SYNERGISTIC EFFECT ON REDUCTION IN BLOOD-PRESSURE WITH COADMINISTRATION OF A RENIN INHIBITOR OR AN ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR WITH AN ANGIOTENSIN-II RECEPTOR ANTAGONIST

The effects of coadministration of a renin inhibitor, terlakiren, and an angiotensin-converting enzyme inhibitor, captopril, with the angiotensin II receptor antagonist, losartan, on blood pressure of sodium-depleted guinea pigs were studied. Dose-response relationships for terlakiren (0.1 to 3.0 mg/kg, iv), captopril (0.03 to 1.0 mg/kg, iv), and losartan (0.1 to 6.0 mg/kg, iv) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the response to each dose of the combination of inhibitors, and the results showed that statistically significant synergy with terlakiren and captopril occurred in the presence of losartan. The degree of the synergy indicated that to achieve the same response on blood pressure, the dose of each drug could be decreased approximately 2- to 7-fold when administered in combination. These results indicate that by inhibiting multiple sites in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently. (C) 1994 Wiley-Liss, Inc.