PCA 50941, a novel Ca2+ channel agonist.
PCA 50941 is a novel 1,4-dihydropyridine derivative. Its vasoconstricting effects prompted a systematic comparison with the prototypic Ca2+ channel activator, Bay K 8644. The two compounds exhibit marked analogies and differences in their cardiovascular profiles. PCA 50941 exhibits a pronounced vascular over cardiac selectivity while Bay K 8644 has both potent vasoconstrictor effects and strong cardiac positive inotropic actions. PCA 50941 exhibits either poor positive inotropic effects (isolated guinea-pig atria) or clear negative inotropic effects (isolated perfused rat heart). Both compounds reduced by 10-40% the coronary flow in the perfused rat heart. However, PCA 50941 had slight vasoconstrictor effects in pig coronary arteries, causing their relaxation at nanomolar/micromolar concentrations; this contrasts with the almost pure, marked vasoconstrictor effects of Bay K 8644 in coronary arteries. In the rat aorta PCA 50941 exhibited a biphasic pattern of vasoconstriction and vasorelaxation, and in portal vein it markedly reduced the Ca(2+)-evoked contractions; Bay K 8644 behaved as a pure vasoconstrictor in these two preparations. It is concluded that the racemic compound, PCA 50941, exhibits different degrees of Ca2+ agonism and Ca2+ antagonism by acting upon 1,4-dihydropyridine receptors of different cardiovascular tissues. Its tissue selectivity and its prolonged duration of action give PCA 50941 a cardiovascular profile more favourable than that of other 1,4-dihydropyridine Ca2+ agonist existing to date.
Priego
J
J
Departamento de Investigación, Laboratorios ALTER, Madrid, Spain.
González-Morales
M A
MA
Cillero
F J
FJ
Villarroya
M
M
Sunkel
C
C
de Casa-Juana
M F
MF
López
M G
MG
Artalejo
C R
CR
de Pascual
R
R
García
A G
AG
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects; D009132:Muscles / Q000378:metabolism; D009568:Nitrendipine / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D002120:Calcium Channel Agonists; D004095:Dihydropyridines; D013844:Thiazoles; C084781:PCA 50941; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D017275:Isradipine