Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.

Abstract

The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(l-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r=0.81, n=28, p<0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60±0.43 hours. (Hypertension 1989;13:941-947) O ver the last decade, inhibition of the reninangiotensin system by converting enzyme inhibition has proved very effective for the treatment of hypertension and congestive heart failure.12 Converting enzyme inhibitors block the generation of angiotensin II, a potent pressor hormone. Because converting enzyme is identical to kininase II, it also contributes to the inactivation of the vasodilator hormone bradykinin.3 Accordingly, converting enzyme inhibition does not provide a totally specific means of blocking the reninangiotensin system. Furthermore, the disappearance of angiotensin II from the plasma triggers counterregulatory mechanisms that tend to limit the efficacy of angiotensin converting enzyme (ACE) inhibition. Thus, renin secretion is stimulated and, as a consequence, plasma angiotensin I is elevated. Even in the presence of pronounced ACE inhibition, some angtiotensin II may still be generated. More specific tools for blocking of the reninangiotensin system would be useful. Renin inhibitors have the theoretical advantage of specificity since renin has no known substrate other than angiotensinogen.5 So far, at least experimentally, renin has been blocked by means of various approaches: specific renin antibodies, 6 phospholipids, 78 peptides related to the renin prosegment, 9 pepstatin and its derivatives, 1011 and analogues of the renin substrate. The latter are derived from the minimal sequence of angiotensinogen reacting with renin.12 Actual inhibitors of this class contain a reduced bond between two amino acids at the cleavage site of renin. 13 The inhibitors seem to act by mimicking the transition state of the substrate formed during hydrolysis. Such compounds hav...

Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension.

“…17 This finding is consistent with observations in sodium-replete, normotensive subjects treated with captopril 25 ' 26 and the renin inhibitor CGP 38560A 18 -26 and suggests that blood pressure maintenance in normotensive subjects is not primarily dependent on the renin-angiotensin system. When enalkiren was administered to supine hypertensive patients, a dissociation was noted between PRA suppression and hypotensive response.…”

R-PEP-27, a Potent Renin Inhibitor, Decreases Plasma Angiotensin II and Blood Pressure in Normal Volunteers

“…Total and active renin concentration in these subjects increased signif icantly during administration of the renin inhibitor, 18 as in other studies of the effects of renin inhibition. 19 Anderson et al 20 have demonstrated that enalkiren significantly reduces the blood pressure, plasma re nin activity, and plasma aldosterone concentration in hypertensive subjects, but does not change urinary prostacyclin excretion.…”

“…Nussberger and colleagues 17 reported that in normal subjects on an unrestricted diet who were pretreated with furosemide (40 mg orally), the administration of CGP-38560A (N-(2(R)-benzyl-3-terf-butyl-sulfonylproprionyl)His-Cha-Val-n-butylamide) did not affect blood pressure despite significant reductions in plasma renin activity and angiotensin II concentra tion. Similarly, Delabays and colleagues 18 reported only a slight reduction in blood pressure in normal subjects treated with enalkiren ([N- (3-…”

ES-8891, an orally active inhibitor of human renin.

“…22 In this study, blood pressure in the volunteers did not fall despite the decrease in PRA; this was in accordance with previous results obtained after intravenous infusion of renin inhibitors (enalkiren and CGP 38560A) in normal subjects. 20 - 22 This suggests that maintenance of blood pressure in normal sodium-unrestricted subjects is less dependent on the renin-angiotensin system. 23 Nakamura et al 24 have reported that renin mRNA is increased significantly with an elevation of PRA after treatment with ACE inhibitors.…”