The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three renin inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma renin activity, immunoreactive renin, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment.

01 Mar 1992·British Journal of Clinical PharmacologyQ2 · MEDICINE

Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor.

Q2 · MEDICINE

Article

Author: J. Ménard ; P. Corvol ; Tt T. Guyenne ; D. Chauveau ; F. Cumin ; G. Chatellier

1. In order to investigate accurately the biochemical effects of renin inhibition in man, we have developed a sensitive assay to measure angiotensin I (1‐10) decapeptide. 2. Angiotensins were extracted from plasma by adsorption to phenylsilylsilica, and angiotensin I (Ang I) was quantified by radioimmunoassay. The detection limit was 0.77 fmol ml‐1, and the extraction recovery of [125I]‐Ang I added to albumin buffer was 83% at the inflection point (10 fmol ml‐1) of the standard curve. The overall recovery was 98.5 +/‐ 3.5%. The intra‐ and inter‐ assay reproducibility was 10.4% and 9.7% respectively. Cross‐reactivity of the antiserum used was low (less than 0.3%) with all angiotensin peptides tested except Ang (2‐10) nonapeptide. 3. A human pharmacological model was subsequently used to assess in vivo the biochemical effects of the renin inhibitor CGP 38560A. Six healthy volunteers received 20 mg lisinopril, a long‐acting ACE‐inhibitor. During the following 24 h, the renin‐angiotensin system was reset with typically elevated active plasma renin and Ang I, at respectively 275 and 429% of basal values. 4. In a randomized three‐way cross‐over protocol, the six volunteers received a 30 min infusion of the renin inhibitor CGP 38560A (125 or 250 micrograms kg‐1) or 5% glucose. The fall in plasma Ang I was 92% and 97.5% after the lowest and highest dose of the renin inhibitor, respectively. A concomitant increase in active plasma renin was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

01 Oct 1991·Clinical nephrologyQ4 · MEDICINE

Renin inhibitors in hypertension.

Q4 · MEDICINE

Review

Author: Luther, R R ; Boger, R S ; Glassman, H N

The renin-angiotensin system (RAS) is an important modulator of blood pressure and fluid balance. The clinical success of angiotensin converting enzyme inhibitors (ACEIs) in the treatment of hypertension has stimulated the search for antagonists of renin. Because renin is highly specific for its substrate, angiotensinogen, renin inhibitors may emerge as clinically preferable alternatives to ACEIs, which affect multiple biological systems, including bradykinin and prostaglandin metabolism. Recent advances in renin inhibitor chemistry have produced highly specific and potent, transition-state analogs of angiotensinogen. Several compounds (e.g., enalkiren, ditekiren, CGP 38560A, and RO 42-5892) have been tested in man. These renin inhibitors produce dose-dependent decreases in plasma renin activity (PRA) which are dissociated from the dose-dependent decreases in blood pressure (BP). Potential explanations for this dissociation include methodologic errors in PRA assays and alternate sites or mechanisms of drug action, including inhibition of noncirculating tissue renin. A prolonged hypotensive effect is seen following single doses of enalkiren and RO 42-5892, and repeated dosing with enalkiren results in sustained hypotensive effect without tachyphylaxis. Renin inhibitors can reduce blood pressure irrespective of baseline renin status and sodium balance. However, high-renin patients generally respond more vigorously, and the hypotensive response is enhanced by sodium depletion. In general, renin inhibitors have been safe and well tolerated in limited clinical studies. New generation renin inhibitors with higher potency and greater oral bioavailability may join the antihypertensive armamentarium.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Phase 1	-	Novartis Pharma AG	-

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