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Renin Release Regulation During Acute Renin Inhibition in Normal Volunteers

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.