ru-28318 and Hypertension

Antimineralocorticoid drugs are widely prescribed as hypertensive agents, with an efficacy comparable to other drugs (thiazide diuretics, beta-blockers), especially in low-renin hypertension. However they require a prolonged lag-time (several weeks) in order to obtain maximal hypotensive effect. There is no hypokalemia and its possible cardiac and metabolic consequences. They are sometimes responsible for dose-dependent sexual side effect. Knowing the pathophysiology of these effects as well as the precise renal and extra-renal mechanism of action of antimineralocorticoids should lead to the discovery of new specific, efficient and safe compounds for which there is need in the management of hypertension.

Topics: Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Spironolactone

In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.

Topics: Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Brain; Chlorides; Desoxycorticosterone; Diuresis; Hypertension; Injections, Intraventricular; Kidney; Male; Mineralocorticoid Receptor Antagonists; Potassium; Rats; Rats, Wistar; Receptors, Mineralocorticoid; RNA, Messenger; Sodium; Sodium Chloride, Dietary; Spironolactone; Time Factors; Transcription, Genetic

We recently showed that brain mineralocorticoid receptors (MRs) are involved in blood pressure and kidney function control in normotensive Wistar rats. We now assessed the involvement of brain MRs in spontaneously hypertensive rats (SHR), in which the presence of adrenocorticoids has been shown to be required for the development of hypertension. The effect of a single intracerebroventricular (ICV) injection of an MR antagonist (RU28318) on systolic blood pressure (SBP) and renal function was examined in conscious adult SHR and Wistar-Kyoto rats (WKY) maintained on a standard-sodium diet (0.4% Na(+)). In WKY, a long-lasting decrease in SBP was caused by the ICV injection of 10 ng RU28318 as previously reported in Wistar rats, associated with increased urinary excretion of water and electrolytes. In SHR maintained on the standard diet, the ICV injection of RU28318 (10 or 100 ng) had no effect on cardiovascular and renal functions. However, the ICV injection of 10 ng RU28318 in SHR after 3 weeks of high sodium intake (8% Na(+)) caused a long-lasting decrease in SBP. The effect was present at 8 hours (DeltaSBP 34+/-2 mm Hg), persisted at 24 hours (DeltaSBP 29+/-1 mm Hg), and disappeared at 48 hours after the injection. The hypotension was not associated with changes in heart rate, urinary excretion of water and electrolytes, and plasma renin activity, whereas renal denervation did not affect the decrease in SBP. A more pronounced decrease in SBP (49+/-3 mm Hg at 8 hours) was observed with 100 ng RU28318. This dose of the antagonist was without effect after subcutaneous administration. Thus, brain MRs appear to participate in the maintenance of hypertension in conscious adult SHR sensitized by sodium loading.

Topics: Animals; Blood Pressure; Brain; Denervation; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Injections, Intraventricular; Kidney; Male; Mineralocorticoid Receptor Antagonists; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Mineralocorticoid; Sodium, Dietary; Spironolactone; Time Factors

Brain control of arterial blood pressure in man and in animals has been studied increasingly over the last few decades. Despite our knowledge about short term regulation (chemoreceptor and baroreceptor reflexes) there is much more uncertainty about the degree of involvement of brain mechanisms in long term control of blood pressure, and in hypertension. The last decade, a role of brain mineralocorticoid receptors (MR) has been outlined in animal experiments. Stimulation of brain MR by aldosterone or related mineralocorticoids induces an increase in blood pressure and hypertension under chronic conditions. These effects of mineralocorticoid excess can be blocked by specific MR antagonists administered centrally. Stimulation of brain glucocorticoid receptors, as compared to stimulation of brain MR, has an opposite effect, i.e. decreases blood pressure. As in the typical peripheral target organs of aldosterone, in the brain, enzymatic protection of MR against glucocorticoids appears to play an important role. We showed that in conscious normotensive rats intracerebroventricular (i.c.v.) injection of a specific MR antagonist (RU28318) in a low dose (10 ng) decreases blood pressure by about 20% without affecting heart rate. A similar but smaller effect (not statistically significant) was observed in conscious female rats. Only in the male rats an increased diuresis occurred and this may have contributed to the observed hypotension. We conclude that hypertension caused by mineralocorticoid excess may depend on a concerted action of the steroid on the kidney and on the brain. The mechanism by which brain MR increases blood pressure is unknown. It is possible that increased sympathetic outflow and renal mechanisms are involved. Interference with brain MR not only affects blood pressure but it also has effect on renal function.

Topics: Animals; Blood Pressure; Brain; Female; Hypertension; Kidney; Male; Mineralocorticoid Receptor Antagonists; Rats; Rats, Wistar; Receptors, Mineralocorticoid; Spironolactone

The role of brain mineralocorticoid receptor (MR) sites in the pathogenesis of mineralocorticoid hypertension was studied after an intracerebroventricular injection of the MR antagonist RU-28318. Male Wistar rats received subcutaneously implanted deoxycorticosterone acetate (DOCA) pellets and were maintained on 0.9% saline as drinking solution. Under these conditions hypertension developed in approximately 5 wk as assessed in conscious rats by means of the tail-cuff technique. During the development of this hypertension (after 3 wk of DOCA-salt treatment) a single intracerebroventricular injection of the specific MR antagonist RU-28318 reduced systolic blood pressure (SBP) as measured with the tail-cuff method. A decrease in SBP was observed 2-24 h after this intracerebroventricular injection, with the lowest SBP values occurring at 8 h. In these animals (3 wk after DOCA implantation) continuous direct blood pressure recording via chronic cannulation revealed, on the day of the intracerebroventricular injection of RU-28318, a slight increase in arterial pressure during the light phase, followed by a decrease during the dark phase. In the established hypertensive rats (5 wk after DOCA RU-28318 on the arterial pressure or heart rate was detectable. It is concluded that central MR blockade during the development of the DOCA-salt hypertension reduces blood pressure within 24 h assessed with 1) the indirect method at certain time points after exposure to warming and stress and 2) the direct method during the dark phase of the diurnal cycle.

Topics: Animals; Blood Pressure; Brain; Desoxycorticosterone; Heart Rate; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Rats; Rats, Wistar; Receptors, Mineralocorticoid; Sodium Chloride; Spironolactone

Topics: Adrenalectomy; Aldosterone; Amiloride; Animals; Blood Pressure; Brain; Cerebral Ventricles; Hippocampus; Hypertension; Infusions, Parenteral; Mineralocorticoid Receptor Antagonists; Rats; Receptors, Mineralocorticoid; Spironolactone

The development of hypertension in the S/JR rat is accelerated and exacerbated by a high salt consumption. It has been reported that the intracerebroventricular infusion of RU28318, a selective mineralocorticoid antagonist, at doses that are ineffective when administered subcutaneously, inhibits the development of the hypertension produced by the subcutaneous infusion of aldosterone or deoxycorticosterone in normotensive rats. RU28318 was continuously infused intracerebroventricularly or subcutaneously in Dahl S/JR rats before or after the onset of hypertension induced by a high-salt diet. The centrally infused mineralocorticoid antagonist inhibited the initiation of the increase in blood pressure, when the infusion was started concomitantly with the high-salt diet, and blocked its further increase in rats whose blood pressure had already become significantly elevated with 2 wk of a high-salt diet. The subcutaneously infused mineralocorticoid antagonist had no effect. These data serve to strengthen the hypothesis that the mineralocorticoid receptor in the brain is crucial to the genesis of certain forms of hypertension.

Topics: Animals; Blood Pressure; Brain; Diet; Female; Hypertension; Injections, Intraventricular; Male; Mineralocorticoids; Rats; Rats, Mutant Strains; Receptors, Mineralocorticoid; Receptors, Steroid; Sodium Chloride; Spironolactone

The apparent mineralocorticoid excess syndrome of patients ingesting large amounts of licorice or its derivatives is thought to be caused by the antagonism by these compounds of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD inactivates cortisol and corticosterone, allowing the more abundantly produced glucocorticoids access to the mineralocorticoid receptor (MR) in the kidney, where they act as mineralocorticoids. We have found that the infusion of both glycyrrhizic acid, an active principle of licorice, and carbenoxolone, a synthetic analogue, into a lateral ventricle of the brain [intracerebroventricular (icv)] of a rat, at a dose less than that which has an effect when infused subcutaneously, produces hypertension. Furthermore, the hypertension produced by the oral administration of carbenoxolone or glycyrrhizic acid is blocked by the icv administration of RU 28318, an MR antagonist, at a dose below that which has an effect on blood pressure when infused subcutaneously. While the oral administration caused saline polydipsia and polyuria typical of chronic systemic mineralocorticoid excess, the icv licorice derivatives produced hypertension without affecting saline appetite. Sensitizing the rats to mineralocorticoid hypertension by renal mass reduction and increasing salt consumption was not necessary for the production of hypertension. These findings provide additional evidence for a central role in blood pressure control by mineralocorticoids that is distinct from their renal effects. They also suggest that more is involved in licorice-induced hypertension than only inhibition of 11 beta-HSD.

Topics: Administration, Oral; Animals; Blood Pressure; Brain; Carbenoxolone; Corticosterone; Glycyrrhetinic Acid; Glycyrrhizic Acid; Hypertension; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Spironolactone

The chronic intracerebroventricular (icv) infusion of aldosterone in rats and dogs elevates the blood pressure within 10-14 days at doses far below those that produce hypertension systemically. The effect in rats is dose dependent and blocked by the concomitant icv infusion of the antimineralocorticoid, prorenone. The effect of the icv infusion of RU28318, another specific spironolactone mineralocorticoid antagonist, on the hypertension produced by chronic subcutaneous (sc) administration of aldosterone in sensitized rats was reported. Miniosmotic pumps were used to deliver 1 micrograms/h aldosterone sc and 1.1 micrograms/h RU8318 icv. Over a 24-day period the indirect systolic blood pressure of the control, RU28318 icv, and aldosterone sc plus RU28318 icv groups increased from 105 to 123 mmHg and were not significantly different from each other, whereas the aldosterone sc group increased to 156 mmHg. RU28318, icv or sc, did not alter the increase in urine volume produced by aldosterone sc, and there was no significant differences in weight between the groups. This study provides evidence of the importance of the central nervous system in the pathogenesis of hypertension produced by systemic mineralocorticoid excess.

Topics: Aldosterone; Animals; Blood Pressure; Cerebral Ventricles; Hypertension; Infusions, Parenteral; Male; Mineralocorticoid Receptor Antagonists; Rats; Rats, Inbred Strains; Reference Values; Sodium, Dietary; Spironolactone

Hypertension was induced in male rats by administration of a glucocorticoid agonist, RU 26988. Systolic blood pressure (SBP) increased by 35 mmHg. Administration of an antimineralocorticoid derivative, RU 28318, did not modify hypertension. In contrast administration of a steroid derivative with antiglucocorticoid properties, RU 38486, prevented glucocorticoid-induced hypertension in a large part. SBP augmented only by 10 mmHg. The glucocorticoid increased total and active, ouabain-sensitive, 22Na efflux, as measured from caudal arteries, whereas concomitant administration of the antiglucocorticoid derivative prevented these changes. It is suggested that glucocorticoid-induced hypertension may be related to vascular Na pump activation and to the subsequent ionic changes. These changes, as well as hypertension, are antagonized by steroid derivatives with antiglucocorticoid properties.

Topics: Androstanols; Animals; Blood Pressure; Estrenes; Glucocorticoids; Hypertension; Male; Mifepristone; Mineralocorticoids; Rats; Rats, Inbred Strains; Sodium; Spironolactone