Spontaneously hypertensive and Wistar Kyoto rats are genetically disparate.

Spontaneously hypertensive rats (SHR) are one of the most common animal models used to study essential hypertension in humans. Because SHR and normotensive Wistar Kyoto (WKY) rats were both established from the same parental, normotensive Wistar stock, WKY animals have been used almost exclusively as control animals in studies of SHR. Recently, the suitability of WKY rats as normotensive controls for SHR has been challenged. To establish whether or not SHR and WKY rats share the same immunologic backgrounds, we initially performed a series of skin grafting experiments on these animals. In all cases, grafts of SHR donor skin to WKY recipients and of WKY donor skin to SHR recipients resulted in complete rejection within 7 to 10 days. In addition, grafts of WKY donor skin to other WKY recipients resulted in graft rejection. By contrast, skin grafts between SHRs were always accepted. To further characterize the genetic distinctions between SHR and WKY rats, allelic profiles based on a series of immunologic and biochemical markers were established for each strain. These findings clearly establish that SHR and WKY rats differ at the major histocompatibility complex, in specific blood group antigens, and in a panel of isozymic markers. Moreover, whereas SHRs have the same genetic profiles irrespective of source, some colonies of WKY rats are outbred, as judged by their variant allelic profiles.     

Action of 3-beta adrenolytics on plasma renin activity measured by radioimmunology in genetically hypertensive rats]

Spontaneously hypertensive rats (SHR) have basal levels of plasma renin activity (PRA) lower than the ones observed in normal Sprague Dawley rats. Three beta blocking agents are orally administered to unanesthetized spontaneously hypertensive and normotensive rats. Propranolol and S 464 reduce PRA in spontaneously hypertensive and normotensive control rats. Pindolol do not lower PRA in normotensive rats but increases levels of PRA in spontaneously hypertensive rats. These results are discussed.     

Protein kinase C activity in platelets from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY)

Calcium-activated phospholipid dependent protein kinase (protein kinase C) activity in platelets was measured in 4, 12, and 20-week-old SHR and WKY. At age 4-weeks, there was no significant difference in protein kinase C activity and systolic blood pressure between SHR and WKY. In 12 and 20-week-old SHR, both protein kinase C activity and systolic blood pressure were significantly higher than in the age-matched WKY. These results suggest that protein kinase C may be involved in the control of blood pressure in SHR and WKY.     

Plasma vasopressin variation and renin activity in normal active humans.

Plasma concentrations of vasopressin and plasma renin activity were measured every 30 min for 24 h in 5 normal active humans, in 1 normal woman confined to bed (except for brief periods up to the bathroom), in 2 active patients with primary aldosteronism and in 1 patient with low-renin hypertension. Plasma vasopressin varied markedly over the day and night in a pattern suggesting episodic secretion of the hormone in the normal subjects. Assumption of upright posture was accompanied by a rise in plasma levels from undetectable to 20--50 pg/ml. Episodic secretion, however, also occurred during bed rest and sleep. In contrast, patients with primary aldosteronism and low-renin hypertension had plasma vasopressin levels considerably lower than the normals, and their profiles of plasma concentration lacked the peaks seen in normals. In the normals, although vasopressin and renin secretion often coincided, only 2 of 6 studies showed a significant correlation between the plasma levels of the two hormones. This study, therefore, shows that vasopressin is secreted periodically in normal humans, that upright posture is an important modulator of secretory activity and that the renin-angiotensin system may or may not influence the pattern of secretion. In addition, it underlines the necessity of recumbency in establishing the existence of a circadian rhythm of plasma vasopressin levels.     

The effects of TRH on prolactin, plasma renin activity, water and electrolyte excretion in normal males.

The effect of TRH induced secretion of TSH and prolactin (hPrl) on plasma renin activity (PRA), water and electrolyte excretion, was studied in 7 normal males before and after an intravenous injection of 2 ml normal saline or 200 microgram TRH. Plasma hPrl and TSH rose significantly (p less than 0.01) in all 7 subjects after TRH but not after saline injection. No significant differences in the hourly excretion of sodium, potassium and free water clearance were noted before and after either saline or TRH injection. Mean PRA values of the 7 subjects were similar after either the 2 ml saline of TRH injection. Our results indicate that despite a correlation between basal hPrl and sodium excretion as well as free water clearance, acute TRH induced elevation of hPrl is not associated with changes of urinary sodium and potassium excretion, free water clearance and PRA in normal males. These findings provide some evidence against a direct osmoregulatory role of hPrl in man.     

The activity of kidney lysosomal hydrolases and renin in hypertensive rats.

In renal cortices of hypertensive rats the activity of renin and β-glucuronidase is significantly enhanced, while the activity of acid phosphatase remains pratically unchanged. A significant decrease in protein content accompanies the rise in enzyme activity. The distribution pattern of renin, β-glucuronidase and acid phosphatase after isopycnic centrifugation of cortical homogenates from hypertensive animals is different from that of controls.     

Plasma catecholamines and dopamine-beta-hydroxylase activity in spontaneously hypertensive rats.

Levels of plasma norepinephrine and total catecholamines in spontaneously hypertensive rats bred from a normotensive Kyoto strain of Wistar rats increase between their 8th to 12th week post utero concomitant with the development of hypertension, but levels of plasma norepinephrine are not significantly different between the spontaneously hypertensive strain, a normotensive Kyoto strain and a N.I.H. strain of Wistar rats at either 8 or 12 weeks of age. Plasma total catecholamine levels in the spontaneously hypertensive strain are significantly higher at 12 weeks of age than those in either control strain, while plasma levels of dopamine-β-hydroxylase show no consistant relationship between the three strains. It, therefore, appears unlikely that increased sympathetic neuronal activity is an etiological factor in this form of hypertension.     

Intestinal calcium transport in spontaneously hypertensive rats (SHR) and their genetically matched WKY rats

Calcium transport across the basolateral membranes of the enterocyte represents the active step in calcium translocation. This step occurs by two mechanisms, an ATP-dependent pump and a Ca2+/Na+ exchange process. These studies were designed to investigate these two processes in jejunal basolateral membrane vesicles (BLMV) of the spontaneously hypertensive rats (SHR) and their genetically matched controls, Wistar-Kyoto (WKY) rats. The ATP-dependent calcium uptake was stimulated several-fold compared with no ATP condition in both SHR and WKY, but no differences were noted between rate of calcium uptake in SHR and WKY. Kinetics of ATP-dependent calcium uptake at concentrations between 0.01 and 1.0 microM revealed a Vmax of 0.67 +/- 0.03 nmol/mg protein/20 sec and a Km of 0.2 +/- 0.03 microM in SHR and Vmax of 0.69 +/- 0.12 and a Km of 0.32 +/- 0.14 microM in WKY rats. Ca2+/Na+ exchange in jejunal BLMV of SHR and WKY was investigated in two ways. First, sodium was added to the incubation medium (cis-Na+). Second, Ca2+ efflux from BLMV was studied in the presence of extravesicular Na+ (trans-Na+). Both studies suggest a decreased exchange of calcium and Na+. Kinetic parameters of Na(+)-dependent Ca2+ uptake at concentrations between 0.01 and 1.0 microM exhibited Vmax of 0.05 +/- 0.01 nanmol/mg protein/5 sec and a Km of 0.21 +/- 0.13 microM in SHR and Vmax of 0.11 +/- 0.02 nanmol/mg protein/5 sec and a Km of 0.09 +/- 0.05 in WKY, respectively. These results confirm that the intestinal BLMV of SHR and WKY rats have two mechanisms for calcium extrusion, an ATP-dependent Ca2+ transport process and a Na+/Ca2+ exchange process. The ATP-dependent process appears to be functional in SHR; however, the Ca2+/Na+ exchange mechanism appears to have a marked decrease in its maximal capacity. These findings suggest that calcium extrusion via Ca2+/Na+ is impaired in the SHR, which may lead to an increase in intracellular calcium concentration. These findings may have relevance to the development of hypertension.     

Plasma norepinephrine concentrations: No differences among normal volunteers and low,high or normal renin hypertensive patients

Plasma norepinephrine concentrations were measured by a sensitive radioenzymatic method in 51 patients with essential hypertension and 26 age-matched normal volunteers under conditions of ad libitum sodium intake, after volume expansion by infusion of saline intravenously, and after volume contraction by administration of furosemide orally. The hypertensive patients were classified into low, normal and high renin groups both by renin-sodium indexing and by their renin response to furosemide and saline administration. Plasma norepinephrine concentrations were similar among normal volunteers and patients with low, normal or high renin hypertension while the people were either recumbent or after they stood for 5 min. These and other results do not support the hypothesis that abnormal activity of the sympathetic nervous system accounts for the low or high renin values seen in many hypertensive patients.     

Protein kinase C activity and reactivity to phorbol ester in vascular smooth muscle from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY)

Protein kinase C (PKC) activity in aortic and renal arterial smooth muscle from SHR (20-23 wk male; mean arterial pressure = 178 mm Hg) and WKY (age/sex matched; mean arterial pressure = 126 mm Hg) was quantitated. Activity was greatest in the particulate fractions relative to the soluble fractions in all sources. The only difference between SHR and WKY was in the soluble fraction from SHR renal arteries, which had 2 fold more activity (255 pmol/mg/min) when compared with WKY (136 pmol/mg/min). This difference was not apparently related to force modulation, since the magnitude of isometric force development in renal arteries in response to phorbol 12,13-dibutyrate was not different between SHR and WKY. The magnitude of force developed in response to phorbol 12,13-dibutyrate and PKC activity in the particulate fraction was greatest in aorta vs. renal arteries in both WKY and SHR. These results suggest that regional vascular differences in the amount of PKC activity may exist which are not apparently related to a disease state (i.e., hypertension). These differences may be related to differential sensitivity to phorbol ester-mediated contractions in isolated smooth muscle.     

Cardiovascular effects of prorenin blockade in genetically spontaneously hypertensive rats on normal and high-salt diet

Recent reports have demonstrated a potential role of tissue prorenin in the pathogenesis of cardiovascular and renal damage. This study was designed to examine the role of prorenin in the pathogenesis of target organ damage in spontaneously hypertensive rats (SHRs), the best naturally occurring experimental model of essential hypertension. To this end, we studied 20-wk-old male SHRs receiving a normal diet and 8-wk-old male SHRs given food with 8% NaCl. One-half the rats in each group were given prorenin inhibitor (PRAM-1, 0.1 mg.kg(-1).day(-1)) via osmotic minipumps; the other half served as controls. Arterial pressure, left ventricular function, cardiovascular mass indexes, cardiac fibrosis, and renal function were examined at the end of the experiment. Arterial pressure was unaffected by PRAM-1 in rats on either regular or salt-excess diets. In those rats receiving a normal diet, the blockade of prorenin activation consistently reduced left ventricular mass but affected no other variable. Salt-loaded rats given PRAM-1 for 8 wk demonstrated (1) reduced serum creatinine level, (2) decreased left ventricular mass, (3) improved left ventricular function, and (4) reduced left ventricular fibrosis. These data demonstrated that the blockade of nonproteolytic activation of prorenin exerted significant cardiovascular and renal benefit in SHRs with cardiovascular damage produced by salt excess and suggested that the activation of cardiovascular or renal prorenin may be a major mechanism that mediates cardiac and renal damage in this form of accelerated hypertension.     

Plasma renin system during exercise in normal men

The exercise-related increase in plasma renin activity (PRA) and in the plasma concentration of angiotensin II (ANG II) and aldosterone (Aldo) was studied in 43 healthy volunteers whose 24-h urinary sodium excretion (UVNa) ranged from 10 to 250 mmol. Arterial blood samples were obtained at rest and during bicycle ergometry. Compared with rest, PRA, ANG II, and Aldo rose to a similar extent during light and moderate exercise. However, at peak exercise ANG II increased significantly more (P less than 0.001) than PRA and Aldo. Thus, with increasing intensity of exercise, the slope of the linear regression of ANG II on PRA became significantly (P less than 0.001) steeper, whereas at maximal exercise the Aldo response did not follow the acute rise in ANG II. At rest as well as during exercise, Aldo rose with increasing ANG II, but the stimulatory effect of ANG II on Aldo was attenuated with higher sodium intake, as estimated from UVNa. Finally, independent of the level of physical activity, UVNa was negatively correlated with PRA, ANG II, and Aldo.     

Effect of brain serotonin on the arterial pressure and plasma renin in normal and hypertensive rats]

The effects of changes in brain serotonin content after injections of p-chlorophenylalanine (p-CPA), L-5-hydroxytryptophan (L-5HTP) and 5-6-dihydroxytryptamine (5-6DHT) on the mean arterial pressure (MAP), plasma renin activity (PRA) and peripheral levels of atrial natriuretic peptide (ANP) have been studied in normal and hypertensive (2K:1C model) male Wistar rats. The p-CPA (250 mg/kg) and L-5HTP (200 mg/kg) were injected i.p., while 5-6 DHT (15 micrograms/animal in 10 mu/animal vehicle) was injected into lateral brain ventricles. The effects were studied 24 h after the p-CPA injection, 2 h after L-5HTP and 10 or 20 days after 5-6DHT administration. The fall in brain serotonin produced by p-CPA and 5-6DHT did not modify the MAP values in the normal and hypertensive rat model, whereas the increase induced after L-5HTP injection only caused a slight decrease in arterial pressure in normotensive animals. The ARP experimented remarkable rises in the normal and hypertensive rats, these values increasing after L-5HTP and falling after p-CPA and 5-6 DHT injections. Similar changes are detected in the normal group after administration of these substances related to serotoninergic brain activity. The ANP levels rose after renal artery constriction, and they are not affected by the above mentioned substances. Only p-CPA and 5-6DHT reduced a low decrease in the ANP levels 10 days after their administration.(ABSTRACT TRUNCATED AT 250 WORDS)