Lack of role for nitric oxide in cholinergic modulation of myocardial contractility in vivo

Despite intensive investigation, the role of nitric oxide (NO) in cholinerg ic modulation of myocardial contractility remains unresolved. The left ante rior descending coronary artery of 34 anesthetized, open-chest dogs was per fused via an extracorporeal circuit. Segmental shortening (SS) was measured with ultrasonic crystals and coronary blood flow (CBF) was measured with a n ultrasonic flow transducer. An intracoronary infusion of ACh (20 mug/min) was performed, with CBF held constant, under baseline and during dobutamin e, CaCl2, or amrinone at doses increasing SS by similar to 50% (10 mug/min, 15 mg/min, and 300 mug/min ic, respectively). ACh-induced responses during dobutamine were also assessed following treatment with the NO synthase inh ibitor N-G-nitro-L-arginine methyl ester (L-NAME; 300 mug/ min ic for 15 mi n). The effects of sodium nitroprusside (SNP; 80 mug/min ic), an exogenous NO donor, bradykinin (2.5 mug/min ic), a nonmuscarinic releaser of endothel ial NO, and bilateral vagal stimulation (before and after L-NAME) were eval uated during dobutamine. ACh had no effect on SS under baseline or during C aCl2, but it decreased SS during dobutamine or amrinone (-23 +/- 4% and -30 +/- 5%, respectively). Vagal stimulation also reduced SS during dobutamine . L-NAME did not alter the ACh- or vagal-induced decreases in SS during dob utamine. Neither SNP nor bradykinin affected SS during dobutamine. In concl usion, ACh and vagal stimulation have a negative inotropic effect during st imulation of the beta -adrenergic receptors that is independent of NO. The persistence of this effect during amrinone suggests that a mechanism downst ream from adenylate cyclase is involved.