Abstract
<title>Abstract</title> <p>Accumulating evidence implicates the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in cardiovascular impairments. Although the detrimental cardiovascular effects of ADMA have largely been attributed to endothelial dysfunction, recent studies suggest that ADMA also directly affects cardiomyocyte function. However, the action of ADMA on myocardial contractility remains poorly understood. Here, we tested the hypothesis that continuous exposure to 10 µM exogenous ADMA alters the contractile responsiveness of rat right ventricular papillary muscles to sympathetic and parasympathetic stimulation using the β-adrenergic agonist isoproterenol (ISO, 1 µM) and the muscarinic agonist acetylcholine (ACh, 10 µM). We assessed force development, force-frequency relationship (FFR), contraction and relaxation kinetics, and post-rest potentiation (PRP). ADMA did not alter basal contractility or the force-frequency relationship but reduced force generation at high stimulation frequency. However, ADMA altered autonomic regulation of papillary muscle contraction in a frequency-dependent manner. Specifically, ADMA altered the inhibitory effect of ACh on ISO-induced positive inotropic and negative lusitropic responses, as well as on the ISO-mediated increases in the maximal velocities of contraction and relaxation. These effects were frequency dependent: ADMA attenuated the antagonistic effect of ACh on ISO responses at low stimulation frequencies but enhanced it at higher frequencies. Finally, ADMA attenuated ISO-induced potentiation of PRP while enhancing the inhibitory effect of ACh on PRP. Our findings identify a previously unrecognized mechanism by which ADMA directly modulates myocardial function through frequency- and time-dependent regulation of the interaction between β-adrenergic and muscarinic signaling, suggesting that elevated ADMA levels may contribute to abnormal ventricular contractile regulation in cardiovascular disease.</p>