ROLE OF MYOCYTE NITRIC-OXIDE IN BETA-ADRENERGIC HYPORESPONSIVENESS INHEART-FAILURE

Background The positive inotropic response to beta-adrenergic stimulat ion is attenuated at the isolated myocyte level in heart failure. Nitr ic oxide (NO) has a negative inotropic effect and attenuates the respo nse to isoproterenol. It has been suggested that NO synthesis is incre ased in failing myocytes. How ever, the pathophysiological consequence s after induction of NO in myocyte contractility are less clear in the setting of heart failure. Methods and Results We examined the effects of an NO synthase (NOS) inhibitor on contractile function in myocytes isolated from 11 dogs with rapid pacing-induced heart failure (ejecti on fraction, 29+/-2%) and 8 control dogs (ejection fraction, 74+/-3%). Sarcomere shortening velocity was measured as an index of contractili ty under four experimental conditions: at baseline, after adding isopr oterenol (ISO; 1 nmol/L), after an NOS inhibitor (N-pi-nitro-L-arginin e methyl ester [L-NAME], 0.1 nmol/L), and after L-NAME plus ISO. L-NAM E alone had no effects on basal sarcomere shortening velocity in eithe r control or heart failure myocytes. However, L-NAME significantly aug mented the inotropic response to isoproterenol in heart failure myocyt es (107.1+/-7.3% [ISO alone] versus 140.6+/-10.7% [ISO plus L-NAME] in crease from baseline; P<.05) but not in control myocytes (135.5+/-9.9% [ISO alone] versus 137.1+/-11.4% [ISO plus L-NAME]; P=NS). Myocardial NOS activity measured by the conversion of arginine to citrulline was significantly increased in dogs with heart failure compared with that in control dogs. Conclusions The increased NO induction in failing my ocytes does not alter baseline sarcomere mechanics but attenuates the positive inotropic response to isoproterenol. Thus, myocyte NO plays a n important role in the autocrine regulation of the contractile functi on of myocytes in congestive heart failure.