Enhanced cAMP-induced nitric oxide-dependent coronary dilation during myocardial stunning in conscious pigs

The goal of the current study was to determine the effects of cAMP-mediated coronary reactivity in conscious pigs with stunned myocardium induced by 1 .5 h coronary stenosis (CS) and 12 h coronary artery reperfusion (CAR). Dom estic swine (n = 5) were chronically instrumented with a coronary artery bl ood flow (CBF) probe, hydraulic occluder, left ventricular pressure gauge, wall-thickening crystals in the ischemic and nonischemic zones, and a coron ary sinus catheter. The hydraulic occluder was inflated to induce a CS with a stable 38 +/- 1% reduction in CBF for 1.5 h. Before flow reduction and d uring CAR, cAMP-induced coronary vasodilation was investigated by forskolin (20 nmol.kg(-1).min(-1)). Enhanced CBF responses [+62 +/- 9%, P < 0.05, co mpared with pre-CS (+37 +/- 3%)] were observed for forskolin at 12 h after CAR as well as for bradykinin and reactive hyperemia. With the use of a sim ilar protocol during systemic nitric oxide (NO) synthase inhibition with N- <omega>-nitro-L-arginine (30 mg.kg(-1).day(-1) for 3 days), the enhanced CB F responses to forskolin, bradykinin, and reactive hyperemia were not obser ved after CS. Isolated microvessel preparations from pigs (n = 8) also demo nstrated enhanced NO production to direct stimulation of adenylyl cyclase w ith forskolin (+71 +/- 12%) or NKH-477 (+60 +/- 10%) and administration of 8-bromo-cAMP (+74 +/- 13%), which were abolished by protein kinase A or NO synthase inhibition. These data indicate that cAMP stimulation elicits dire ct coronary vasodilation and that this action is amplified in the presence of sustained myocardial stunning after recovery from CS. This enhanced cAMP coronary vasodilation is mediated by an NO mechanism that may be involved in myocardial protection from ischemic injury.