The mechanism of action of endothelin in human lung.
1 The peptides endothelin-1 (ET-1) and endothelin-2 (ET-2) elicited potent and sustained contractions of human isolated bronchus and pulmonary artery. 2 ET-1 is one of the most potent contractile agonists investigated in these tissues with an EC50 value of 18.3 nM (95% confidence interval: 12.9, 25.9 nM: n = 26) in bronchus and 3.2 nM (95% confidence interval: 0.4, 23.9 nM; n = 5) in the arterial preparation. 3 ET-1 is 2.5 times more potent than ET-2 in both the airway and vascular tissues, and both forms of the peptide have geometric mean EC50 values 5 times greater than in the isolated bronchial tissue than in the pulmonary artery. 4 Neither pretreatment with the voltage-dependent calcium (VDC) channel antagonist verapamil (10 microM) nor with indomethacin (25 microM) significantly altered the response curve to ET-1 in human isolated bronchus. Removal of calcium from the Krebs-Henseleit solution did not affect ET-1-induced responses. 5 Specific binding on the smooth muscle of human airway and pulmonary arterial tissue to both ET-1 and ET-2 was detected in autoradiographic studies. There appeared to be no difference between the peptides in the location nor the density of binding sites. 6 We conclude that contraction of human bronchial tissue by ET-1 is not dependent upon influence of extracellular calcium nor release of prostaglandins or thromboxane A2. It is likely that the action of ET-1 in this tissue is due to binding of this peptide to specific receptors located on the smooth muscle.
McKay
K O
KO
Department of Pharmacology, University of Sydney, N.S.W., Australia.
Black
J L
JL
Armour
C L
CL
D001665:Binding Sites; D001980:Bronchi / Q000187:drug effects; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins