Acute dilatory and negative inotropic effects of homocysteine are inhibited by an adenosine blocker.

1. Previous studies have shown that homocysteine elicits acute negative inotropic and coronary vasodilatory effects in rat hearts. In addition, this earlier work suggested that the inotropic action is mediated via an endothelium-derived agent that is neither nitric oxide (NO) nor a cyclooxygenase product, while the coronary actions were found to be antagonized by the NOS inhibitor l-NNA. Current experiments, which utilized coronary-perfused rat hearts, were designed to determine if muscarinic or adenosine receptors are involved in these acute actions of homocysteine. 2. Left ventricular developed pressure was used as a measure of systolic function in electrically paced, Langendorff-perfused heart with coronary pressure being used to monitor coronary vascular tone. Acute effects of homocysteine (10-300 micromol/L) were examined in the presence and absence of 1 yen 10(-6) mol atropine or 7 yen 10(-5) mol 8-(p-sulfophenyl) theophylline (SPT), a non-selective adenosine receptor antagonist. 3. Atropine had no effect on either the inotropic or vascular actions of homocysteine. In contrast, SPT partially antagonized both actions of the amino acid with the antagonism of the vasodilation being much greater than its inhibition of the negative inotropic effect. Experiments with adenosine demonstrated that the selected dose of SPT elicited marked rightward shifts in the dose-response curves for both the inotropic and vascular actions. 4. Current results suggest that adenosine plays a role in both the negative inotropic and vasodilatory actions of homocysteine. However, the relatively minor antagonistic action of SPT on the inotropic effect of homocysteine suggests that additional endothelium-derived mediators underlie its effects on contractility.