There is evidence of crucial central nervous system involvement in the pathogenesis of mineralocorticoid-excess salt hypertension, as well as data indicating that corticosterone is the predominant ligand for the type I adrenocorticoid receptor in the brain. Miniosmotic pumps were used to deliver artificial cerebrospinal fluid (CSF), aldosterone (10 ng/h), corticosterone (10 or 20 ng/h), aldosterone (10 ng/h) plus corticosterone [10 ng/h intracerebroventricularly (icv)], or aldosterone (10 ng/h) plus corticosterone (20 ng/h icv). All animals were sensitized to mineralocorticoid hypertension by removing the right kidney and offering saline to drink. Indirect blood pressure by the unheated tail-cuff method and weights were measured twice weekly; 24-h urine volumes were measured once a week. The blood pressures of the four groups did not differ statistically before infusion. The blood pressures of those animals receiving CSF or corticosterone were not significantly elevated after 4-5 wk of intracerebroventricular infusion, whereas the aldosterone group had become significantly elevated within 2 wk. A similar study was done comparing the effects of intracerebroventricular infusion of aldosterone (10 ng/h), aldosterone (10 ng/h) and RU26988 (20 ng/h), and RU26988 (20 ng/h). RU26988, a selective type II receptor agonist, had no effect on the blood pressure, nor did it alter the pressor effect of intracerebroventricular aldosterone. The concomitant infusion of corticosterone antagonized the increase in blood pressure in a dose-dependent manner. Neither steroid nor their combinations produced significant differences in daily urine volume or body weight gain compared with the CSF group.

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.

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.

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