Amlodipine enhances NO production induced by an ACE inhibitor through a kinin-mediated mechanism in canine coronary microvessels

Our previous study found that angiotensin-converting enzyme (ACE) inhibitor s and amlodipine induce NO release from coronary microvessels through a kin in-dependent mechanism. The goal of this study was to determine whether aml odipine could potentiate NO formation during ACE inhibition. Coronary micro vessels were isolated from 16 mongrel dogs. Nitrite, the hydration product of NO, from coronary microvessels was quantified by using the Griess reacti on. Bradykinin and kallikrein all significantly increased nitrite release f rom coronary microvessels in a concentration-dependent manner. The ACE inhi bitor, ramiprilat, potentiated these effects. Amlodipine also markedly pote ntiated nitrite production by ramiprilat. For instance, amlodipine (10(-10) M) enhanced nitrite release induced by ramiprilat (10(-7) M) from 122 +/- 9 to 168 +/- 14 pmol/mg (p < 0.05 vs. ramiprilat). Nitrite release potentia ted by ramiprilat and amlodipine was entirely blocked by N-omega-nitro-L-ar ginine methyl ester (L-NAME, an inhibitor of NO synthase), HOE 140 (Icatiba nt, a specific B-2-kinin receptor antagonist), and dichloroisocoumarin (DCI C, a serine protease inhibitor that blocks local kinin formation). These re sults clearly show that there is a synergistic effect on NO formation when amlodipine is combined with ACE inhibition. Our data suggest that kinin-med iated coronary NO production may contribute importantly to the beneficial t herapeutic action of ACE inhibitors, especially in combination with amlodip ine in the treatment of heart disease.