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 μmol/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 μmol/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 μmol/L (±)-cicletanine (EC50 = 9.0 ± 0.7 nmol/L; P< .05). The potentiating effect of 10 μmol/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 μmol/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.