Discovery of inhibitors of human renin with high oral bioavailability.

Knowledge of the sequence of a bioactive protein (angiotensinogen) and the availability of a natural product inhibitor lead (pepstatin) were the starting point for discovery of potent penta- and hexapeptide renin inhibitors. Study of the metabolism and disposition of these substances forced the discovery of simpler inhibitors leading to the discovery of oral activity in Terlakiren (22). Modification of physical properties led to the synthesis of aminopiperidine 30, which was identified by oral efficacy profiling. Structural modification to give enzymatic stability produced the bioavailable benzylsuccinate inhibitor 34. Its bioactive monomethylamine metabolite (35, CP-108,671) was subsequently found to have uniformly high oral bioavailability and activity in various species including primates.

Effect of chronic intrarenal prostaglandin E2 infusion and angiotensin II blockade on arterial pressure in the dog.

The present investigation demonstrates that chronic intrarenal PGE2 infusion results in a PRA-induced increase in arterial pressure. This conclusion is supported by an 8-fold rise in PRA and the marked reduction of arterial pressure during saralasin and CEI infusion. If the chronic effects of endogenously released PGE2 are similar to arterial administration, then the net effect of chronically elevated renal PGE2 in the dog appears to be a moderate, sustained hypertension.

Prostaglandin E2-induced hypertension in conscious dogs.

The effects of continuous intrarenal prostaglandin E2 (PGE2) infusion (7 days) on sodium and water balance, plasma renin activity (PRA), and sodium and water balance, plasma renin activity (PRA), and mean arterial pressure (MAP) were examined in conscious, unilaterally nephrectomized dogs maintained on a fixed sodium intake of 55 meq/day. PGE2 infusion (2 microgram/min) resulted in a sustained threefold increase in both urine output and water intake without a measurable change in glomerular filtration rate. PRA increased from 0.4 +/- 0.1 during the control period to 2.2 +/- 0.9 ng AI.ml-1.h-1 on day 1 and averaged 3.6 +/- 0.5 for the remaining 6 days of PGE2 infusion. Concurrently, MAP increased from 102 +/- 3 to a maximum of 117 +/- 4 mmHg on day 5; changes in PRA and MAP were significantly correlated (r = 0.96, P less than 0.001). Sodium excretion increased from 54.5 +/- 3 to 88.0 +/- 19 meq/day on day 1, and then declined to an average of 64.8 +/- 1 meq/day for the remaining 6 days of infusion. All variables returned to the control level during the recovery period. Intravenous infusion of PGE2 (2 microgram/min) yielded directionally similar but statistically insignificant effects. It is concluded that chronic intrarenal PGE2 infusion results in marked diuresis, polydipsia, a moderate loss of sodium, enhanced PRA, and mild hypertension.

Sympathetic nerve activity: role in regulation of blood pressure in the spontaenously hypertensive rat.

Sympathetic nerve activity (SNA) and high pressure baroreceptor regulation of SNA were studied in the Okamoto strain of spontaneously hypertensive rat (SHR). Mean arterial pressure (MAP) and SNA were not significantly affected by anesthesia with low doses of pentobarbital (20-25 mg/kg). Thus, most of these studies were performed in anesthetized rats. SNA in visceral sympathetic nerves increased rapidly with age up to 24 weeks and slowly thereafter. MAP increased with SNA, following the same time course. Both SNA and MAP in SHR were significantly greater than that found in normotensive Wistar control rats of comparable ages. Abolition of ganglionic transmission with hexamethonium in both SHR and normotensive controls reduced postganglionic SNA and MAP to comparable levels. In SHR less than 16 weeks old, increased baroreceptor stimulation effectively inhibited SNA with the same sensitivity as found in Wistar control rats. However, older SHR appeared to lose their ability to completely inhibit SNA during induced hypertension, whereas in Wistar control rats as old as 52 weeks, elevation of blood pressure to 165.3 +/- 2.3 mm Hg completely suppressed SNA. These results suggest that SNA may play an important role in the development and maintenance of hypertension in SHR, and that central sympathetic centers, uninhibited by baroreceptor afferents, become active during the development of hypertension in the SHR.