Comparison of in vitro effects of cicletanine, its enantiomers and major metabolite on rat thoracic aorta

Abstract

The effects of cicletanine ((+/-)-cic)), its optical isomers (BN-50417,(+)-cic); (BN-50418,(-)-cic) and major metabolite (BN-50699,cic-Met) on active tension were investigated in rat thoracic aortas. (+/-)-cic, (+)-cic, (-)-cic shifted the K(+)-concentration response curve to the right and depressed the maximum contractile response. Cic-Met was devoid of inhibitory effect on K(+)-induced contractions. (-)-Pinacidil had a far more potent inhibitory effect on K(+)-induced contractions than the cicletanine enantiomers and shifted the K(+)-concentration response curve to the right without affecting the maximum contractile response. (+/-)-Cic and nifedipine caused a concentration-related inhibition of Ca(2+)-induced contractions. Nifedipine was far more potent than (+/-)-cic in this respect. The slope of the Schild plot for nifedipine was not different from unity contrary to the significantly different slope for (+/-)-cic. (+/-)-Cic, (+)-cic, (-)-cic and cic-Met (3 x 10(-5) M to 3 x 10(-4) M) caused a concentration-related relaxation of noradrenaline (NA), serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha)-induced contractions. In NA-precontracted preparations (-)-cic (10(-4) M-3 x 10(-4) M) had a stronger relaxant effect than (+)-cic. Cic-Met was a weaker antagonist of NA-induced contractions than (+) and (-)-cic. The enantiomers were far less potent relaxing NA-induced contractions than phentolamine. (+)-Cic, (-)-cic and cic-Met had a similar relaxant effect on 5-HT-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)