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

Abstract

The effects of coadministration of a renin inhibitor, terlakiren, and an angiotensinconverting 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 mgikg, iv), and losartan (0.1 to 6.0 mgikg, 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. o 1994 WiIey-Liss, Inc.

Comparison of antihypertensive effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist and a diuretic in patients with hypertension not controlled by angiotensin receptor blocker monotherapy

“…However, the clinical significance of this finding remains debatable, in that it was derived mostly from studies with limitations of methodology, such as experimental conditions [5][6][7][8][9][10], evaluation of a normotensive population [11], blood pressure assessment exclusively by office measurements [14,16,17], or use of ACEI or ARB monotherapy at submaximal doses [13,15,17]. Interestingly, it has been suggested that the administration of an ACEI might not provide additional antihypertensive effect if the angiotensin II type 1 (AT 1 ) receptor has been effectively blocked by an ARB [11].…”

“…Accumulating evidence suggests that the combination of an ACEI with an ARB provides a greater blood pressure-decreasing effect than either drug given as monotherapy [5][6][7][8][9][10][11][12][13][14][15][16][17]. However, the clinical significance of this finding remains debatable, in that it was derived mostly from studies with limitations of methodology, such as experimental conditions [5][6][7][8][9][10], evaluation of a normotensive population [11], blood pressure assessment exclusively by office measurements [14,16,17], or use of ACEI or ARB monotherapy at submaximal doses [13,15,17].…”

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

“…11 (9)(10)(11)(12)(13)(14) b,d valsartan alone. The AUC 0 -24 of plasma active renin concentration for the A150ϩV80 combination was significantly higher than that achieved with 160 mg of valsartan and similar to that achieved by A300 alone.…”

“…Thus, we investigated whether a combination of the orally active potent alkane carboxamide renin inhibitor aliskiren (150 mg) (9,10) and the AT1R antagonist valsartan (80 mg), which inhibit the RAS at the first and last steps, respectively, results in a stronger blockade of the RAS and larger decreases in aldosterone excretion than higher doses of each RAS inhibitor given alone. Synergistic effects of a combination of a renin inhibitor and AT1R blocker on BP have been demonstrated in a preclinical study (11). We have used the same clinical and laboratory methods as those previously used to differentiate the combination of an ACE inhibitor and AT1R antagonist from each component (12,13).…”

Synergistic decrease in blood pressure by captopril combined with losartan in spontaneous hypertensive rats

“…Therefore, our current results of greater attenuation of BP with combined therapy of ACE inhibitors with ARBs indicate that multi-step therapeutic intervention more effectively blocks the renin-angiotensin system. This is supported by other trials in which combined therapy of captopril with renin inhibitors such as CP-80,794 (Fossa et al, 1992) or terlakiren (Fossa et al, 1994) also produced a synergistic effect on lowering blood pressure.…”