Renin release regulation during acute renin inhibition in normal volunteers.

Abstract

Blockade of the renin-angiotensin system by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (Ang II) antagonist is accompanied by a reactive rise in renin release. This rise is generally attributed to interruption of the short feedback loop between Ang II and renin release. Similarly, after the administration of a renin inhibitor, the plasma concentrations of active and total renin are increased and plasma renin activity is suppressed. The aim of the present study was to investigate if a fall in the plasma Ang II level is the unique determinant of the rise in the active renin (AR) level that follows renin Inhibition. Six normal male volunteers participated in three successive 240-minute experiments at weekly intervals according to a single-blind randomized Latin square design. For experiment 1, Ang II was infused at 2 ng/kg/min from 0 to 60 minutes and at 4 ng/kg/min from 60 to 120 minutes. For experiment 2, 0.3 mg/kg of the new potent renin inhibitor Ro 42-5892 was injected at 30 minutes followed by infusion at 0.1 mg/kg/hr from 30 to 240 minutes. For experiment 3, Ang II and Ro 42-5892 were administered simultaneously at the same doses as described above. The mean±SEM Ang II concentration increased from 10.2±1.6 to 33.7±11.2 pg/ml after infusion of exogenous peptide. It decreased from 9.5±0.9 to 1.4±03 pg/ml after the injection of Ro 42-5892 and increased from 15.6±2.9 to 37.1 ±11.8 pg/ml after the simultaneous infusion of both compounds. At 120 minutes, Ang II infusion decreased the AR level from 30±5 to 12±4 pg/ml and Ro 42-5892 increased it from 28±4 to 209 ±40 pg/ml. After the combined infusion of Ang II and Ro 48-5892, the AR level rose by only 42% (from 22±4 to 38±5 pg/ml) and was still threefold higher than during the infusion of Ang II only. It is concluded that the exogenous infusion of an excess of Ang II minimizes but does not completely suppress the renin stimulation secondary to the administration of renin inhibitor. Although the fall in the plasma Ang II level appears to be a major stimulus of renin release, our results suggest that Ro 42-5892 may also have a direct intrarenal effect, possibly at the level of the juxtaglomerular cells, where renin and Ang II have been codetected and are locally produced.

Angiotensin receptor blockers in diabetic nephropathy

“…The acute response to renin inhibition in healthy subjects studied under similar conditions included a remarkable rise in plasma renin mass, comparable to levels in this study [48]. Over the irbesartan dose range studied, we found no evidence in the healthy subjects of a dose dependency of the renin response: PRA levels had peaked by the earliest time point sampled, at the lowest irbesartan dose.…”

Continuous versus intermittent angiotensin converting enzyme inhibition in renal hypertensive rats.

“…Because plasma Ang II is not the best index of local production of Ang II and most Ang I and Ang II are produced outside of the plasma, 24 the rise in PRC, which reflects the interruption of the intrarenal feedback loop between Ang II and renin release, may represent a more sensitive index of the degree of RAS blockade. 25 Indeed, PRC was much higher in CI rats, at both day 1 and day 30, especially 24 hours after gavage, which demonstrates a more complete and continuous blockade of the RAS in rats treated by osmopumps. The fall in PRS measured by an enzymatic assay is an index of the consumption of angiotensinogen when renin is produced in excess.…”

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42–5892) in hypertensive patients

“…Hence, efforts are being made to synthesize non-peptidic renin inhibitors with higher oral bioavailabity [28]. In spite of the low bioavailability remikiren should be an effacious drug in terms of plasma renin inhibition following oral administration, since plasma concentrations above the in vitro IC5o of 0.8 nM (0.5 ng ml-') were [11,13,14,29,30] and in hypertensive patients [12]. In the patients of the reported studies, an excellent correlation between the inhibition of the angiotensin I production rate (APR) in vivo, which presents the net inhibition of plasma renin (PRA corrected for IRR), and the plasma concentrations of remikiren was found.…”