Reduced coronary vasodilator responses to amlodipine in pacing‐induced heart failure in conscious dogs: role of nitric oxide

This study examined whether NO is involved in the in‐vivo coronary vasodilator effects of amlodipine (a calcium channel blocker) and whether heart failure (HF) alters the coronary responses to amlodipine. Nine conscious dogs were chronically instrumented to measure circumflex coronary blood flow (CBF) and coronary diameter (CD). Drugs were administered directly into the circumflex artery through an indwelling catheter to avoid systemic changes. HF was induced by right ventricular pacing (240 b.p.m., 3 weeks). Compared with control (C), in HF, coronary responses to acetylcholine (1–10 ng kg −1 ) were reduced while responses to nitroglycerin (0.1–0.5 μg kg −1 ) were unchanged. In C, amlodipine (30–150 μg kg −1 ), increased dose‐dependently CBF and CD. After LNA (a NO synthase inhibitor, 2 mg kg −1 ), amlodipine produced less increases in CBF and CD (+121±26 ml min −1 and +76±35 μm versus +196±40 ml min −1 and +153±39 μm respectively for 150 μg kg −1 amlodipine alone, both P <0.05). In HF, the coronary responses to amlodipine were reduced (150 μg kg −1 of amlodipine increased CBF and CD +121±23 ml min −1 and +77±21 μm respectively, both P <0.05). After LNA, the CBF responses to amlodipine tended to be reduced (+94±19 ml min −1 at 150 μg kg −1 ) but CD responses were significantly reduced (+41±16 μm, P <0.05). The supplementation with L ‐arginine did not enhance the coronary responses to amlodipine. These results indicate that, in conscious dogs, NO participates in the coronary responses to amlodipine and in HF, the coronary responses to amlodipine are reduced, which is related to a reduced NO production.British Journal of Pharmacology (2002) 136 , 264–270; doi: 10.1038/sj.bjp.0704701