MODULATION OF L-TYPE CA CURRENT BY DENOPAMINE, A NONPARENTERAL PARTIAL BETA(1) STIMULANT, IN RABBIT VENTRICULAR CELLS

The effects of denopamine, a nonparenteral partial beta agonist which is used clinically in Japan, on the L-type Ca2+ current (I-Ca) were ex amined in rabbit ventricular cells. Denopamine stimulated basal I-Ca w ith a maximum response of +33.2% and a concentration for half-maximal response (EC(50)) of 0.039 mu M. The maximun response of I-Ca was only a quarter of that induced by isoprenaline (ISO), while 10 mu M denopa mine elicited 70-75% of the maximum inotropic response in the papillar y muscle preparations. The denopamine stimulation of I-Ca was abolishe d by selective beta(1) antagonists (atenolol or bisoprolol). Pretreatm ent with forskolin or dialysis with cAMP also abolished the stimulatio n. Denopamine, in turn, inhibited ISO-stimulated I-Ca. This inhibition was not affected by pretreatment with pertussis toxin or prazosin. Th e presence of denopamine at various concentrations caused a rightward shift in the concentration/response curve for ISO stimulation of I-Ca. The Schild plot for this effect had a slope of 0.99 and K-p of 0.20 m u M In the presence of guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) (0.5 mM) in the pipette, denopamine (10 mu M) stimulated the I-Ca t o 86+/-5% of the maximum response induced by ISO. These findings indic ate that denopamine modulates I-Ca exclusively through the beta(1) adr enoceptor-adenylate cyclase pathway, that the stimulatory GTP-binding protein regulates the agonistic potency of denopamine, and that the si gnal from the beta(1) adrenoceptors is amplified between I-Ca and the tension development, which would contribute to the spare capacity of b eta adrenoceptors.