PN 200-110, a new calcium antagonist: electrophysiological, inotropic, and chronotropic effects on guinea pig myocardial tissue and effects on contraction and calcium uptake of rabbit aorta.
The compound isopropyl 4-(2,1,3- benzoxadiazol -4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dim ethyl-3- pyrid inecarboxylate (code name PN 200-110 [PN]) was investigated for calcium antagonistic effects in experiments in vitro. Action potentials recorded with intracellular microelectrodes in guinea pig papillary muscles were changed little by PN, 10(-7) M, except for a slight shortening of the duration of the plateau phase. Slow action potentials elicited in partially depolarized papillary muscles were gradually diminished and finally blocked by this concentration of PN. Contractile force was diminished in normal and partially depolarized muscles. The rate of spontaneously beating guinea pig right atria was decreased dose dependently, and the EC25 was 4.5 x 10(-10) M. The EC25 for the negative inotropic effects measured on paced guinea pig left atria was 1.5 x 10(-8) M. No membrane-stabilizing effects were found. Calcium-induced contraction of rabbit aorta in depolarizing bath solution was inhibited with an apparent pA2 of 10.3. Contraction elicited by graded depolarization at a constant calcium concentration was inhibited with an EC50 of 1.4 x 10(-9) M. Under resting conditions PN did not alter net uptake of 45Ca2+. KCl-stimulated uptake was inhibited with an EC50 of 3.6 x 10(-9) M. Neither noradrenaline-induced contractions nor noradrenaline-stimulated net uptake of 45Ca2+ were inhibited by a concentration of PN as high as 10(-5) M. PN thus is selective on cardiac tissue with respect to negative chronotropic versus inotropic activity and on rabbit aorta with respect to potential-operated versus receptor-operated channels.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003864:Depression, Chemical; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria; D006339:Heart Rate / Q000187:drug effects*; D017275:Isradipine; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010069:Oxadiazoles / Q000494:pharmacology*; D010210:Papillary Muscles / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits
D002121:Calcium Channel Blockers; D010069:Oxadiazoles; D002118:Calcium; D017275:Isradipine