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 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.

We have developed the technique used by Honstra (1970, British Journal of Haematology, 19, 321) for studying platelet function using a filter and have studied the effects of vincristine (VCR) on platelet aggregation induced by adenosine diphosphate (ADP) in the rat.The filter (Veco Ltd) has 20 pm pores and is supported in a chamber with connecting polyethylene tubing with a total volume of approximately 1 ml. This is inserted into the abdominal aorta of heparinized male Wistar rats anaesthetized with urethane. Proximal and distal blood pressure were recorded with a mean pressure drop of approximately 5 mmHg across the filter. ADP was infused at rates of 0.16-4.2 ,ug/min for 30 s proximal to the filter. Platelet aggregation was apparent by a rise in proximal and fall in distal pressure from which an aggregation index was calculated.In 10 control rats two dose-response curves were constructed. The second, after a saline bolus intravenously, showed less aggregation than the first. In 10 test rats vincristine (0.03 mg/kg) was injected intravenously after the first curve and highly significant depression was seen in the second. There was no significant difference between the first doseresponse curves in test and control animals but the differences in the second curves were significant at all infusion rates ( P < 0.001-< 0.02).VCR depolymerizes platelet microtubules in vitro. We have shown that in the dose used platelet aggregation was depressed in vivo in the rat within minutes. 86.Prostacyclin (PGI,) is synthesized by vascular enuothelial cells and is one of the most potent inhibitors of platelet aggregation so far described. PGI, may therefore play an important role in haemostasis. Like other prostaglandins (PG) which inhibit platelet aggregation (e.g. PGE, and PGDJ, an essential property of PGI, is its ability to stimulate adenylate cyclase activity in platelet membranes, and thereby to raise platelet cyclic AMP levels. The greater potency of PGI, compared with other PG types on platelets raised the question as to whether it is also the most potent agonist in other PG-responsive tissues.We have been interested in the role of PG types as boneresorbing agents in the pathogenesis of malignant hypercalcaemia. Previous studies suggested that PGE, had the greatest bone-resorbing activity but it had been impossible to test the effects of the more unstable prostanoids (PG endoperoxides, thromboxanes and PGI,) in conventional bone culture systems. We have made use of a hormone-responsive induced transplantable osteogenic sarcoma in the rat as a model of bone cell metabolism. In freshly isolated tumour cells, the ability of various stable PG types to stimulate cyclic AMP production is closely related to their bone-resorbing activity. We have studied the actions of some unstable prostanoids on these cells compared with their effects on human blood platelets.Cyclic AMP production by intact platelets and adenylate cyclase activity in isolated platelet membranes were elevated by PGI, and by PGE,, PGD,, PGE, and PGF2, in decrea...