Enkephalins modulate the responsiveness of rat atria in vitro to norepinephrine

Potential interactions between opiate peptides and catecholamines in mammalian heart were examined using isolated spontaneously beating rat atria as a test system. Methionine-enkephalin (ME), leucine-enkephalin (LE), phe-met-arg-phe amide (FMRFamide), D-ala², N-methyl-phe⁴, met (O)⁵-ol-enkephalin (FK 33-834), methionine-enkephalin arg⁶ arg⁷ (ME arg⁶ arg⁷) and β-endorphin had no effect on basal beating rate of isolated atria at all concentrations up to 10^?5 M. The positive chronotropic effect of norepinephrine (NE) on atrial rate is, however, significantly attenuated by enkephalin peptides. Thus, the maximal chronotropic effect of NE (an increase from 317±7.0 to 473±7.3 beats per minute (bpm) in 250 gm rats at a dose of 10^?5 M NE) is decreased by 42% in the presence of 10^?7 m ME. The action of ME is completely blocked by addition of 10^?7 M naloxone, which by itself has no effect on NE-induced positive chronotropy or basal beating rate. The dose-effect curve for ME attenuation of NE-induced positive chronotropy is bell-shaped, i.e., both 10^?8 M and 10^?5 M ME have no significant effect on NE positive chronotropy. Other enkephalin peptides acted in a similar manner to ME; LE (10^?7 M) and FK 33-834 (10^?8 M) decreased maximal NE-induced positive chronotropy 42 and 27%, respectively. The molluscan cardioexcitatory peptide FMRFamide (10^?7 M) also decreased maximal NE positive chronotropy, about 30%. In contrast, β-endorphin did not significantly affect NE stimulation of atrial rate. We conclude that enkephalins can modulate the noradrenergic responsiveness of rat atria in vitro. The possible physiological relevance of this interaction is discussed.