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1 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
3 Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
4 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
* To whom correspondence should be addressed. E-mail: kennedyrichardh{at}uams.edu.
Previous studies have shown that chronic hyperhomocysteinemia is associated with an adverse cardiac remodeling and heart failure. This study, which utilized coronary-perfused hearts and superfused papillary muscle, was designed to determine if homocysteine acts acutely to alter cardiac contractile function. Left ventricular developed pressure was used as a measure of systolic function in Langendorff-perfused heart, while isometric developed tension was used in papillary muscle. All preparations were bathed in physiological buffer and paced electrically. Initial results showed that homocysteine elicits a relatively rapid onset (maximum effect observed within 5 min), concentration-dependent (10 - 300 µM), and moderate negative inotropic action (maximum decrease in tension was approximately 15% of control values) in Langendorff-perfused hearts but not in papillary muscle. In contrast, effluent from homocysteine-treated hearts decreased contractility in papillary muscle, and all inotropic actions were largely eliminated when brief Triton X-100 treatment was utilized to inactivate the coronary endothelium in the intact heart. The homocysteine-induced decrease in contractile function was not antagonized by L-NNA, a nitric oxide synthase inhibitor, or the cyclooxygenase inhibitor indomethacin. Thus, data suggest that pathophysiological concentrations of homocysteine elicit an acute negative inotropic effect on ventricular myocardium that is mediated by a coronary endothelium-derived agent other than NO or products of cyclooxygenase. Future studies are required to elucidate the mechanism by which homocysteine acts to elicit the release of the proposed endothelial mediator, the identity of the proposed paracrine agent, and the mechanism of its negative inotropic action.
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