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

Abstract

1. 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. 2. 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). 3. 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 microg kg(-1)) were unchanged. In C, amlodipine (30 - 150 microg 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 microm versus +196+/-40 ml min(-1) and +153+/-39 microm respectively for 150 microg kg(-1) amlodipine alone, both P<0.05). In HF, the coronary responses to amlodipine were reduced (150 microg kg(-1) of amlodipine increased CBF and CD +121+/-23 ml min(-1) and +77+/-21 microm respectively, both P<0.05). After LNA, the CBF responses to amlodipine tended to be reduced (+94+/-19 ml min(-1) at 150 microg kg(-1)) but CD responses were significantly reduced (+41+/-16 microm, P<0.05). The supplementation with L-arginine did not enhance the coronary responses to amlodipine. 4. 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.

Figure 1

Changes of mean coronary blood flow (CBF) and coronary diameter (CD) responses to intracoronary acetylcholine (Ach), nitroglycerin (NTG) and adenosine (Ade) before and after induction of heart failure. In heart failure, the coronary responses to acetylcholine and adenosine were impaired while the responses to nitroglycerin were unchanged. *P<0.05 versus corresponding baseline values. P value in each graph is the P value obtained by ANOVA for comparison between the control state and heart failure.

Figure 2

Changes of mean coronary blood flow (CBF) and coronary diameter (CD) in response to intracoronary amlodipine infusion in the control state and heart failure. Amlodipine increased CBF and CD in both states, but these responses were significantly reduced in heart failure. *P<0.05 versus corresponding baseline values. P value in each graph is the P value obtained by ANOVA for comparison between the control and heart failure.

Figure 3

Changes of mean coronary blood flow (CBF) and coronary diameter (CD) in response to intracoronary amlodipine infusion in the absence or presence of LNA in the control state and heart failure. In the presence of LNA, the coronary effects of amlodipine were markedly reduced in the control state. In heart failure, the CD response was also altered but the CBF response was minimally affected. *P<0.05 versus corresponding baseline values. P value in each graph is the P value obtained by ANOVA for comparison between the control and heart failure.

Figure 4

The implication of nitric oxide in the coronary responses to amlodipine before and after development of heart failure was assessed by the difference between the effects of amlodipine in the presence and absence of LNA. The difference was obtained by subtracting the effects of amlodipine in the presence of LNA from the effects of amlodipine alone in each state. In heart failure, the difference was significantly smaller for the CBF and there was a trend to a reduction for the CD. *P<0.01 versus corresponding values at same dose.

Figure 5

Changes of mean coronary blood flow (CBF) and coronary diameter (CD) in response to intracoronary amlodipine at the dose of 150 μg kg⁻¹ in the absence or presence of L-arginine in the control state and in heart failure. There was no difference in coronary responses with or without L-arginine in both states.