Comparison of in vitro effects of cicletanine, its enantiomers and major metabolite on rat thoracic aorta.
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)
Mikkelsen
E O
EO
Institute of Pharmacology, University of Aarhus, Denmark.
Sehested
J
J
Poulsen
S H
SH
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D002395:Catecholamines / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D020110:Pinacidil; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000959:Antihypertensive Agents; D015220:Calcium Channels; D002395:Catecholamines; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D020110:Pinacidil; C038068:cicletanine; D009543:Nifedipine; D011188:Potassium; D002118:Calcium