(Circulation. 1997;95:1111-1114.)
© 1997 American Heart Association, Inc.
Articles |
Role of Myocyte Nitric Oxide in ß-Adrenergic Hyporesponsiveness in Heart Failure
the Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Correspondence to Hiroyuki Tsutsui, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan.
Background The positive inotropic response to ß-adrenergic stimulation is attenuated at the isolated myocyte level in heart failure. Nitric oxide (NO) has a negative inotropic effect and attenuates the response to isoproterenol. It has been suggested that NO synthesis is increased in failing myocytes. However, the pathophysiological consequences 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 (ejection fraction, 29±2%) and 8 control dogs (ejection fraction, 74±3%). Sarcomere shortening velocity was measured as an index of contractility under four experimental conditions: at baseline, after adding isoproterenol (ISO; 1 nmol/L), after an NOS inhibitor (N
-nitro-L-arginine methyl ester [L-NAME], 0.1 nmol/L), and after L-NAME plus ISO. L-NAME alone had no effects on basal sarcomere shortening velocity in either control or heart failure myocytes. However, L-NAME significantly augmented the inotropic response to isoproterenol in heart failure myocytes (107.1±7.3% [ISO alone] versus 140.6±10.7% [ISO plus L-NAME] increase 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 myocytes does not alter baseline sarcomere mechanics but attenuates the positive inotropic response to isoproterenol. Thus, myocyte NO plays an important role in the autocrine regulation of the contractile function of myocytes in congestive heart failure.
Key Words: heart failure • endothelium-derived factors • cells • contractility • receptors, adrenergic, beta
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