Contractile activity of three endothelins (ET-1, ET-2 and ET-3) on the human isolated bronchus.
1. The effects of three endothelins: (i) the classical or human/porcine endothelin (ET-1); (ii) [Trp6, Leu7] endothelin (ET-2) and (iii) [Thr2, Phe4, Thr5, Tyr6, Lys7, Tyr14] endothelin or rat endothelin (ET-3) were tested on the human isolated bronchus. 2. ET-1 produced a concentration-dependent contraction of the human isolated bronchus that proceeded in two different steps. The first step was observed at very low concentrations (pD2 = 11.01 +/- 0.17, n = 10) but corresponded to a low intrinsic activity (Emax = 15.6 +/- 1.8% of Emax = 26.1 +/- 2.9% of ACh 3 x 10(-3) M, n = 5, P less than 0.05), reduced by nicardipine 10(-6) M (Emax = 6.0 +/- 2.6% of ACh 3 x 10(-3) M, n = 5, P less than 0.05) and strongly inhibited in calcium-free medium. The second step of the action of ET-1 corresponded to a lesser potency (pD2 = 7.90 +/- 0.17, n = 9) but a higher intrinsic activity (Emax = 82.5 +/- 4.7% of ACh 3 x 10(-3) M). This effect was not significantly modified by nicardipine 10(-6) M or by Bay K 8644 10(-7) M. Neither of the two effects was modified by indomethacin 3 x 10(-6) M. 3. The effects of ET-2 and ET-3 were qualitatively similar to those of ET-1 but quantitatively different; for these two steps of contracting activity and for potency and efficacy the ranking was: ET-1 greater than ET-2 = ET-3. 4. Thus, ET-1 appears to be the most potent of these three substances in its effect on the human isolated bronchus. Its activity seems to involve the action of voltage-dependent calcium channels at low concentrations (10-12 to 10-9M), whereas other mechanisms are involved at higher concentrations (10-8 to 3 x 10-7M).
Advenier
C
C
Department of Pharmacology, Faculté de Médecine Paris-Ouest, France.
Sarria
B
B
Naline
E
E
Puybasset
L
L
Lagente
V
V
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000595:Amino Acid Sequence; D001980:Bronchi / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016232:Endothelins; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D016232:Endothelins; D010455:Peptides; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009529:Nicardipine; D007213:Indomethacin