Comparison of the effects of neuropeptide Y (NPY) and 4-norleucine-NPY on isolated perfused rat hearts; effects of NPY on atrial and ventricular strips of rat heart and on rabbit heart mitochondria

Abstract

Isolated perfused rat hearts were used to compare the effects of the synthetic neuropeptide Y (NPY) and 4-norleucine-NPY on cardiac function. Each peptide exhibited both negative inotropic and chronotropic effects, and also caused coronary vasoconstriction leading to a reduction in coronary flow. A comparison of the IC50 values from dose-response curves using 10(-14) to 10(-7) M peptides (IC50 is the peptide concentration that produced a 50% decrease of the maximal effect) indicated that NPY was more potent as inhibitor of contractility and less potently inhibited coronary flow and heart rate, whereas 4-norleucine-NPY had more inhibitory influence on coronary flow and heart rate and less on cardiac contractility. This difference in potencies suggests that the inhibitory effects of NPY on contractility, coronary flow and heart rate may be independent of each other. Since NPY also decreased the contractile force of isolated left atrial and right ventricular strips of the rat heart, the coronary flow decrease cannot be the cause of the negative inotropy of isolated heart. Pretreatment of atrial and ventricular strips with NPY did not influence the positive inotropic effect produced by the cardiac glycoside ouabain indicating that sarcolemmal Na+, K+-ATPase was not involved in the inhibitory inotropic effect of NPY. Further studies towards elucidating the mechanism of the negative inotropy of cardiac muscles using isolated heart mitochondria revealed that NPY uncoupled oxidative phosphorylation and blocked mitochondrial calcium uptake; the former event fosters negative inotropy. Since these effects on mitochondria occurred at concentrations 100-fold higher than those required for negative inotropy, the two effects of NPY may not be related.