STEREOSELECTIVE INHIBITION OF THROMBOXANE-INDUCED CORONARY VASOCONSTRICTION BY 1,4-DIHYDROPYRIDINE CALCIUM-CHANNEL ANTAGONISTS

The biological activity of the (+)‐S‐ and (−)‐R‐enantiomers of niguldipine, of the (−)‐S‐ and (+)‐R‐enantiomers of felodipine and nitrendipine, and of rac‐nisoldipine and rac‐nimodipine was investigated in vitro and in vivo. Inhibition of coronary vasoconstriction due to the thromboxane A2 (TxA2)‐mimetic U‐46619 in guinea pig Langendorff hearts, displacement of (+)‐[3H]isradipine from calcium channel binding sites of guinea pig skeletal muscle T‐tubule membranes, and blood pressure reduction in spontaneously hypertensive rats were determined. The enantiomers were obtained by stereoselective synthesis. Cross‐contamination was <0.5% for both S‐ and R‐enantiomers of niguldipine and nitrendipine and <1% for those of felodipine. From the doses necessary for a 50% inhibition of coronary vasoconstriction, stereoselectivity ratios for (+)‐(S)‐/(−)‐(R)‐niguldipine, (−)‐(S)‐/(+)‐(R)‐felodipine, and (−)‐(S)‐/(+)‐(R)‐nitrendipine of 28, 13, and 7, respectively, were calculated. The potency ratio racnisoldipine/rac‐nimodipine was 3.5. Ratios obtained from binding experiments and antihypertensive activity were (+)‐(S)‐/(−)‐(R)‐niguldipine = 45 and 35, (−)‐(S)‐/(+)‐(R)‐felodipine = 12 and 13, (−)‐(S)‐/(+)‐(R)‐nitrendipine = 8 and 8, and rac‐nisoldipine/rac‐nimodipine = 8 and 7, respectively. Highly significant correlations were found between the in vitro potency of the substances to prevent U‐46619‐induced coronary vasoconstriction and their affinity for calcium channel binding sites as well as their antihypertensive activity. The mechanism of TxA2‐induced coronary vasoconstriction in guinea pig Langendorff hearts can be readily explained by a transmembrane influx of extracellular Ca2+ susceptible to stereoselective blockade by 1,4‐dihydropyridine calcium channel antagonists. Copyright © 1990 Wiley‐Liss, Inc.