Inhibition of Endogenous Nitric Oxide Synthase Augments Contractile Response to Adenylyl Cyclase Stimulation Without Altering Mechanical Efficiency in Patients With Idiopathic Dilated Cardiomyopathy

Abstract

itric oxide (NO) is an important regulator of cardiac function. 1,2 In patients with congestive heart failure (CHF) the concentrations of NO and tumor necrosis factor-increase in proportion to the severity of heart failure. 3,4 Previous studies have shown that inhibition of cardiac NO synthase (NOS) augments the positive inotropic response to -adrenergic receptor stimulation in human heart failure, suggesting that increased activity of myocardial NOS and NO attenuates -adrenergic responsiveness. [5][6][7] In patients with severe CHF, the increase in intracellular cyclic AMP and myocardial contractility in response toadrenergic receptor stimulation is reduced, 5 which reflects cardiac desensitization to -receptor agonists, 8 partly modulated by the increased production of NO in the myocardium. 5 Previous studies have shown that forskolin produces beneficial cardiac effects by directly stimulating adenylyl cyclase in the failed human heart, especially in those with a relative insensitivity to -adrenergic receptor stimulation. 9 Colforsin daropate (NKH477; 6-(3-dimethyl-aminopropionyl) forskolin hydrochloride) is a new water-soluble forskolin derivative, which experimental studies have shown to be able to generate positive inotropic and vasodilatory actions. 10,11 Furthermore, we previously reported that NKH477 might be a superior alternative to dobutamine for mechanical energy transduction in patients with left ventricular (LV) systolic dysfunction. 12 It remains to be clarified how NO modulates -adrenergic post-receptor signaling, such as adenylyl cyclase stimulation in the failing human heart. The objective of this study was to address the role of NO by evaluating the effects of cardiac NOS inhibition on LV hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation with colforsin daropate in patients with idiopathic cardiomyopathy (IDC). Methods Study SubjectsWe examined 13 patients (10 men, 3 women, mean age 56±13 years) who were undergoing diagnostic cardiac catheterization for the evaluation of heart failure on their first admission to hospital. All patients showed normal sinus rhythm and were diagnosed as IDC by the absence of coronary artery disease or other known causes of dilated cardiomyopathy. The patients were in New York Heart Association functional class II (n=8) or class III (n=5) with a LV ejection fraction (LVEF) of less than 40%. None of Background Increased nitric oxide (NO) in the failing heart attenuates the myocardial contractile response to -adrenergic receptor stimulation. However, the physiological effects of NO on the -adrenergic post-receptor signaling system are unknown. The objective of the present study was to examine the effects of cardiac NO synthase (NOS) inhibition on left ventricular (LV) hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation in human heart failure. Methods and ResultsThe study group comprised 13 patients with heart failure because of idiopathic cardiomyopathy (IDC). Emax was examined as an index of LV contractility, LV...

Inhibition of TGF-β1 by eNOS gene transfer provides cardiac protection after myocardial infarction

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Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase

“…29,30 Consequently, NO decreases cardiac pressure overload, attenuates cardiac hypertrophy, and retards progression of heart failure. We previously reported that overexpression of eNOS attenuated cardiac hypertrophy induced by chronic isoproterenol infusion.…”

Colforsin-induced vasodilation in chronic hypoxic pulmonary hypertension in rats

“…Thus, colforsin is expected to increase cardiac output by increasing ventricular contractility, as well as by decreasing both venous and arterial tones (i.e., preload and afterload). Indeed, colforsin is considered for the treatment of acute heart failure in a clinical setting [14][15][16]. However, although colforsin was shown to attenuate PH in previous animal studies [17], its clinical usefulness in the treatment of PH is yet to be established.…”