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 (ICa) were examined in rabbit ventricular cells. Denopamine stimulated basal ICa with a maximum response of +33.2% and a concentration for half-maximal response (EC50) of 0.039 microM. The maximum response of ICa was only a quarter of that induced by isoprenaline (ISO), while 10 microM denopamine elicited 70-75% of the maximum inotropic response in the papillary muscle preparations. The denopamine stimulation of ICa was abolished by selective beta 1 antagonists (atenolol or bisoprolol). Pretreatment with forskolin or dialysis with cAMP also abolished the stimulation. Denopamine, in turn, inhibited ISO-stimulated ICa. This inhibition was not affected by pretreatment with pertussis toxin or prazosin. The presence of denopamine at various concentrations caused a rightward shift in the concentration/response curve for ISO stimulation of ICa. The Schild plot for this effect had a slope of 0.99 and Kp of 0.20 microM. In the presence of guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S) (0.5 mM) in the pipette, denopamine (10 microM) stimulated the ICa to 86 +/- 5% of the maximum response induced by ISO. These findings indicate that denopamine modulates ICa exclusively through the beta 1 adrenoceptor-adenylate cyclase pathway, that the stimulatory GTP-binding protein regulates the agonistic potency of denopamine, and that the signal from the beta 1 adrenoceptors is amplified between ICa and the tension development, which would contribute to the spare capacity of beta adrenoceptors.
Department of Laboratory Medicine, Kyoto Prefectural University of Medicine, Japan.
Y
Y
Habuchi
T
T
Yamamoto
M
M
Nishio
H
H
Tanaka
J
J
Morikawa
M
M
Yoshimura
D000262:Adenylyl Cyclases / Q000378:metabolism; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D011817:Rabbits; D015398:Signal Transduction
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D015220:Calcium Channels; D004983:Ethanolamines; D001262:Atenolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol; C037293:denopamine