Pharmacological dissection of Ca2+ channels in the rat aorta by Ca2+ entry modulators.
Ca2+ agonists, Bay K 8644 and CGP 28392, induced concentration-dependent contractions in segments of rat aorta partially depolarized with 15 mmol/l K+. The responses caused by Bay K 8644 were greater than those elicited by CGP 28392. The actions of these Ca2+ agonists were blocked by nifedipine. CGP 28392 and mainly Bay K 8644 increased the contractions induced by different K+ concentrations but did not alter those caused by noradrenaline (NA) and higher K+ concentrations. Bay K 8644 enhanced and nifedipine reduced the contractions elicited by Ca2+ addition in a Ca2(+)-free solution containing K+ (25, 50 or 75 mmol/l). This enhancement was blocked by nifedipine. Nifedipine and verapamil reduced more effectively the responses induced by K+ than those caused by NA; they did not modify contractions evoked by Ca2+ ionophore A23187. They also reduced the increases in K+ contractions elicited by CGP 28392 and Bay K 8644. Bay K 8644 increased 45Ca2+ uptake induced by K+ and did not affect that caused by NA. Nifedipine blocked this increase as well as 45Ca2+ uptake elicited by NA and K+. Basal 45Ca2+ efflux was not modified by verapamil and Bay K 8644. NA and K+ significantly increased this efflux in normal solution, but not in Ca2(+)-free medium. Bay K 8644 enhanced 45Ca2+ efflux induced by K+ in normal medium, whereas it did not affect those elicited by NA and K+ in a solution without Ca2+. This Ca2+ agonist had scant ability to induce Ca2+ efflux in a Ca2(+)-free medium. These results indicate that in this vascular preparation: (1) Ca2+ agonists (Bay K 8644 particularly) have the ability to produce Ca2+ influx (and subsequent contraction) and Ca2+ efflux by activation of voltage-operated Ca2+ channels (VOCs), only when they are preactivated with K+; (2) VOCs and receptor-operated Ca2+ channels (ROCs) appear to constitute two different populations, and (3) Ca2+ antagonists possess, in comparison with Ca2+ agonists, a small range of selectivity to block only VOCs; the latter drugs are better to pharmacologically discriminate between VOCs and ROCs in the rat aorta.
Rico
I
I
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma, Madrid, España.
Alonso
M J
MJ
Salaices
M
M
Marín
J
J
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011725:Pyridines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C040525:CGP 28392; D009543:Nifedipine; D011188:Potassium; D002118:Calcium