Pharmacology of Ca2+ channels in smooth muscle.
The influence of noradrenaline and protein kinase C modulators on (+)-[3H]isradipine binding to voltage-dependent calcium channels has been studied in membranes of equine portal vein smooth muscle and intact strips isolated from rat portal vein. Specific (+)-[3H]isradipine binding to intact strips was increased by noradrenaline and phorbol esters. The increase in isradipine binding induced by noradrenaline was inhibited by 1 microM prazosin and H7 (a protein kinase C inhibitor), while that induced by phorbol esters was only inhibited by H7. In strips pretreated with 10 micrograms/ml pertussis toxin for 6 h, the noradrenaline-induced increase in isradipine binding was unchanged. In contrast, isradipine binding to membranes was unaffected by noradrenaline or GTP-gamma-S. Only phorbol esters had a stimulatory effect on isradipine binding when membranes were incubated in a medium containing 10 microM ATP and 1 mM Mg2+. Scatchard plot analysis reveals that the stimulation of isradipine binding by both noradrenaline and phorbol esters appears to result from a decrease in KD rather than an effect on the maximal binding capacity. Contractions evoked by noradrenaline were concentration-dependently depressed by isradipine. About 30% of the response was resistant to inhibition, while KCl-induced contractions were completely blocked. However, noradrenaline-induced contractions were more sensitive to isradipine inhibition than were KCl-induced contractions. These results suggest that activation of protein kinase C modulates isradipine binding to voltage-dependent Ca2+ channels.
Mironneau
J
J
Laboratoire de Physiologie Cellulaire et Pharmacologie Moléculaire INSERM CJF 88-13, Bordeaux, France.
D000818:Animals; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017275:Isradipine; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011189:Potassium Chloride; D011493:Protein Kinase C; D009638:Norepinephrine; D017275:Isradipine