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Role of myocyte nitric oxide in beta-adrenergic hyporesponsiveness in heart failure
S Yamamoto1, H Tsutsui, H Tagawa
1Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Background:
The positive inotropic response to beta-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 pi-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.
Insights
Increased nitric oxide (NO) in heart failure myocytes attenuates the response to isoproterenol. Inhibiting NO synthase restored contractility, revealing NO
Area of Science:
- Cardiovascular Physiology
- Myocyte Contractility
- Heart Failure Pathophysiology
Background:
- Beta-adrenergic stimulation's positive inotropic effect is reduced in heart failure.
- Nitric oxide (NO) has a negative inotropic effect and can blunt responses to isoproterenol.
- Elevated NO synthesis in failing myocytes is suspected, but its impact on contractility is unclear.
Purpose of the Study:
- To investigate the role of nitric oxide (NO) in modulating myocyte contractility in heart failure.
- To determine if inhibiting NO synthase (NOS) can restore contractile responsiveness to beta-adrenergic stimulation.
Main Methods:
- Isolated myocytes from dogs with pacing-induced heart failure and control dogs were studied.
- Sarcomere shortening velocity was measured under baseline, isoproterenol (ISO), NOS inhibitor (L-NAME), and combined conditions.
- Myocardial NOS activity was assessed by arginine to citrulline conversion.
Main Results:
- L-NAME alone did not affect basal contractility in either group.
- L-NAME significantly enhanced the ISO-induced increase in contractility in heart failure myocytes.
- Myocardial NOS activity was significantly higher in heart failure dogs compared to controls.
Conclusions:
- Increased NO production in failing myocytes attenuates the positive inotropic response to isoproterenol.
- Myocyte-derived NO plays a key role in the autocrine regulation of contractile function in heart failure.
- Inhibition of NO synthesis can restore beta-adrenergic responsiveness in failing myocytes.