Caffeine-induced contractions in rabbit isolated renal artery are differentially inhibited by calcium antagonists.
Caffeine (1-60 mM) induced concentration-dependent, endothelium-independent phasic contractile responses in isolated rabbit renal artery ring preparations. For concentrations of caffeine over 2 mM, responses were mainly the result of intracellular calcium ion mobilization since they were relatively resistant to removal of calcium ions from the bathing medium. The L-type slow calcium channel blocker, nifedipine (10 microM), had no effect and high concentrations of verapamil and diltiazem (10-30 microM) only slight and inconsistent effects (not concentration-dependent) upon these caffeine responses. Likewise, the highly lipophilic calcium antagonists flunarizine and lidoflazine (3-30 microM) only slightly displaced caffeine concentration-response curves to the right and reduced the maximum response. These small inhibitory effects of flunarizine and lidoflazine were not augmented in a calcium-free medium. In contrast, the other lipophilic calcium antagonists, bepridil and fendiline (3-30 microM), produced marked, non-competitive type inhibition of caffeine responses, completely inhibiting responses to the alkaloid at the highest concentration. Furthermore, the inhibitory effects of bepridil and fendiline were markedly augmented in calcium-free medium. These results clearly differentiate bepridil and fendiline from the other calcium antagonists studied. In addition they provide further evidence for effects other than at the cell membrane which could theoretically contribute to the efficacy of bepridil and fendiline as anti-anginal agents.
John
G W
GW
Department of Pharmacology, Riom Laboratories CERM, France.
Fabrègues
E
E
Kamal
M
M
Massingham
R
R
D000818:Animals; D015764:Bepridil / Q000494:pharmacology; D002110:Caffeine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005275:Fendiline / Q000494:pharmacology; D005444:Flunarizine / Q000494:pharmacology; D007700:Kinetics; D008013:Lidoflazine / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D011817:Rabbits; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002110:Caffeine; D015764:Bepridil; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; D008013:Lidoflazine; D005444:Flunarizine; D005275:Fendiline