Pinacidil antagonism of endothelin-induced contractions of smooth muscle in the lungs: differences between tracheal and pulmonary artery preparations.
Contractions to endothelin and their reversal by pinacidil have been examined in isolated preparations of guinea pig and rat trachea and rat pulmonary artery. Indomethacin attenuated endothelin (less than or equal to 10 nM) on guinea pig trachea, but not on the rat tissues. This indicates that part of the effect of endothelin on guinea pig trachea is indirect and mediated by cyclooxygenase products. Endothelin (direct effects) was more potent on pulmonary artery than on guinea pig or rat trachea (negative log EC50 values: 8.42, 7.71 and 7.76, respectively) and was also a more effective spasmogen on pulmonary artery (maximum was the tissue maximum, i.e., greater than or equal to 80 mM K+) than on trachea (maximum was 60-70% of the tissue maximum to 10 microM carbachol). Pinacidil was less effective preventing (anti-spasmogenic) than reversing (spasmolytic) contractions to endothelin on either tissue type. This is compatible with different mechanisms for the initiation and maintenance of smooth muscle contraction in these tissues. As a spasmolytic against endothelin (0.03 microM), pinacidil was less potent on rat pulmonary artery than on guinea pig or rat trachea (negative log IC50 values: 4.45, 5.65 and 5.49, respectively). This may reflect 1) the greater tone induced by endothelin on pulmonary artery, 2) a smaller receptor reserve for endothelin in trachea and/or 3) a different mechanism whereby endothelin contracts pulmonary vascular smooth muscle compared with tracheal smooth muscle.
O'Donnell
S R
SR
Department of Physiology and Pharmacology, University of Queensland, St. Lucia, Brisbane, Australia.
Wanstall
J C
JC
Zeng
X P
XP
D000818:Animals; D016232:Endothelins; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010455:Peptides / Q000037:antagonists & inhibitors*; D020110:Pinacidil; D011651:Pulmonary Artery; D051381:Rats; D011919:Rats, Inbred Strains; D014132:Trachea; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors; D014665:Vasodilator Agents / Q000494:pharmacology*
D016232:Endothelins; D006146:Guanidines; D010455:Peptides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D020110:Pinacidil