INHIBITION OF L-TYPE CALCIUM CURRENTS IN GUINEA-PIG VENTRICULAR MYOCYTES BY THE KAPPA-OPIOID AGONIST-U50488H DOES NOT INVOLVE BINDING TO OPIATE RECEPTORS

In guinea pig ventricular myocytes the K-opioid agonist N-[2-(1-pyrrol idinyl)-cyclohexyl]-benzeneacetamide methanesulfonate salt (U50488H) i nhibited L-type calcium currents (I-Ca) as measured by the patch clamp technique in a dose-dependent fashion. The basal, as well as the isop renaline and 8-Br-cAMP-stimulated, I-Ca were found to be reduced by U5 0488H. The inhibition was reversible and was not prevented on preincub ation with pertussis toxin or the receptor antagonists naloxone and na ltrexone. Naltrexone alone also caused an inhibition of I-Ca. Leucine enkephaline, a peptide opiate agonist, had no effect on I-Ca. U50488H did not alter the current/voltage relationship of the calcium current. The inhibition was independent of the cytosolic calcium concentration because it was also observed in the presence of 10 mM BAPTA in the pi pette. If the compound was applied intracellularly via a perfused patc h pipette there was no inhibition of I-Ca. The calcium current stimula ted by the dihydropyridine calcium agonist Bay K 8644 was also reduced by U50488H. Conversely the inhibition of I-Ca by U50488H could be ant agonized by Bay K 8644. In conclusion, these results demonstrate that binding to specific membrane receptors is not involved in the inhibiti on of L-type calcium current by U50488H and other nonpeptide opioid ag onists. A direct interaction with the channel molecule at the exterior of the cell is probably involved.