Phosphodiesterase inhibition by naloxone augments the inotropic actions of β‐adrenergic stimulation

Abstract

In a shock state, naloxone generates the cardiovascular pressor effect by displacing the endogenous opiate-like peptide beta-endorphin, resulting in restoration of the normal response to catecholamines. In addition to this opioid antagonistic effect, the non-opiate receptor-mediated effect has also been proposed. The aim of this study was to define the mechanism of non-opiate receptor-mediated action of naloxone. In guinea-pig ventricular tissues, cumulative concentration-response curves for isoproterenol as well as for forskolin and 3-isobutylmethylxanthine (IBMX) were obtained by increasing the concentration stepwise. To assess the effect on the phosphodiesterase (PDE), the effects of naloxone on contractile forces induced by isoproterenol (0.05 microM) in the presence of IBMX, cilostamide (a PDE III inhibitor), or rolipram (a PDE IV inhibitor) were observed. Naloxone-induced changes in cAMP production by isoproterenol both in the absence and in the presence of IBMX were measured. Naloxone-induced changes in cAMP production by forskolin in the presence of IBMX were also measured. Naloxone (30 microM) produced a leftward shift of the isoproterenol concentration-response curve (0.01-2 microM) without changing the maximal response. Forskolin (0.5-10 microM) produced a concentration-dependent increase in contractile forces. Naloxone increased the maximal inotropic response of forskolin. Naloxone showed no effect on the IBMX concentration-response curve. In the presence of IBMX (200 microM), naloxone did not alter the contractions evoked by isoproterenol or forskolin. Whereas naloxone increased contractile forces significantly (approximately 25%) more than that of isoproterenol in the presence of rolipram, no alteration of contractile forces in the cilostamide-incubated muscles was observed. Naloxone caused a concentration-related increase of cAMP in the absence of IBMX, but caused no change in its presence. The enhancement of myocardial contractility by naloxone in the presence of stimulation of adenylyl cyclase activity appears to be mediated by inhibition of PDE, specifically PDE III.