Angiotensinergic versus nonangiotensinergic hemodynamic effects of converting enzyme inhibition in patients with chronic heart failure. Assessment by acute renin and converting enzyme inhibition.

Abstract

BACKGROUND The contribution of nonangiotensinergic effects of converting enzyme inhibitors to their hemodynamic effects in patients with chronic heart failure is not clear. A comparison of the effects of renin and converting enzyme inhibition should help to clarify this issue. METHODS AND RESULTS Thirty-six patients with chronic heart failure (New York Heart Association class II or III) were randomly assigned to receive double-blind either intravenous placebo, the renin inhibitor remikiren, or the converting enzyme inhibitor enalaprilat followed by coinfusion of a second placebo infusion, the addition of remikiren to enalaprilat, or the addition of enalaprilat to remikiren, respectively. Systemic hemodynamics (Swan-Ganz and radial artery catheters) were measured before (rest and submaximal recumbent bicycle ergometry), during (rest), and at the end (rest and exercise) of each 45-minute single- or combination-infusion period. Placebo did not change hemodynamics or renin activity. Effective inhibition of the renin-angiotensin system by remikiren and enalaprilat was indicated by increases of plasma immunoreactive renin together with rapid and complete inhibition of renin activity after remikiren and an increase after enalaprilat (all P < or = .05). Remikiren and enalaprilat rapidly and to a similar extent reduced resting blood pressure through a reduction of systemic vascular resistance, and these changes were significantly correlated to baseline plasma renin activity. Both compounds also decreased pulmonary artery, pulmonary capillary wedge, and right atrial pressures to a similar extent (P < .05). During exercise, pulmonary capillary wedge and right atrial pressures were equally reduced and stroke volume index was increased with remikiren and enalaprilat (P < .05) for both). The combination of converting enzyme with renin inhibition or vice versa did not cause additional hemodynamic changes. CONCLUSIONS Specific renin inhibition in patients with chronic heart failure produces short-term hemodynamic effects that are almost indistinguishable from those of converting enzyme inhibition. This finding and the lack of additional effects of converting enzyme inhibition added to renin inhibition suggest that nonangiotensinergic effects of converting enzyme inhibitors do not play a significant role in their short-term hemodynamic effects in patients with chronic heart failure.

Renal and cardio-protective effects of direct renin inhibition: a systematic literature review

“…Right atrial pressure during exercise and systemic vascular resistance at rest were also significantly reduced. Cardiac index and stroke volume index significantly increased during exercise following remikiren treatment [18]. The changes in vascular hemodynamics were similar to those observed with the ACE inhibitor enalaprilat.…”

“…Direct renin inhibitors such as remikiren [9,[16][17][18][19][20][21][22], enalkiren [23,24], zankiren [10,25,26] and aliskiren [27][28][29][30][31][32][33][34] inhibit the renin system at its point of activation by reducing plasma renin activity (PRA) and thus inhibiting the formation of Ang I and Ang II. In studies in which individuals with and without hypertension were administered remikiren [9,[17][18][19][20][21][22]35,36], enalkiren [23,24] zankiren [10,26], or aliskiren [27][28][29][30]33,34] rapid reductions in PRA were observed in the order of magnitude of 65-95%.…”

“…In studies in which individuals with and without hypertension were administered remikiren [9,[17][18][19][20][21][22]35,36], enalkiren [23,24] zankiren [10,26], or aliskiren [27][28][29][30]33,34] rapid reductions in PRA were observed in the order of magnitude of 65-95%. Moreover, PRA suppression has been reported to be maintained 1 week after cessation of DRI treatment [37].…”

“…Remikiren [9,[16][17][18][19][20][21][22], enalkiren [24], zankiren [10] and aliskiren [27][28][29][30][31]33,34] disrupt the negative-feedback loop by which Ang II normally suppresses renin release from the kidney, thereby stimulating a reactive increase in plasma renin concentration (PRC); large PRC increases are thus observed with all of these drugs.…”

“…Briefly, BP reductions with remikiren [16][17][18][19]21,22,35,36,[46][47][48][49][50] varied among studies. Although a couple of studies showed peak BP reductions of 12.0/ 3.1 mmHg following oral treatment with remikiren 300-600 mg in patients with hypertension [21,35,36,48], the BP-lowering efficacy of remikiren 600 mg was insufficient in other studies [19,21,22].…”