Loss of nitric oxide production in the coronary circulation after the development of dilated cardiomyopathy: a specific defect in the neural regulation of coronary blood flow.

1. The aims of our study were to determine the role of nitric oxide (NO) in cholinergic reflex dilation of the coronary circulation in normal healthy conscious dogs and after the development of pacing-induced dilated cardiac myopathy and overt congestive heart failure. 2. Dogs were instrumented using sterile surgical techniques under general anaesthesia and allowed to fully recover. The Bezold-Jarisch reflex was stimulated by the intra-atrial injection of veratrine or the intravenous injection of PGI2, while the carotid chemoreflex was stimulated by the intracarotid injection of nicotine. Experiments were performed before and after the development of overt congestive heart failure (HF) caused by rapid left ventricular pacing for 4 weeks. 3. The release of NO, or NO-mediated vascular relaxation following administration of acetylcholine (ACh) may have little physiological significance since as ACh is released from nerve endings in vivo. Stimulation of the Bezold-Jarisch or carotid chemoreflex resulted in typical vagal cholinergic reflex coronary vasodilation, an increase in coronary blood flow and a decrease in coronary vascular resistance, which was substantially reduced following NO synthesis inhibition with nitro-L-arginine. 4. After the development of severe congestive HF, the production of NO by sieved coronary microvessels from the heart was markedly reduced accompanied by a 60-80% reduction in both the mRNA (northern blot) and protein (western blot) for endothelial NO synthase in the aorta. 5. After the development of severe pacing-induced HF, activation of the Bezold-Jarisch or carotid chemoreflex no longer resulted in coronary vasodilation due to the disappearance of NO production from the coronary circulation. 6. Therefore, cholinergic reflex coronary vasodilation is mediated by NO. Because coronary blood vessels lose the ability to produce NO after the development of HF, reflex cholinergic coronary vasodilation is markedly altered, uncovering a previously undiscovered specific defect in the integrated control of the coronary circulation in the failing heart.