Aspirin enhances the antihypertensive effect of captopril in spontaneously hypertensive rats

Activation of renal or vascular prostaglandin mechanisms (or both) has been proposed to contribute to the antihypertensive action of captopril. In conscious spontaneously hypertensive rats (SHR) studied in the established phase of hypertension, the blood pressure-lowering effect of captopril, 30 mg/kg/12 hr p.o. given for 7 days, was greatly enhanced by the addition of aspirin, 200 mg/kg/day s.c. Systolic blood pressure decreased from 185 +/- 6 and 182 +/- 4 to 135 +/- 3 mm Hg in rats treated, respectively, with captopril and aspirin or captopril alone, and was unaltered by either vehicle or aspirin alone. Water intake was inconsistently affected by captopril but was increased (p less than 0.01) by aspirin and was even higher after captopril-aspirin treatment (p less than 0.01). Urine volume was elevated in all 3 drug-treated groups, increasing threefold after captopril-aspirin treatment. Excretion of sodium and potassium was unchanged by any treatment regimen. In the vehicle group, prostaglandin F2 alpha excretion, measured by radioimmunoassay, ranged between 65 and 93 ng/8 hr and was twofold to fourfold higher than that of prostaglandin E2. Prostaglandin F2 alpha was unaffected during captopril treatment, whereas prostaglandin E2 excretion decreased to 12 +/- 2 ng/8 hr (p less than 0.01) by Day 7. Long-term aspirin treatment, either with or without captopril, did not cause sustained inhibition of renal prostaglandin excretion, although a transient effect occurred within the first four hours of administration. These results indicate 1) aspirin potentiates the blood pressure-lowering effect of captopril in SHR, an effect that is associated with a threefold increase in urine flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ontogenesis of hypertension and responsiveness to antihypertensive agents in spontaneously hypertensive rats

Heart rate, systolic blood pressure and responses of spontaneously hypertensive rats (SHR) to guanethidine, timolol, minoxidil and phentolamine were monitored at 2, 6 and 12 months of age. All antihypertensive agents produced significant and comparable reductions in systolic blood pressure at 6 and 9 months of age, at which time systolic blood pressures were maximally elevated, but had very little effect at 2 months when pressures were only marginally higher. However, at 12 months of age, SHR maintained their response to guanethidine and timolol but responded less well to minoxidil and, especially, to phentolamine. Aortic strips of SHR contracted less than those of normotensive rats to both KCl and norepinephrine at all ages and also relaxed less to nitroglycerin. SHR aortic strips appeared to specifically lose the ability to contract to norepinephine at 12 months of age. It is suggested that a progression of change in responsiveness to antihypertensive agents exists for SHR. Furthermore, this progression will differ for agents with differing mechanisms of action and is probably a result of physical and/or biochemical factors which combine to alter the responsivity of SHR vascular smooth muscle.     

Interaction between lifetime captopril treatment and NaCI-sensitive hypertension in spontaneously hypertensive rats and Wistar-Kyoto rats.

DESIGN: Previous studies that were based on daytime arterial pressure recordings indicate that lifetime treatment with captopril exacerbates the hypertensive response to a high NaCl diet in spontaneously hypertensive rats (SHR) but has no such effect in normotensive Wistar-Kyoto (WKY) rats. The present study used 24-h recording methods to examine the hypothesis that during the normal waking hours of rats (night-time) the hypertensive response to a high NaCl diet is exacerbated in SHR and induced in WKY rats treated with lifetime captopril. METHODS: SHR and WKY rats were (1) untreated, (2), lifetime captopril treated or (3) lifetime captopril treated but removed from the treatment 2 weeks prior to exposure to a high (8%) NaCl diet RESULTS: Compared to untreated SHR, in SHR that were continuously treated with captopril, the high NaCl diet caused a more rapid and greater rise in arterial pressure. Discontinuation of the captopril treatment did not significantly diminish this NaCl-sensitivity. In untreated WKY rats, the high NaCl diet did not alter mean arterial pressure, but in the lifetime captopril-treated WKY rats the high NaCl diet induced a rapid rise in arterial pressure. In WKY rats, discontinuation of the lifetime captopril treatment did not diminish this NaCl-induced rise in arterial pressure, even though baseline mean arterial pressure in this group is similar to that in untreated WKY rats. CONCLUSIONS: Lifetime captopril treatment accelerates the hypertensive response to a high NaCl diet in SHR, and it induces a similar response in WKY rats. In both strains, the lifetime captopril treatment causes a change in the response that is not dependent on concurrent administration of the drug. This finding further suggests that lifetime captopril treatment causes a long-term resetting of cardiovascular response mechanisms.     

Dietary sodium and the antihypertensive effect of nifedipine in spontaneously hypertensive rats.

To assess the interaction of dietary sodium and the antihypertensive response to a calcium antagonist, spontaneously hypertensive rats (SHR) were given a diet of regular or increased (120 v 342 mumol Na+/g food) sodium intake from 4 until 16 weeks of age. Nifedipine was added at 10 weeks of age. This level of sodium intake did not enhance the development of hypertension in SHR. In rats with the regular sodium intake, nifedipine caused only a minor decrease in blood pressure. In contrast, with increased sodium intake nifedipine caused a marked antihypertensive response, preventing the rise in blood pressure occurring between 10 and 16 weeks of age. This enhanced response was associated with a diminished blood pressure fall from ganglionic blockade. These results indicate that modest increases in sodium intake enhance the blood pressure response to a calcium antagonist possibly by potentiating its inhibitory effects on sympathetic activity.     

Kidney renin gene expression in spontaneously hypertensive rats

We studied the expression of kidney renin gene in hypertensive animals by measuring the kidney renin messenger (m) RNA. The kidney renin mRNA was quantified by densitometric Northern blot analysis using a 32P-labelled rat renin genomic DNA fragment as a hybridization probe. Spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) were treated with a low-sodium diet plus furosemide, captopril or propranolol for a week. Plasma renin activity (PRA) in SHR and WKY was increased similarly by sodium depletion and by treatment with captopril. PRA in both strains was not decreased significantly by treatment with propranolol. Both sodium depletion and captopril treatment caused significant increases in the kidney renin mRNA in SHR and WKY. However, the increases in the kidney renin mRNA of SHR were greater than those in the corresponding WKY (SHR, 10.0- and 22.1-fold increases; WKY, 6.2- and 7.8-fold increases, respectively). Propranolol had no effect on the kidney renin gene expression in either WKY or SHR. These results indicate that SHR show an enhanced expression of the renin gene in the kidney compared with WKY in response to stimuli that increase renin release.     

Vascular reactivity in the spontaneously hypertensive stroke-prone rat. Effect of antihypertensive treatment

This study investigated vascular responsiveness in stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of antihypertensive treatment on this responsiveness. Weanling (4-week-old) male and female SHRSP and Wistar-Kyoto rats (WKY) received either the antihypertensive combination treatment of hydralazine plus hydrochlorothiazide in drinking water or tap water alone (controls) for 15 weeks. Whereas the antihypertensive combination prevented the development of hypertension in treated SHRSP (SHRSP-T), blood pressure remained unchanged in treated WKY (WKY-T). Femoral arterial smooth muscle responsiveness to KCl, norepinephrine, and calcium (in the presence of either 40 mM KCl or 1 microM norepinephrine) was not altered in SHRSP when compared with WKY. A significant increase in the sensitivity of femoral arteries to KCl and calcium (in the presence of 40 mM KCl) was seen, however, in SHRSP-T and WKY-T. An increased sensitivity to norepinephrine and calcium (in the presence of 1 microM norepinephrine) was seen only in SHRSP-T. Isoproterenol-induced relaxation was significantly attenuated in both SHRSP and SHRSP-T. Relaxation induced by sodium nitroprusside and calcium (membrane stabilization) was not different between the four groups. These results show that femoral arterial smooth muscle responsiveness to vasoconstrictor stimuli is not altered in SHRSP but that beta-adrenergic-mediated relaxation is attenuated. Antihypertensive treatment resulted in an enhanced responsiveness to these vasoconstrictor stimuli but had no effect on the relaxation properties of femoral arterial smooth muscle.     

Osmotic regulation of vasopressin and renin in spontaneously hypertensive rats

Abnormalities in the vasopressin and renin systems have been reported in spontaneously hypertensive rats (SHR). Therefore, studies were performed to evaluate the responsiveness of these systems to changes in plasma osmolality and sodium concentration. These variables were manipulated in vivo by intraperitoneal administration of distilled water, isotonic saline, or hypertonic saline to 8- and 18-week-old SHR and normotensive Wistar-Kyoto rats (WKY). Animals were decapitated 30 minutes later, and trunk blood was collected. The hypertonic saline injections resulted in an increase in plasma osmolality and serum sodium at both ages (p less than 0.001). Serum vasopressin was higher in all groups of animals receiving hypertonic saline (1200 mosm/kg H2O; p less than 0.05), but the magnitude of increase was not significantly different in the SHR and WKY at either age. Serum renin activity was lower in SHR than in WKY following acute decreases in serum sodium at 8 weeks, but it was the same for both strains at 18 weeks. Both kidney renin content and concentration were lower in SHR than in WKY at 18 weeks but not at 8 weeks. Therefore, the suppressed renin response to acute osmotic challenge in 8-week-old SHR is not the consequence of reduced kidney renin content. The vasopressin response to osmotic stimulation also was evaluated in vitro using hypothalamoneurohypophyseal explants obtained from 5-, 8-, and 18-week-old SHR and WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular atrial natriuretic factor receptors in spontaneously hypertensive rats.

OBJECTIVE: The aim was to investigate vascular receptors for atrial natriuretic factor (ANF) in spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats (WR) at different ages. METHODS: Relaxation and guanylate cyclase responses of blood vessels to atrial natriuretic factor were investigated, as was the binding of 125I-ANF to vascular membranes and ANF receptor subtypes, using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in reducing conditions, after solubilisation and irreversible binding of 125I-ANF. RESULTS: Vascular relaxation responses of aorta showed an increased sensitivity to ANF in four week old SHR [pD2 = 8.9 (SEM 0.1) v 8.5(0.1) in WKY rats, p < 0.05] while sensitivity was similar for the three strains at older ages. Production of cyclic GMP in mesenteric arteries in response to 100 nmol.litre-1 ANF was greater (p < 0.05) in SHR than in WKY rats at four weeks of age, but was similar in older rats. The density of binding sites for ANF in mesenteric arteries, however, was lower in SHR at four weeks (p < 0.01), and increased in older rats, becoming similar to that of normotensive rats at 12 weeks of age. Affinity of ANF sites was similar in all strains. The proportion of high and low molecular weight ANF binding peptides in solubilised blood vessel membranes on SDS-PAGE was similar in all strains except in four week old SHR, in which binding to the high molecular weight band (presumably the guanylate cyclase containing receptor) was increased relative to the low molecular weight band (non-cyclase-coupled receptor) in comparison to other strains and ages. CONCLUSIONS: Activity of guanylate cyclase in response to occupancy of ANF receptors may be increased in young SHR. Normal relaxation of blood vessels in response to ANF in older SHR could result in failure to counteract the increased vasoconstrictor activity present in these rats, which could play a role in the increase in blood pressure.     

Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.     

Portal hypertension ameliorates arterial hypertension in spontaneously hypertensive rats

Systemic hemodynamic effects of portal hypertension in arterial hypertension and their relationship to serum bile acid levels were investigated using spontaneously hypertensive rats 2 and 15 weeks after partial portal vein ligation (SHR-PVL) or sham operation (SHR-SH) and normotensive controls. Mean arterial pressure in SHR-PVL at 2 weeks was decreased to normal due to a decrease in peripheral resistance. Mean arterial pressure and peripheral resistance in SHR-PVL at 15 weeks did not differ from SHR-SH. Resolution of this arterial hypotensive effect and systemic hyperdynamic circulation was associated with decreased portal-systemic shunting. Bile acid levels were increased in both SHR-PVL groups. These results suggest that an endogenous circulating vasodilator(s) associated with portal hypertension ameliorates the systemic vasoconstriction in SHR. Bile acids, while not direct mediators of these hemodynamic events, may be prototypic of this vasodilator. This arterial hypertensive model may aid further investigation of the mechanisms contributing to the hyperdynamic state in portal hypertension.     

Therapeutic benefit of captopril in salt-loaded stroke-prone spontaneously hypertensive rats is independent of hypotensive effect

In the present study we examined whether the angiotensin I converting enzyme inhibitor, captopril, would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and renal pathology over a 26-week period. In the control group of six untreated SHRSP fed Stroke-Prone Rodent Diet and 1% NaCl drinking solution, all animals developed severe hypertension and stroke by 16.1 weeks of age. In eight salt-loaded SHRSP treated with oral captopril (50 mg/kg/day) beginning at 8.4 weeks of age, systolic blood pressure was slightly but temporarily suppressed and then continued to rise; by 12 weeks of age systolic blood pressure reached levels of severe hypertension, 240 +/- 8 mm Hg, and did not differ from that of untreated SHRSP. No deaths or brain lesions were noted in captopril-treated SHRSP despite severe hypertension maintained through 26 weeks of age when the study ended. Captopril treatment prevented increases in urinary protein excretion (14 +/- 2 v 63 +/- 16 mg/day at 11.7 weeks of age, P less than .01) and the severe brain, renal, and cardiac vascular lesions observed in untreated SHRSP. When maintained on Stroke-Prone Rodent Diet and saline, plasma renin activity of untreated SHRSP surviving until 14.5 weeks of age was markedly increased (29.1 +/- 9.4 ng Ang I/mL/h) compared with either untreated SHRSP (9.2 +/- 2.5 ng Ang I/mL/h, P less than .01) or Wistar-Kyoto rats (3.5 +/- 1.0 ng Ang I/mL/h, P less than .01) maintained on standard diet and water.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain kinins are responsible for the pressor effect of intracerebroventricular captopril in spontaneously hypertensive rats

The role of the brain kallikrein-kinin system in the regulation of arterial blood pressure of normotensive and spontaneously hypertensive rats was evaluated. Intracerebroventricular administration of the kinin antagonist [DArg0]Hyp3-Thi5,8[DPhe7]bradykinin caused no change in mean blood pressure in Wistar-Kyoto, Sprague-Dawley, or spontaneously hypertensive rats. The antagonist proved to be very potent in blocking the pressor effect of intracerebroventricular bradykinin (32 +/- 3 vs. 3 +/- 1 mm Hg, p less than 0.01). It was specific, as the pressor effect induced by other unrelated peptides was similar during the infusion of either vehicle or kinin antagonist (angiotensin II, 25 +/- 4 vs. 26 +/- 2 mm Hg; prostaglandin E2, 48 +/- 3 vs. 47 +/- 8 mm Hg; norepinephrine, 17 +/- 2 vs. 18 +/- 2 mm Hg; leucine-enkephaline, 15 +/- 2 vs. 16 +/- 1 mm Hg; neurotensin, 18 +/- 2 vs. 19 +/- 1 mm Hg; substance P, 19 +/- 2 vs. 19 +/- 2 mm Hg). Intracerebroventricular administration of 1 mg captopril, an inhibitor of kininase II (one of the enzymes responsible for kinin degradation), caused no change in mean blood pressure in normotensive rats, whereas it increased mean blood pressure by 44 +/- 9 mm Hg (p less than 0.01) in spontaneously hypertensive rats. This increase in mean blood pressure was blocked and then reversed into a hypotensive effect (22 +/- 6 mm Hg, p less than 0.05) during the infusion of kinin antagonist. Our data suggest that the pressor effect induced by intracerebroventricular captopril is due to a transient elevation in endogenous brain kinin levels, supporting the hypothesis that the brain kallikrein-kinin system plays a role in the central regulation of blood pressure in spontaneously hypertensive rats.     

Significance of brain renin for pathogenesis of hypertension: effect of antihypertensive drugs on active and inactive renins in the brain of spontaneously hypertensive rat

Relationship between blood pressure and brain renin was studied in four groups of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); as controls (n = 5), administered captopril (n = 5), trichlormethiazide (n = 5) and atenolol (n = 5). 1) Inactive renin in the hypothalamus of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and striatum of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. 2) Inactive renin in the hypothalamus of trichlormethiazide administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of trichlormethiazide-administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. 3) Inactive renin in the hypothalamus of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. These results suggest that the production and/or activation of renin in the hypothalamus, thalamus, midbrain and striatum play an important role in the initiation and/or development of hypertension of SHR by the local generation of angiotensin II.     

Renal nerve contribution to NaCl-exacerbated hypertension in spontaneously hypertensive rats

Previous studies demonstrate that bilateral renal denervation enhances urinary sodium excretion and delays the onset of hypertension in young (7-week-old) spontaneously hypertensive rats (SHR) maintained on ordinary laboratory chow. We interpret these data as suggesting that increased renal nerve activity in this model contributes to hypertension by causing excess sodium retention. More recent studies show that dietary NaCl supplementation increases blood pressure and peripheral sympathetic nervous system activity in NaCl-sensitive SHR (SHR-S). The present study tests the hypothesis that the renal nerves contribute to the rise in arterial pressure caused by dietary NaCl supplementation in this model. SHR-S were fed a high (8%) or basal (1%) NaCl diet beginning at age 7 weeks. Bilateral renal denervation was carried out 2 weeks after the initiation of the diets, at which time systolic blood pressure was significantly higher in the high (compared with the basal) NaCl group. Systolic blood pressure was reduced slightly less in denervated SHR-S on the high (compared with basal) NaCl diet during the following 5 weeks. Renal denervation performed 1 week before initiation of the diets attenuated the subsequent development of hypertension equally in both groups. Both renal denervation and the high NaCl diet increased alpha 2-adrenergic receptor numbers in the kidney; renal denervation caused an approximately equal increase in alpha 2-adrenergic receptor binding in SHR-S on high and basal NaCl diets. The high NaCl diet increased plasma noradrenaline concentration, and renal denervation lowered mean arterial pressure but did not decrease circulating catecholamines in either diet group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of antihypertensive therapy upon myosin isozyme distribution in spontaneously hypertensive rats.

INTRODUCTION: Myosin isozymes have been known to become altered during the development and regression of myocardial hypertrophy, but the mechanism by which the shifting takes place is not known. The present paper describes the effects of antihypertensive drugs, with a known mechanism of action, upon myocardial mass, blood pressure and myosin isoforms in spontaneously hypertensive rats (SHR). METHODS: SHR were treated with antihypertensive drugs and their blood pressure, myocardial mass and myosin isoforms determined. RESULTS: A shift of myosin isoform from the V3 to the V1 type and normalization of myocardial hypertrophy were seen in rats treated with captopril but not in those treated with diuretics. Clonidine and guanethidine increased the V3 form in association with moderate control of blood pressure and no change in myocardial mass. Treatment with a beta-blocker regressed hypertrophy, controlled hypertension but increased the V3 form. Treatment with minoxidil normalized blood pressure, increased cardiac mass and increased the V3 type. CONCLUSIONS: Treatment with different antihypertensive drugs does not cause similar types of shifts in myosin isoform and has divergent effects upon blood pressure and heart weight. Furthermore, there is no correlation between myocardial mass, blood pressure and myosin isozyme shifts. We conclude that factors other than blood pressure, myocardial mass and catecholamines modulate the shifting of myosin isoforms. Since captopril had a greater remedial effect upon myosin isoforms in our study than the more commonly used agents, we recommend that the current criteria for selection of antihypertensive drugs and the relation between those drugs and cardiac function be re-evaluated.     

Renal arteriolar diameters in spontaneously hypertensive rats. Vascular cast study

The relation between the arteriolar diameters and hypertensive glomerulosclerosis was studied by using microvascular casts and histological evaluation. Spontaneously hypertensive rats 4 weeks of age were divided into three groups: nontreated, captopril (40 mg/kg/day)-treated, and trichlormethiazide (1 mg/kg/day) with hydralazine (20 mg/kg/day)-treated. Wistar-Kyoto rats served as controls. At 6 weeks old, the captopril-treated rats showed a lower blood pressure and a larger afferent arteriolar diameter compared with the control rats. At 20 weeks old, the nontreated group exhibited hypertension and a lower arteriolar diameter ratio (afferent to efferent, 0.89 versus 1.22 in control group) because of afferent constriction and efferent dilatation, seen equally in the outer and inner cortexes. Glomerulosclerosis was accentuated only in the inner cortex of the nontreated group (score, 63 versus 29 in control group). In the two treated rat groups, the blood pressure was reduced and arteriolar diameter ratios were similar to those in the control group (1.18 and 1.26). The sclerosis score in the trichlormethiazide with hydralazine-treated rats (score, 26) was lower than in the nontreated rats but not the captopril-treated rats (score, 36). These results indicated that 1) in the hypertensive rats, despite a reduced diameter ratio, glomerulosclerosis was more severe in the inner cortex; 2) two therapies reduced blood pressure and reversed the arteriolar changes, but a decrease in glomerulosclerosis was seen only in the trichlormethiazide with hydralazine-treated rats; and 3) for development of glomerulosclerosis, factors other than hemodynamics may be important in addition to intraglomerular pressure.     

Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension.

The treatment response to beta-adrenoceptor blocking drugs was compared in two groups of patients with primary (essential) hypertension and different renin levels. Each group consisted of 25 patients and was equally distributed regarding age, severity and stage of hypertension. In the first group (group 1), the mean upright plasma renin activity was 0.8 ng ml-1h-1 (range 0.3 to 1.5) and the patients were considered to have low renin hypertension. In the other group (group 2) the patients had a mean plasma renin activity of 2.1 ng ml-1h-1 (range 1.1 to 5.1) and were considered to have normal to high renin hypertension. In both groups the patients were initially treated with beta-blocking drugs; in group 1 with a beta-blocker corresponding to an average dose of 311 mg propranolol a day for at least eight weeks and in group 2 with propranolol 320 mg a day in a fixed dose for eight weeks. The hypotensive response differed significantly between the two groups (p less than 0.001). In group 1 the pretreatment blood pressure was 197/117 mm Hg supine and 198/120 mm Hg standing. During treatment blood pressure decreased only 5/3 mm Hg supine and 9/5 mm Hg standing. The pretreatment blood pressure in group 2 was 187/114 mm Hg supine and 186/117 mm Hg standing. Beta-blocking therapy reduced blood pressure 36/23 and 34/18 mm Hg, respectively (both p less than 0.001). Pulse rates fell significantly in the two groups, both in the lying and standing positions. In 17 patients with low renin hypertension (group 1), a volume-depleting drug was added (spironolactone, 14 patients; thiazides, 3 patients) and this achieved a marked fall in blood pressure levels of 38/16 mm Hg supine and 37/19 mm Hg standing (both p less than 0.001). These results suggest the following: (1) Most patients with normal to high plasma renin activity respond well to moderate doses of propranolol. (2) Propranolol given in the same doses is almost without antihypertensive effect in patients with low renin hypertension. (3) A volume factor may be operating in patients with low renin hypertension since a hypotensive effect is demonstrated after the addition of volume-depleting drugs. (4) Determination of plasma renin activity with adequate methods can predict the treatment response to hypotensive agents.     

Potassium depletion ameliorates hypertension in spontaneously hypertensive rats

The hemodynamic effect of moderate K+ depletion in hypertension is unknown. Since severe K+ depletion reduces systemic vascular resistance in normotensive rats, we determined the effect of K+ depletion on the natural history of hypertension in spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) and SHR were fed a K+-replete, a moderately K+-depleted, or a severely K+-depleted diet. After 6 weeks, systemic vascular resistance was reduced by 25% in WKY on the severely K+-depleted diet while mean arterial pressure and systemic vascular resistance were comparable in WKY on the other two diets. In SHR on the severely K+-depleted diet for 6 weeks, muscle K+ was reduced by 23% and growth rate by 65%. In SHR on the moderately K+-depleted diet, growth rate was reduced by 23% after 3 weeks. By 6 weeks, however, muscle K+ was reduced by 5 to 6% and growth rate was comparable to that in SHR receiving the K+-replete diet. The administration of either K+-depleted diet prevented the development of hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 122 +/- 3; K+-replete, 155 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups) and reversed established hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 128 +/- 3; K+-replete, 171 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups). The protective effect of K+ depletion was mediated by a 40% reduction in systemic vascular resistance. These results suggest that K+ depletion has a potent antihypertensive effect in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

DOCA-salt induced malignant hypertension in spontaneously hypertensive rats

DOCA-salt hypertension was produced in 10 male 10-week-old normotensive Wistar-Kyoto (WKY) rats receiving deoxycorticosterone acetate (DOCA; 100 mg/kg, subcutaneous pellet) and 1% NaCl drinking water and was compared with data from 10 age- and sex-matched WKY receiving normal tap water (C). These data were also compared with spontaneously hypertensive (SHR) rats similarly treated. After 10 weeks on these programmes, systemic and regional haemodynamics were determined in conscious rats using microsphere techniques. DOCA-salt treatment increased mean arterial pressure (MAP), total peripheral resistance index (TPRI), cardiac and renal weights in both WKY and SHR. In contrast to SHR (C), the SHR (DOCA) demonstrated more severe MAP elevation (204 +/- 4 versus 185 +/- mmHg; P less than 0.01), more severe systemic and regional (especially renal) vasoconstriction, and malignant vasculitis associated with azotaemia and hyperuricaemia. The hyperuricaemia was related inversely to renal blood flow (r = -0.74; P less than 0.01) and directly to renal vasoconstriction (r = 0.65; P less than 0.05) in SHR (DOCA). These data suggest that in both WKY and SHR, DOCA and salt produced marked cardiovascular changes and SHR rats developed malignant hypertension.