 5 weeks. 2. Urinary 6-keto-prostaglandin F1 alpha (the stable hydrolysis product of prostacyclin) and kallikrein excretion were significantly elevated in rats receiving potassium. 3. No difference was observed in sodium excretion during the initial days of potassium supplementation; however, the potassium-supplemented animals excreted relatively more sodium over the 5 week period. 4. Plasma renin activity was significantly reduced in those animals receiving potassium after 5 weeks. 5. It is proposed that a combination of increased systemic and/or renal prostacyclin and kallikrein synthesis may, in combination with reduced renin activity, contribute to the attenuation of blood pressure in potassium-supplemented spontaneously hypertensive rats.     

Calmodulin reduces ouabain-sensitive ATPase of cardiac sarcolemmal membranes: high reduction in spontaneously hypertensive rats

Calmodulin and calcium effects on cardiac ouabain-sensitive adenosine triphosphatase (ATPase) activity were studied in young spontaneously hypertensive rats (SHR) and in their normotensive control Wistar-Kyoto rats (WKY). Cardiac sarcolemmal membranes from SHR showed significantly higher ouabain-sensitive ATPase activity than membranes from WKY rats. This activity was unaffected by calmodulin or calcium alone. However, when both calmodulin and calcium were added, ouabain-sensitive activity was significantly reduced without changes in the total ATPase activity. The calcium-dependent calmodulin effect was dose-dependent and greater in SHR than in WKY membranes. An altered interaction between the calcium-calmodulin system and sodium handling by the plasma membrane in SHR may play a role in the pathogenesis of hypertension.     

Metoclopramide and domperidone block the antihypertensive effect of bromocriptine in hypertensive patients

This study was conducted in normotensive and hypertensive subjects at the Vargas Hospital of Caracas. Normotensive subjects received, in a cross-over fashion, placebo, metoclopramide (MTC), or domperidone (DOMP), 40 mg of each drug, daily for 1 week. The first group of patients under placebo for 1 week received a single 2.5-mg oral dose of bromocriptine (Br). The second group of patients received 30 mg MTC daily (divided into three doses) for 1 week. At the end of the period a single dose of 2.5 mg Br was administered to each patient. The third group of eight hypertensive patients received DOMP for 1 week at 30 mg/d and then a single 2.5-mg Br dose. Cardiovascular and biochemical parameters including arterial pressure, heart rate, plasma renin activity, and plasma aldosterone were evaluated during the 6-hour period before and after the administration of Br. Neither DOMP nor MTC significantly modified blood pressure and heart rate in normotensive patients. Br reduced both systolic and diastolic arterial pressure in hypertensive subjects. The peak of the antihypertensive effect appeared 3 hours after drug administration, but reduction of arterial pressure lasted approximately 6 hours. At the same time, Br reduced plasma aldosterone levels and plasma renin activity. MTC and DOMP reversed the antihypertensive effect of Br and its effect on aldosterone levels and plasma renin activity. We conclude from these findings that Br acts as an antihypertensive agent at peripheral and central levels by stimulating dopamine-2 receptors, which are involved in the aldosterone and renin secretion.     

Influence of age on glomerular binding of angiotensin II in normotensive and spontaneously hypertensive rats

1. Glomerular angiotensin II (ANG II) binding has been studied in normotensive (NTR) and spontaneously hypertensive (SHR) rats at 5, 10, 15 and 20 weeks of age. 2. Binding of 125I-labelled ANG II by glomeruli from NTR and SHR was similar at 5 and 10 weeks of age, with 5 week values of 426.4 (range 384-469) and 400.2 +/- 245 fmol/mg of protein; however, at 15 and 20 weeks ANG II binding by SHR glomeruli was significantly greater than by NTR, with 20 week values of 614.7 +/- 245 and 308.3 +/- 31.8 fmol/mg of protein, respectively (P less than 0.01). 3. The ANG II binding affinity constant (Ka) of glomeruli from NTR and SHR was comparable at 5, 10 and 15 weeks of age, with values of 1.5 (range 1.1-1.9) and 1.08 +/- 0.35 nmol/l, respectively, at 5 weeks; whereas at 20 weeks the Ka for SHR glomeruli was significantly greater than for NTR, with values of 1.85 +/- 0.45 and 0.66 +/- 0.22 nmol/l, respectively (P less than 0.001). 4. Age-related changes in glomerular binding of ANG II in SHR were not found to be related to changes in either plasma renin activity or systolic blood pressure.     

Plasma renin activity in diabetes mellitus.

1. The plasma renin activity (PRA) was measured in 76 diabetic patients who were attending an outpatients clinic. Of these patients 16 had untreated hypertension and 28 had diabetic complications, which ranged from microaneurysms to renal failure and blindness. 2. Compared with age- and sex-matched normotensive control subjects, both normotensive and hypertensive diabetic patients had significantly higher PRA (P less than 0.001). 3. Hypertensive diabetic patients also showed a higher PRA than matched hypertensive control subjects (P less than 0.005). There were no significant differences between diabetic patients with hypertension or complications compared with those without these features. 4. Although this elevation of PRA could be due to a change in another component of the renin-angiotensin system, hypersecretion of renin is the most likely explanation.     

Glandular kallikrein, renin and tonin in tissues of diabetic and hypertensive rats

The submaxillary gland and kidney of diabetic and hypertensive rats were compared for their content of glandular kallikrein and the activities of tonin and renin. The submaxillary glands and the kidneys of both diabetic Wistar strain and hypertensive rats contained significantly less glandular kallikrein than non-diabetic Wistar strain and hypertensive rats (reduction fron 40 to 76%). The renin activity of the kidney showed only a slight change in spite of diabetes, whereas the activity of the submaxillary gland decreased in parallel with the reduction of the kallikrein content when diabetes was induced. On the other hand, the tonin of the submaxillary gland, which has a potent hypertensive activity like renin, was not affected by induction of diabetes. However, the tonin activity in hypertensive rats was significantly higher (p less than 0.001) than that in the normotensive rats (His-Leu, 168.7 +/- 10.1 vs. 131.5 +/- 17.3 nmol/min X mg protein).     

Effect of chronic clonidine treatment and its abrupt cessation on mean blood pressure of rats with a normal or an elevated blood pressure.

1. Clonidine (6 mg of base/l of water) was given as drinking fluid to normotensive rats or rats with established or early hypertension. 2. Spontaneous hypertensive rats (6 months old: average dose of clonidine, 0.6 mg 24 h-1 kg-1) showed a sustained fall in blood pressure over 3 weeks. 3. The same clonidine solution given for 6 weeks to two-kidney Goldblatt rats with early-stage hypertension (average dose of clonidine: 1 mg 24 h-1 kg-1) or spontaneously hypertensive rats (clonidine dose: 1 mg) induced a fall in mean blood pressure, but no change in normotensive rats. 4. Replacement of clonidine by water induced hypertension and lability which led to death in hypertensive but not in normotensive rats.     

Kidney renin gene expression after renin inhibition in the marmoset.

1. The effects of renin inhibitor ES-8891 on renin synthesis and its secretion by the kidney were investigated in normotensive sodium-depleted marmosets. We measured plasma renin activity, plasma immunoreactive renin concentration, plasma angiotensin II concentration and kidney renin mRNA content after oral administration of ES-8891 (60 mg day-1 kg-1) for 1 week. 2. The mean blood pressure was significantly decreased (P less than 0.01) on day 7 after oral administration of ES-8891. There was no significant change in heart rate during the administration. 3. Oral administration of ES-8891 for 1 week markedly decreased the plasma renin activity, the plasma immunoreactive renin concentration and the plasma angiotensin II concentration (to 18%, 41% and 24% of the corresponding control values; P less than 0.05 for each, n = 5). 4. The kidney renin mRNA content in ES-8891-treated marmosets was significantly lower than that in normal controls (4.2 +/- 3.5 versus 12.8 +/- 5.5 pg/micrograms of total RNA, means +/- SD, P less than 0.05, n = 5). 5. Oral administration of the renin inhibitor ES-8891 for 1 week not only inhibited plasma renin activity but also decreased renin synthesis and its secretion by the kidney.     

Stimulation of active renin release in normal and hypertensive pregnancy

1. Active plasma renin concentration but not total renin concentration is reduced in women with pregnancy-induced hypertension compared with normotensive pregnant women. This study was conducted to determine whether women with pregnancy-induced hypertension are able to stimulate release of active renin. 2. Active plasma renin concentration was measured as the generation of angiotensin I at physiological pH in the presence of excess renin substrate, and total renin concentration was determined in the same way after trypsin activation. Inactive plasma renin concentration was calculated as the difference between total renin and active plasma renin concentrations. 3. Resting active plasma renin concentration was significantly greater in third-trimester primigravidae compared with normotensive non-pregnant women and active plasma renin and total renin concentrations rose significantly without a fall in inactive plasma renin concentration in both groups after 2 h ambulation, suggesting increased release of active plasma renin and not conversion of circulating inactive to active renin. These responses were blunted in women taking oral contraceptives. 4. Although the active plasma renin concentration was significantly reduced in third-trimester primigravidae with pregnancy-induced hypertension, total renin concentration was not significantly different compared with normotensive women of similar gestation and in both groups 30 min 60 degrees head-up tilt increased active but not inactive plasma renin concentration. 5. These studies show that in normal pregnancy active plasma renin concentration can be stimulated to a similar extent as in non-pregnant women, despite a higher resting level. This appears to be due to increased secretion of active plasma renin rather than conversion of circulating inactive to active renin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of propranolol on blood pressure and renin in renal hypertension in the rat

1. Propranolol was administered to groups of mature rats before and during the development of renal hypertension induced by ligation of the aorta between the renal arteries. 2. At a dose 10 mumol (3 mg) of propranolol/kg, administered by intraperitoneal injection, the onset and severity of hypertension were not affected, although plasma renin concentration was significantly lower than in the untreated hypertensive rats in the first 5 days after the operation. 3. With 200 mumol (60 mg) of propranolol/kg, administered in the drinking water, peak blood pressure 5 days after aortic ligation was lower than in the untreated control rats, but plasma renin concentration was no lower than with the smaller dose. 4. The development of severe hypertension despite reduction in plasma renin concentration on the low dose of propranolol suggests the participation of renal vasopressor factors other than renin in this model. 5. A higher dose of propranolol reduced the rise in plasma concentration to an equal extent but the rise of blood pressure at 5 days was also reduced, which supports this concept.     

Sympathetic Hyperactivity during Hypothalamic Stimulation in Spontaneously Hypertensive Rats

To determine whether sympathetic hyperactivity of hypothalamic origin contributes to keep blood pressures high in spontaneous hypertension, aortic pressures and sympathetic nerve spike potentials were recorded during electrical stimulation of the posterior hypothalamus in urethane-anesthetized normotensive or hypertensive rats. Basal sympathetic nerve activity was higher in spontaneously hypertensive rats than in either normotensive or deoxycorticosterone acetate-salt hypertensive ones even before stimulation began. Blood pressure elevations produced by hypothalamic stimulation were always preceded by substantial increases in amplitude and rate of neural firing. Changes in amplitude could not be quantified, but rates of neural firing accelerated much more in spontaneous hypertensives than in normotensives during stimulation with 50- and 100-μA currents. Similar differences between deoxycorticosterone acetate-salt hypertensives and either normotensives or spontaneous hypertensives were not statistically significant. Nerve activity invariably became quiescent immediately after hypothalamic stimulation was discontinued, and recovery from this poststimulatory inhibition was faster in spontaneously hypertensive than in normotensive rats. Although spontaneous hypertensives generally also had stronger pressor responses to various sympathomimetic stimuli, responses to hypothalamic stimulation were enhanced to a greater extent than those to either norepinephrine or sympathetic nerve stimulation. Because this selectivity indicates participation of mechanisms other than augmented cardiovascular reactivity, further enhancement of responsiveness to hypothalamic stimuli was attributed to the associated increase in sympathetic nerve firing. These results are in accord with the hypothesis that the blood pressure elevation in rats with established spontaneous hypertension is a result, at least in part, of sympathetic hyperactivity emanating from the posterior hypothalamus.     

Thyroid function and blood pressure in two new strains of spontaneously hypertensive and normotensive rats

1. The influence of thryoid function on the development of hypertension was studied in strains of spontaneously hypertensive (SH) and normotensive rats. 2. Surgical thyroidectomy decreased systolic blood pressure more markedly in SH rats than in normotensive rats. The effects of oral administration of 5 and 100 micrograms of thyroxine 24 h-1 100 g-1 were studied in the thyroidectomized animals. In the two strains the blood pressure returned to control levels only after administration of the larger dose. 3. The evolution of body weight, total plasma tri-iodothyronine (T3) and tetraiodothyronine (T4) concentrations were followed as a function of age in SH rats and normotensive rats from 5 to 21 weeks. At each age, SH rats showed significantly larger body weight and decreased T4 concentrations. Plasma T3 in SH rats was lower than in normotensive rats until 15 weeks of age, after which the difference was not significant. At 11 weeks, plasms free T3 and T4 concentrations were slightly lower in SH rats than in normotensive rats. 4. The more marked hypotensive effects of surgical thyroidectomy in SH rats cannot be related to increased thyroid function.     

The effect of a reduced sodium intake on post-renal transplantation hypertension in rats

In an experimental model of post-renal transplantation hypertension in rats, we studied the effect of a reduction of sodium intake on the development of this type of hypertension. Systolic blood pressure, plasma renin concentration and renal function were measured regularly in recipients of an allogeneic kidney transplant that had previously undergone active immunological enhancement. Transplant recipients on a normal diet showed a rise in systolic blood pressure during the second week after transplantation. The systolic blood pressure of recipients on a low sodium diet remained normotensive throughout the 15 weeks follow-up period. The plasma renin concentration was low in the hypertensive recipients on a normal diet, as compared with unilaterally nephrectomized controls. Although the plasma renin concentration of recipients on a low sodium diet fell below that of unilaterally nephrectomized controls on a low sodium diet, it was higher than that of recipients on a normal diet. The renal function of transplant recipients was greatly reduced compared with that of control rats. The glomerular filtration rate was reduced to a greater extent than the effective renal plasma flow. In a separate experiment it was revealed that a similar reduction in the glomerular filtration rate of kidneys permanently damaged by temporary ischaemia did not result in an increase in the systolic blood pressure. Survival up to 6 weeks after transplantation was the same for both groups of recipients. Recipients on a low sodium diet, however, showed a better 15 weeks survival, probably owing to the absence of hypertension in this group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.     

Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.