Vasorelaxant effects of cicletanine and its (+)- and (-)-enantiomers in isolated human pulmonary arteries.
The purpose of the study was to investigate, in isolated human pulmonary artery, the ability of cicletanine and its (-) and (+)-enantiomers to attenuate the endothelin-1 (Et-1) induced vasoconstriction, and to potentiate vasorelaxation (relative to plateau of the effect of Et-1) by sodium nitroprusside (SNP) and human atrial natriuretic peptide (ANP). In pulmonary artery rings, Et-1 induced a concentration-dependent vasoconstriction with median effective concentration (EC50 = 26+/-2.8 nmol/L. Pretreatment of the vessels with 100 micromol/L (+/-)-cicletanine reduced the effect of Et-1 (EC50 = 36+/-3.5 nmol/L; P < .01). (-)-enantiomer displayed greater capacity to antagonize the vasoconstrictor action of Et-1 (EC50 = 47+/-4.2 nmol/L) v (+)-enantiomer (EC50 = 29.9+/-6.5 nmol/L; P < .01). In arterial rings, precontracted with 10 nmol/L Et-1, ANP caused vasorelaxation (EC50 = 9.7+/-1.9 nmol/ L). The relaxant effect of ANP was potentiated by 100 micromol/L of (-)-(EC50 = 4.2+/-0.6 nmol/L; P < .01), but not (+)-cicletanine (EC50 = 7.6+/-0.7 nmol/L). Sodium nitroprusside relaxed pulmonary artery rings precontracted with 10 nmol/L Et-1 (EC50 = 41+/-11 nmol/L). The effect of SNP was potentiated by 10 micromol/L (+/-)-cicletanine (EC50 = 9.0+/-0.7 nmol/L; P < .05). The potentiating effect of 10 micromol/L (+)-cicletanine was weaker (EC50 = 7.9+/-1.8 nmol/L) than that of (-)-enantiomer (EC50 = 3.3+/-0.54 nmol/L; P < .05). The relaxant effect of SNP was not further potentiated by 100 micromol/L (+/-)-cicletanine. The present results demonstrate that, cicletanine antagonizes Et-1 induced vasoconstriction in an isolated human pulmonary artery and potentiates vasorelaxation by two guanylate cyclase activators, ANP and SNP. (-)-Cicletanine displays greater vasorelaxant activity v (+)-enantiomer.
Bagrov
A Y
AY
Laboratory of Pharmacology, Sechenov Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia.
Droy-Lefaix
M T
MT
Dmitrieva
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RI
D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D019332:Endothelin-1; D011725:Pyridines; D014665:Vasodilator Agents; D009599:Nitroprusside; D009320:Atrial Natriuretic Factor; C038068:cicletanine