Endothelin-1 inhibits L-type Ca currents enhanced by isoproterenol in guinea-pig ventricular myocytes.
To investigate the action of endothelin-1 (ET-1) on L-type Ca currents (ICa,L) in guinea-pig ventricular cells, whole-cell currents were recorded at approximately 36-37 degrees C in enzymatically isolated myocytes. ET-1 (> or =10 nM) suppressed the basal ICa,L to 79+/-8% of control at 20 nM. Bath application of isoproterenol (ISO; 10 nM) enhanced ICa,L to 192+/-28% with about a -10-mV shift of its relationship with membrane potential. ET-1 concentration dependently inhibited this ISO-enhanced ICa,L with a half-maximally inhibitory concentration (IC50) of 168 pM. The inhibitory actions of ET-1 were antagonised by BQ-123 (300 nM), cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp), a specific ETA receptor antagonist. Histamine-enhanced ICa,L was also suppressed by ET-1, but ICa, L potentiated by internal adenosine 3',5'-cyclic monophosphate (cAMP) was unaffected. Preincubation of myocytes with pertussis toxin (PTX, at 5 microgram/ml for >60 min at 36 degrees C) completely occluded the ET-1 action. Thus, stimulation of ETA receptors by subnanomolar ET-1 inhibits ICa,L via PTX-sensitive G-proteins.
Xie
L H
LH
The 3rd Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Horie
M
M
James
A F
AF
Watanuki
M
M
Sasayama
S
S
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology; D006632:Histamine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D008564:Membrane Potentials; D009206:Myocardium / Q000737:chemistry / Q000166:cytology*; D017466:Receptors, Endothelin / Q000032:analysis
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016232:Endothelins; D017466:Receptors, Endothelin; D005576:Colforsin; D006632:Histamine; D000242:Cyclic AMP; D007545:Isoproterenol