The opioid gene preproenkephalin, which codes for two opioid receptor agonist peptides, is expressed in cardiac ventricles at relatively high levels. Recent data from this laboratory demonstrated that opioid receptor agonists impair baseline contractility and inhibit catecholamine stimulation of function in isolated cardiac myocytes. Studies of neural tissue indicate that the preproenkephalin gene is influenced by cAMP, Ca 2+ and c-fos, suggesting it may play a role in stress responses. The objective of this study was to determine whether the cardiac response to stress (i.e. aortic constriction) is associated with changes in opioid mRNA and peptide levels in rat heart, and whether opioid gene expression in the heart is mediated by adrenergic stimulation. The senescent heart exhibits phenotypic and genotypic changes similar to those observed in hearts of younger rats after aortic constriction. A ten-fold increase int he level of preproenkephalin mRNA was observed in rat heart between 1.5 and 18 mo of age. Although not strictly correlated with the mRNA pattern, the levels of Methionine-enkephalin and Leucine-enkephalin in the heart were also elevated with advancing age. After three days of aortic constriction the left ventricular preproenkephalin mRNA level declined to 30% of the level at 8 hours post-constriction and occurred 24-48 hours after a decline in c- fos mRNA level. In cultured neonatal cardiac myocytes, stimulation with 2, 4, 8, or 24 hours of norepinephrine treatment resulted in a marked induction of the preproenkephalin gene compared to vehicle-treated controls. The results are consistent with the hypothesis that the cardiac opioid system is involved in the response of the heart to stress, and show that opioid gene expression can be influenced via an adrenergic pathway.
