Angiotensin II- and angiotensin 3-induced aldosterone release vivo in the rat.

The potential role of angiotensin II and its heptapeptide metabolite, des-aspartyl-angiotensin II, was studied in the conscious unanesthetized rat. Aldosterone release was induced by both peptides at physiologic doses (0.72 nanogram per minute). [I-Sarcosyl-8-alanyl]-angiotensin II (P-113 inhibited angiotensin II more effectively than des-aspartyl-angiotensin II (101 percent as compared to 82 percent). These results indicate that angiotensin controls aldosterone release in the rat and that des-aspartyl-angiotensin II (that is, angiotensin III) may be important in this sequence.

Altered renin release and propranolol potentiation of vasodilatory drug hypotension.

Vasodilating antihypertensive drugs induce hypotension with reflex tachycardia, renin release, and fluid and electrolyte retention. Propranolol can impair this renin release. The studies described here were designed to determine the hemodynamic role of vasodilatory drug-induced renin release and inhibition thereof by propranolol in two animals models, the unanesthetized, normotensive and the unanesthetized, genetically hypertensive rat. In studies with normotensive rats, propranolol impaired renin release and tachycardia resulting from hydralazine and minoxidil and potentiated their hypotensive action. Two additional interventions against the renin-angiotensin system were used in evaluating the mechanism of this potentiation. One was removal of the renin source by nephrectomy, and the second was blockade of angiotensin's vasoconstrictor action using a selective angiotensin antagonist, saralasin (1-Sar-8-Ala-angiotensin II (previously known as P113)).. Both interventions potentiated vasocilatory drug hypotension, as did propranolol, but did not prevent reflex tachycardia. When combined with saralasin propranolol did not add to protentiation by this peptide. A similar pattern of blood pressure decrement and potentiation was seen in genetically hypertensive rats when propranolol or saralasin treatment preceded hydralazine. Propranolol was demonstrated to block hydralazine-induced increases in serum renin activity in genetically hypertensive rats. We conclude that hypotensive potentiation of vasocilating drugs by propranolol in these animal models is mediated to a large extent by impairment of renin release. Persistence of hypotensive tachycardia after nephrectomy and after saralasin in normotensive rats suggests the irrelevance of angiotensin's central nervous system stimulation to this cardiac effect. Clinical studies are underway to quantify the potential importance of this beneficial drug interaction in man.

Sodium chloride suppression of renin release in the unanesthetized rat.

Previous studies have shown that increased sodium chloride in drinking water failed to suppress serum renin activity (SRA) in the etheranesthetized rat. In the absence of anesthesia, sodium chloride decreased SRA by 76% and serum aldosterone by 72%. Deoxycorticosterone acetate, when given alone, produced similar results but was more effective in reducing SRA (96%) when combined with sodium chloride. However, if "light" ether anesthesia was administered prior to blood collection, there was a 10-fold increase in SRA and the effects of sodium chloride were blocked. Thus, in the absence of anesthesia, the renin-angiotensin-aldosterone system of the rat responds, as in other species, to a sodium load.

Side effects of vasodilator therapy.

Vasodilating antihypertensive drugs have in common the capacity to activate the peripheral sympathetic nervous system through the carotid sinus baroreceptor reflex mechanism, thereby increasing heart rate, renin release, and sodium and water retention. They differ in their tendencies to augment cardiac output and to relieve or precipitate cardiac failure and arrhythmias. Vasodilating antihypertensive drugs can produce an array of side effects and toxicity including headache, facial changes, hair growth, varying degrees of sodium and water retention, and rarely systemic lupus erythematosus and allergic reactions. Detailed knowledge of these effects is a prerequisite to skillful individualization of antihypertensive regimens.

Renal alpha 2-adrenergic receptors multiply and mediate sodium retention after prazosin treatment.

Renal nerve stimulation-induced antinatriuresis normally is mediated through post-synaptic alpha 1-adrenergic receptors; however, prazosin-induced alpha 1-adrenergic receptor blockade is associated clinically with sodium retention and not natriuresis. To study whether alpha 2-adrenergic receptors mediate renal nerve stimulation-induced antinatriuresis after chronic prazosin treatment, Sprague-Dawley rats were pretreated for 3 days with prazosin (3 mg/kg/day i.p. plus 0.15 mg/ml drinking water) or vehicle (untreated). In isolated perfused (Krebs-Henseleit; Ficoll, 3.5 g/dl, + albumin, 1.0 g/dl at 36 degrees C) kidneys from untreated rats, subpressor levels of renal nerve stimulation (approximately 1 Hz, 10 V, 1 msec) decreased (p less than 0.05) sodium (from 4.50 +/- 0.42 to 1.71 +/- .23 muEq/min) and urinary excretion rate (from 87.2 +/- 4.1 to 57.9 +/- 3.9 microliter/min). Adding prazosin (30 nM) to the perfusate completely (approximately 90%) reversed this effect (p less than 0.05), while alpha 2-adrenergic receptor blockade with yohimbine (300 nM) had no effect. In perfused kidneys from prazosin-treated rats, renal nerve stimulation decreased (p less than 0.05) sodium (from 3.24 +/- .40 to 1.32 +/- .27 muEq/min) and urinary excretion rate (from 78.7 +/- 5.0 to 54.1 +/- 5.3 microliter/min). However, adding prazosin (100 nM) to the perfusate produced only a slight, insignificant reversal of these effects; prazosin plus yohimbine were required to completely reverse the effects. These results suggest that renal nerve stimulation-induced sodium reabsorption was activated by alpha 1-adrenergic receptors in untreated rats and in part by alpha 2-adrenergic receptors in rats pretreated for 3 days with prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Testosterone regulation of renal alpha 2B-adrenergic receptor mRNA levels.

Androgens regulate blood pressure and renal alpha 2-adrenergic receptors in a parallel fashion in the spontaneously hypertensive rat (SHR). The present studies investigated whether this regulation of renal alpha 2B-adrenergic receptors occurs at the mRNA level. Male and female SHR were gonadectomized at 4 weeks of age. The gonadectomized rats were implanted with or without testosterone propionate. Sham-gonadectomized rats served as controls. Total kidney RNA was purified, and alpha 2B-adrenergic receptor mRNA was quantified with a reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The assay uses a mimic RNA added at known concentrations to the sample RNA. The mimic was constructed from the target sequence in the alpha 2B-adrenergic receptor mRNA plus a 20-bp insertion of a random nucleotide sequence. The amount of alpha 2B-adrenergic receptor mRNA present in each sample was obtained by determining the equivalence point between the amount of RT-PCR product formed in the target band versus the mimic band, which were resolved by gel electrophoresis. Intact males had more than two times as much alpha 2B-adrenergic receptor mRNA as intact females. Castration of males reduced the male-female difference by more than 60%. Ovariectomy slightly increased the alpha 2B-adrenergic receptor mRNA level compared with that of intact females. Treatment with testosterone elevated alpha 2B-adrenergic receptor mRNA levels of gonadectomized males and females to the level of intact males. The alpha 2B-adrenergic receptor mRNA levels correlated remarkably well with renal alpha 2-adrenergic receptor density. We conclude that testosterone regulates renal alpha 2B-adrenergic receptor gene expression at the mRNA level in the SHR.

Renal alpha 1-adrenergic receptor response coupling in spontaneously hypertensive rats.

Renal sympathetic antidiuretic, antinatriuretic, and vasoconstrictor responses are mediated by alpha 1-adrenergic receptors in the normal rat. Since the renal nerve has been implicated in the pathogenesis of rat genetic hypertension, we investigated renal alpha 1-adrenergic receptor coupling to phosphoinositide turnover in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In cortical slices from adult (13-week-old) SHR and WKY, stimulation with norepinephrine (10(-7)-10(-3) M) caused a concentration-dependent increase in accumulation of [3H]inositol phosphates. However, dose-response curves for SHR characteristically displayed a depression of the maximum response as compared with those for WKY. Baseline accumulation of [3H]inositol phosphates was not different between strains (39.4 +/- 2.2 cpm/mg tissue/hr for WKY and 34.4 +/- 2.1 cpm/mg tissue/hr for SHR slices; n = 5 rats/group, determined in triplicate). Antagonist competition studies revealed that norepinephrine-stimulated (10(-4) M) [3H]inositol phosphate accumulation was mediated by alpha 1-adrenergic receptors (IC50) for prazosin: 65 +/- 11 nM for SHR and 64 +/- 5 nM for WKY). The reduction in norepinephrine-stimulated [3H]inositol phosphate accumulation in SHR cortex was not the result of the hypertension, since it was also present in cortical slices from young (4-week-old) SHR in which the blood pressure was not yet significantly different from that in WKY and since [3H]inositol phosphate accumulation was unchanged from control values in rats made hypertensive by treatment with deoxycorticosterone acetate. Scatchard analysis of [3H]prazosin binding in renal cortical membranes of young and adult SHR and WKY revealed no significant differences in alpha 1-adrenergic receptor density or affinity between strains at either age. Our results suggest that renal alpha 1-adrenergic receptor coupling to phospholipase C is less efficient in SHR than in WKY. This impaired response is not the result of hypertension or changes in receptor density; this defect may play a role in increased renal sympathetic nerve activity and in the development or maintenance of hypertension in SHR.

Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis.

Seventy-nine hypertensive nephrosclerosis patients entered a prospective randomized single-blind study to 1) establish the pattern of decay of renal function in this population and the variability therein and 2) to determine if strict diastolic blood pressure (DBP) control (less than or equal to 80 mm Hg) is more effective than conventional levels (90-95 mm Hg) in conserving renal function. Because of unexpected significant improvement in renal function in patients from both groups, which changed the perspectives on the course of this disease as described herein, this report is being published before completion of the trial. The selection criteria were 1) serum creatinine concentration of 1.6-7.0 mg/dl, 2) glomerular filtration rate of less than 70 ml/min/1.73 m2, and 3) absence of diseases (other than hypertension) known to destroy renal function. Renal function was assessed by glomerular filtration rate [( 125I]iothalamate clearance) and serum creatinine concentration. Before randomization, DBP was aggressively treated to reduce it to less than 80 mm Hg. Twenty-two subjects (14 in the strict DBP control group and eight in the conventional DBP control group) have been enrolled in the study for 36 months. In contrast to results from previous studies in humans and rats, renal function improved in both patient groups. Thus, irrevocable progression of renal damage after onset of renal failure from high blood pressure does not necessarily occur, and in fact, long-term improvement of renal function resulted from the effects of the study itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced release of endothelium-derived relaxing factor in mineralocorticoid hypertension.

Ring segments of superior mesenteric arteries studied in vitro were used to determine the role of the vascular endothelium in regulating vascular contractile and relaxant sensitivity in deoxycorticosterone acetate (DOCA)-salt hypertension. Wistar rats were given DOCA (20 mg/kg s.c. twice per week) and 1% NaCl drinking water for 5 weeks. In ring segments containing endothelium, there was a decrease in contractile sensitivity to arginine vasopressin, no change in contractile sensitivity to norepinephrine and KCl, and no change in relaxant sensitivity to acetylcholine or isoproterenol in arteries from hypertensive rats compared with normotensive controls. Removal of the vascular endothelium by rubbing had no effect on the contractile response to arginine vasopressin and KCl or the relaxant response to isoproterenol in control arteries. In arteries without endothelium, DOCA-salt hypertension caused a threefold increase in contractile sensitivity for arginine vasopressin, norepinephrine, and KCl; a 50% reduction in maximal relaxation to isoproterenol; and a threefold decrease in relaxant sensitivity to sodium nitroprusside. Indomethacin (10 microM) had no effect on contraction or relaxation. However, N-monomethyl L-arginine unmasked altered contractile sensitivity to norepinephrine in arteries from DOCA-salt hypertensive rats. These data show that the endothelium compensates for increased contractile and reduced relaxant responses of vascular muscle in DOCA-salt hypertension by increasing the release of endothelium-derived relaxing factor. These data suggest that altered vascular responsiveness is masked by the endothelium, thus preventing these alterations from contributing to increased peripheral resistance during the development of DOCA-salt hypertension.

Vasopressin response in collecting ducts of rats resistant to mineralocorticoid hypertension.

In previous studies we found that vasopressin stimulation of both cyclic AMP (cAMP) formation in cortical collecting tubules (CCT) and sodium reabsorption in isolated perfused kidneys was markedly exaggerated in rats with mineralocorticoid hypertension. In the present study, we tested the response (cAMP accumulation) of cortical and outer medullary collecting tubules (OMCT) to vasopressin in two rat models that are resistant to deoxycorticosterone acetate (DOCA)-induced hypertension, the Wistar-Furth strain and NaCl-deficient rats. The blood pressure of normal outbred Wistar rats rose to hypertensive levels (systolic pressure more than 165 mm Hg) during a 5-week treatment with DOCA (10 mg/week) and 1% saline to drink. Significant hypertrophy of the heart and kidneys was also observed. Vasopressin (10(-8) M)-induced cAMP formation was enhanced 3.4-fold in the CCT (OMCT unchanged) of hypertensive rats compared with normotensive controls. Significant hypertrophy (as indexed by tubule diameter) of the CCT but not the OMCT was also observed in DOCA-salt hypertensive rats. Restriction of dietary NaCl (0.13% in chow, tap water to drink) completely prevented DOCA-induced hypertension, organ and CCT hypertrophy, and enhancement of vasopressin-stimulated cAMP formation in the CCT. In Wistar-Furth rats, DOCA-salt treatment did not alter blood pressure or cause significant organ hypertrophy. However, DOCA-salt treatment enhanced vasopressin-stimulated cAMP formation by 4.1-fold in CCT of Wistar-Furth rats, with significant tubular hypertrophy in the CCT but not the OMCT. We conclude that DOCA-induced hypertension and changes in CCT function are dependent on excess dietary NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex influence on renal alpha 2-adrenergic receptor density in the spontaneously hypertensive rat.

Male spontaneously hypertensive rats (SHR) have higher blood pressure than females. We compared renal alpha 2-adrenergic receptor density among intact SHR and Wistar-Kyoto (WKY) rats of both sexes, male and female SHR gonadectomized at 4 weeks of age, and gonadectomized SHR supplemented with testosterone. Additional groups of SHR were treated with enalapril (30 mg/kg per day), an angiotensin-converting enzyme inhibitor, from 5 to 14 weeks of age. Renal alpha 2-adrenergic receptor density was higher in males than females in both SHR and WKY rats. Female SHR and WKY rats had identical low renal alpha 2-adrenergic receptor density. Castration of male SHR reduced the male-female differences in blood pressure and renal alpha 2-adrenergic receptor density by 60%. Treatment with testosterone raised blood pressure and renal alpha 2-adrenergic receptor density to the intact male levels in both gonadectomized males and females. Treatment with enalapril decreased blood pressure but not renal alpha 2-adrenergic receptor density in both male and female SHR. We conclude that (1) both renal alpha 2-adrenergic receptor density and blood pressure are influenced by sex in SHR and WKY, (2) renal alpha 2-adrenergic receptor density like blood pressure is regulated by androgens, and (3) increased renal alpha 2-adrenergic receptor density is not a consequence of high blood pressure in male SHR.

Renal alpha-adrenergic receptor abnormality in the spontaneously hypertensive rat.

Activation of renal alpha-adrenergic receptors induces vasoconstriction, proximal tubular reabsorption of sodium, and inhibition of renal release. Excesses of these effects are present in varying degrees in animal models of, and in patients with, "essential" hypertension. Since essential hypertension is genetically determined, we sought abnormalities of renal alpha-adrenergic receptors in the Okamoto-Aoki strain of spontaneously hypertensive rats (sr-SHR) and their stroke-prone variant (sp-SHR). Total alpha-adrenergic receptor concentrations were determined by Scatchard analysis of [3H]dihydroergocryptine binding to a renal membrane fraction and were found to be increased (p less than 0.02) in male sr-SHR at 4, 16, and 32 weeks of age and in female sr-SHR at 16 weeks of age as compared to age- and sex-matched Wistar-Kyoto controls. They were also increased in 9-week-old sp-SHR renal membranes (p less than 0.005). Further studies revealed that this increase in renal alpha-adrenergic receptors was due entirely to an increase in alpha 2-receptors as measured by [3H]yohimbine binding rather than to an increase in alpha 1-receptors as quantitated by [3H]prazosin binding. No difference in binding affinities of the various radioligands could be demonstrated between any of the hypertensive and normotensive groups of rats. Plasma norepinephrine levels were elevated (p less than 0.01) in the 4-, 9- and 16-week-old SHR, but not in the 32-week-old hypertensive rats. Thus, high renal alpha 2-adrenergic receptor number is coupled with a significant increase in plasma norepinephrine concentrations during the development of hypertension in SHR. By mediating an enhanced receptor-coupled response, such as increased proximal tubular sodium reabsorption, this abnormality of renal alpha-adrenergic receptors may contribute to some or all of the pathophysiologic derangements leading to hypertension in SHR.

Altered renal alpha 2-adrenergic receptor regulation in genetically hypertensive rats.

Renal alpha 1 and alpha 2-adrenergic receptors were quantified in Dahl salt-sensitive and salt-resistant rats, in Okamoto-Aoki spontaneously hypertensive rats (SHR), in Wistar Kyoto "normotensive" (WKY), and in Charles River rats made hypertensive by the Grollman ligature technique and by DOC-NaCl administration after unilateral nephrectomy. The effect of high dietary NaCl on renal alpha receptors was studied in Dahl, SHR, and WKY rats. Renal alpha 1 and alpha 2 receptor densities were higher (p less than 0.05) in SHR and in Dahl salt-sensitive rats than in their normotensive controls. High dietary sodium increased renal alpha 2 receptors and blood pressure in SHR, WKY and Dahl salt-sensitive, but not in resistant Dahl rats. A study of time relationships revealed that the increase in renal alpha 2 receptors preceded most of the blood pressure elevation due to high dietary sodium. Renal alpha-adrenergic receptor densities of surgical (Grollman) and endocrine (DOC-NaCl) forms of rat hypertension were not different from normotensive controls. Thus, renal alpha 2 receptor density and increase thereof by dietary sodium may be: 1) a biochemical marker for genetic forms of hypertension in the rat, and 2) closely linked to the basic mechanism of high blood pressure.

Prazosin-induced alterations in renal alpha-adrenergic receptor function.

Chronic (3-day) treatment with prazosin causes an increase in renal alpha 2-adrenergic receptor density and the relocation of renal tubular alpha 2-adrenergic receptors from extrajunctional to postjunctional sites. We investigated whether chronic prazosin treatment (2 mg/kg, i.p.) caused a functional alteration of other renal alpha 2-adrenergic receptors, using the isolated perfused rat kidney. Prazosin significantly reduced blood pressure and increased heart rate during the 3-day treatment. Renal nerve stimulation (2-8 Hz, 10 V, 1 msec) caused a frequency-dependent increase in renovascular resistance, which was potently blocked by prazosin in vitro in both control and prazosin-treated rat kidneys. The vasoconstrictor response to the alpha 2-adrenergic receptor-selective agonist BHT 933 (3-300 microM) was significantly higher in kidneys from prazosin-treated rats. Yohimbine (3-300 nM) potentiated the response to renal nerve stimulation in both treatment groups. The increase in vascular resistance following renal nerve stimulation was lower in kidneys from prazosin-treated rats, but the response to the alpha 1-adrenergic receptor agonist methoxamine (0.3-1 microM) was unchanged. Further studies revealed that renal nerve stimulation-evoked norepinephrine release from prazosin-treated rat kidneys was significantly lower than release from untreated controls. This response could be normalized to control levels by a combination of cocaine (10 microM) and yohimbine (100 nM). Thus, chronic prazosin treatment caused enhanced alpha 2-adrenergic receptor-mediated vasoconstriction and facilitated renal prejunctional inhibitory mechanisms. We conclude that with chronic alpha 1 adrenergic receptor blockade there is increased alpha 2-adrenergic receptor function in at least two and possibly three sites in the kidney; these include postjunctional tubular, prejunctional vascular, and possibly extra-junctional vascular sites.

Clonidine and prazosin effects in hypernoradrenergic vasodilator-treated and beta-blocker-treated patients.

Our subjects were seven severely hypertensive patients with blood pressures (BPs) over 140/90 who were using minoxidil, propranolol, and diuretics. Clonidine followed by prazosin was added to their regimen on an outpatient basis to establish the dose-response for BP and catecholamines. Plasma renin activity (PRA), body weight, and renal function were measured. Clonidine was given in doses of 0.2, 0.4, 0.6, and 0.8 mg/day. Supine and standing systolic BP decreased at all dose levels of clonidine (P less than 0.01, P less than 0.05). Diastolic BP decreased in the standing position with doses of 0.4, 0.6, and 0.8 mg (P less than 0.01, P less than 0.05). Subjects were hypernoradrenergic initially with plasma norepinephrine (PNE) 895 +/- 122 pg/ml. PNE was suppressed by 0.2 to 0.8 mg clonidine (P less than 0.01) with near maximal suppression at 0.4 mg daily. Systolic BP correlated with PNE (r = 0.59, P less than 0.001). Supine and standing PRA decreased after 0.2 mg clonidine (P less than 0.05) but not after higher doses. Our findings suggest the antihypertensive action of clonidine is related to PNE suppression but not to that of PRA. Plasma epinephrine (PE), body weight, and renal function did not change. Prazosin was given after clonidine to the same patients in a dose range of 3 to 40 mg/day. With doses of 6 to 40 mg, systolic and diastolic and supine and standing BP fell (P less than 0.001, P less than 0.01). PNE remained elevated throughout all dose levels and did not correlate with BP. Weight rose with prazosin (P less than 0.02) but PE, PRA, and renal function did not change. Hence, clonidine and prazosin induced additional lowering of BP but had different effects of PNE and weight.

Radioimmunoassay and pharmacokinetics of saralasin in the rat and hypertensive patients.

A radioimmunoassay for the new angiotensin antagonist, saralasin (1-Sar-8-Ala-angiotensin II), was developed and applied to pharmacologic studies in rats and hypertensive man. Specificity of the assay was established using naturally occurring angiotensins, potential saralasin metabolites, and other synthetic angiotensin analogues. Saralasin pharmacologic half-life of 3.9 min after intravenous administration to rats was similar to the biochemical half-life of 4.2 min. The pharmacologic half-life in high-renin hypertensive patients averaged 8.2 with a biochemical half-life of 3.2 min. These observations suggest that metabolites of saralasin do not accumulate in sufficient quantity in man or rat to interfere with the assay. The biochemical half-life of 3.2 min is consistent with infusion time of less than 20 min required to achieve a stable plasma concentration and pharmacologic activity of saralasin during constant saralasin infusion into hypertensive man. These studies provide a rational basis of future experimental design for saralasin and possibly other peptide analogues.

Clonidine and the vasodilating beta blocker antihypertensive drug interaction.

Because propranolol is contraindicated in some patients and since clonidine can decrease heart rate and renin release, clonidine was substituted for propranolol in 14 severely hypertensive minoxidil-treated outpatients. Clonidine induced weight loss which, since plasma concentrations were not suppressed, was not due to inhibition of release of antidiuretic hormone or renin. These endocrine interrelations were confirmed by later administration of clonidine to 4 of the subjects under controlled circumstances in our General Clinical Research Center. When substituted for propranolol, clonidine controlled blood pressure and heart rate in 8 of the 9 outpatients whose blood pressure had been previously well controlled. Clonidine and propranolol had additive antihypertensive effects in the other 5 patients. Thus, clonidine can substitute for propranolol or when added to the propranolol-vasodilator combination supply an additional blood pressure-lowering effects. This substitution or addition results in an increase in side effects. In addition, clonidine has a diuretic action under these circumstances by an unknown mechanism.

Autonomic ganglionitis with severe hypertension, migraine, and episodic but fatal hypotension.

We report the clinical, pathologic, and immunohistochemical features of a severe hypertensive patient with recurrent migraine-induced hypotension. The patient died of migraine-induced vasomotor paralysis despite prompt institutions of fluid and sympathomimetic and parasympatholytic agents. Postmortem study revealed autonomic ganglionitis and neuritis.

Defective renal adenylate cyclase response to prostaglandin E2 in spontaneously hypertensive rats.

We activated three known components of the adenylate cyclase system in renal membranes from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. The basal adenylate cyclase activity and responses to plasma membrane receptor activation by parathyroid hormone, isoproterenol and vasopressin were not different between the two strains. The response to prostaglandin E2 (PGE2), however, was less in the SHR than in the WKY at five, (P less than 0.05), 12 (P less than 0.01) and 16 (P less than 0.01) weeks of age. Activation of either the guanosine-5'-triphosphate (GTP) binding regulatory protein (N) with sodium fluoride (NaF) and guanyl-5'-yl-imidodiphosphate [Gpp(NH)p], or the catalytic unit with manganese chloride (MnCl2) or forskolin were not different between the two groups. When the medullary and cortical plasma membrane adenylate cyclase responses were studied separately, the observed decreased response to PGE2 (of SHR) was found to be entirely in the cortex. Also, the NaF response was reduced in the cortical region of the 12-week-old rats, a finding suggesting a possibility of a post receptor defect. These results show that there is a defective renal adenylate cyclase response specific to prostaglandin E2 in SHR. This defect could be related to the development of hypertension, by changing the natriuretic and/or renal vasodilating effects of these prostaglandins.

Altered calcium homeostasis in Dahl hypertensive rats: physiological and biochemical studies.

Abnormal calcium (Ca) homeostasis has been reported in essential hypertension and in the Okamoto-Aoki strain of spontaneously hypertensive rats. These abnormalities include increased urinary excretion of calcium and decreased ionized serum calcium (Ca2+). To pursue these abnormalities we studied the chronology of urinary excretion of electrolytes in a genetically homogeneous strain of hypertensive rat, the Dahl/Rapp salt sensitive (S) and resistant (R) rat (at ages 3, 5, 7, 9, 12, 20 and 32 weeks). We also characterized the renal adenylate cyclase-cAMP system by measuring urinary cAMP excretion and adenylate cyclase response to membrane receptor agonists in renal membranes from S and R rats at day 2 and at 6 and 28 weeks of age. Urinary calcium excretion was higher in S than in R at 3, 5 and 7 weeks (0.48 +/- 0.04 versus 0.24 +/- 0.01 mg/mg creatinine at 7 weeks, P less than 0.01). Sodium and phosphorous excretion were lower in S than in R rats at 5, 7, 9, and 12 weeks, and at 5, 7, 9, 12, 20 and 32 weeks, respectively. Potassium excretion was similar in the two groups. Plasma ionized calcium was lower in S than in R rats (3.9 +/- 0.1 versus 4.5 +/- 0.1 mg/dl, P less than 0.01) only at 7 weeks of age. Plasma parathyroid hormone (PTH) was not different between S and R rats. Cyclic AMP excretion and the renal adenylate cyclase response to PTH when referenced to basal activity was lower in S than in R rats at all ages.(ABSTRACT TRUNCATED AT 250 WORDS)