Neurally Mediated Negative Inotropic Effect Impairs Myocardial Function During Cholinergic Coronary Vasoconstriction in Pigs

Abstract

Background Myocardial dysfunction elicited during cholinergic coronary vasospasm is generally ascribed to myocardial ischemia. However, when pericoronary nerves extend to the ventricles, efferent vagal discharges that elicit coronary vasoconstriction may, at the same time, depress myocardial contractility by releasing acetylcholine into the myocardium. We analyzed whether a neurally mediated effect contributes to impairment of ventricular function during cholinergic coronary vasoconstriction. Methods and Results Left ventricular (LV) function, ECG mapping, and coronary angiography were analyzed during pericoronary application of methacholine (MCh) to the left anterior descending coronary artery in 53 chloralose-anesthetized open-chest pigs. MCh induced local coronary vasoconstriction and depressed coronary blood flow (13.3±3.7 to 6.0±4.6 mL/min [54%]; ANOVA, P <.001), systolic LV pressure (105±10 to 91±10 mm Hg [13%], P <.001), peak LV (+)dP/dt (2890±524 to 2270±447 mm Hg/s [21%], P <.001), peak LV (−)dP/dt (1446±484 to 1048±276 mm Hg/s [27%], P <.001), and regional systolic segment shortening (0.32±0.09% to 0.18±0.14% [43%], P =.02) and caused local ST-segment elevation (0.9±0.8 to 8.4±3.9 mV, P <.001). These changes were not preceded by heart rate variations, were reproducible, and were inhibited by atropine. MCh during perfusion of nitroglycerin (2 μg·kg − 1 ·min − 1 IV) continued to depress LV pressure (9%, P =.002), LV (+)dP/dt (16%, P <.01), LV (−)dP/dt (20%, P <.01), and segment shortening (18%, P =.03) even though coronary blood flow drop was markedly attenuated (7% versus 54%; ANOVA, P <.01). Disruption of pericoronary nerves with phenol attenuated MCh-induced LV pressure fall ( P <.05). Histological data show that cholinergic and adrenergic pericoronary nerves extend into the ventricular myocardium. Conclusions A neurally mediated effect, in addition to ischemia, impairs LV function during cholinergic coronary constriction in a model with pericoronary nerves extending into the ventricles.