ALPHA-ADRENERGIC INHIBITION OF THE BETA-ADRENOCEPTOR-DEPENDENT CHLORIDE CURRENT IN GUINEA-PIG VENTRICULAR MYOCYTES

1. alpha(1)-Adrenoceptor-mediated inhibition of the beta-adrenoceptor-dependent Cl- current was investigated in guinea-pig ventricular myocytes using the patch clamp technique. The Cl- conductance activated by noradrenaline (0.1-10 mu M) with an alpha(1)-blocker (prazosin, 5 mu M) was significantly greater than that activated by noradrenaline alone. Phenylephrine and methoxamine, alpha(1)-agonists, exerted an inhibitory effect on the Cl- conductance activated by isoprenaline. The dose-response relationship for isoprenaline and the Cl- current activation was shifted to higher doses in the presence of phenylephrine (30 mu M). 2. The interaction of alpha(1)- and beta-agonists on Cl- current was also observed on the single channel level; in some of the outside-out membrane patches, phenylephrine (50 mu M) depressed the activity of the single Cl- channel which was induced by 5 mu M adrenaline. 3. Phenylephrine had no effect on the Cl- conductance induced by forskolin (0.5-5 mu M), an activator of adenylate cyclase. The Cl- conductance activated persistently by isoprenaline in GTP gamma S-loaded cells was also insensitive to phenylephrine. The results suggest that the observed alpha(1)-adrenergic attenuation of the beta-adrenergic response is not primarily due to inhibition of adenylate cyclase activity. The alpha(1)-adrenergic action may interfere with the processes leading to enzyme activation in the beta-adrenergic pathway.