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Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF 2α or endothelin
Author(s) -
O'Donnell Stella R.,
Wanstall Janet C.,
Kay Christine S.,
Zeng Xiangping
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12171.x
Subject(s) - medicine , pulmonary artery , forskolin , endothelin 1 , anesthesia , vascular smooth muscle , pharmacology , receptor , smooth muscle
1 The spasmolytic effects of smooth muscle relaxant drugs with different mechanisms of action have been examined on isolated preparations of guinea‐pig trachea and rat pulmonary artery. The preparations were contracted with concentrations of prostaglandin F 2α (PGF 2α ) or endothelin selected to give approximately 80% of the agonist maximum response on each tissue. These concentrations also caused similar levels of tone (% of tissue maximum contraction) on each tissue. 2 With endothelin as the spasmogen, the potassium channel opening drug, pinacidil, was more potent on trachea (– log IC 50 5.49) than on pulmonary artery (4.39), i.e. was airway‐vascular selective, whereas with PGF 2α as the spasmogen it was more potent on pulmonary artery (6.01) than on trachea (5.27), i.e. was vascular‐airway selective. 3 With endothelin as the spasmogen, fenoterol was also airway‐vascular selective (8.35 on trachea; little effect on pulmonary artery), nitroprusside was vascular‐airway selective (7.50 on pulmonary artery; 5.99 on trachea) and forskolin was non‐selective (6.69 on trachea; 6.70 on pulmonary artery). Thus, the airway‐vascular selectivity of the relaxant drugs varied with the drug. 4 On pulmonary artery, pinacidil, nitroprusside and forskolin were all more potent against PGF 2α than against endothelin, i.e. 42, 4 and 7 fold respectively. On trachea, these drugs were equipotent against PGF 2α and endothelin. 5 The results suggest that, in pulmonary artery, but not in trachea, the relative contribution of protein kinase C activation and calcium influx to the maintenance of tonic contractions to endothelin and PGF 2α may be different. If protein kinase C activation should be the predominant mechanism for endothelin in pulmonary artery, then it may be more difficult to reverse this with relaxant drugs that lower intracellular calcium. 6 The study indicates that the airway‐vascular selectivity of relaxant drugs can be spasmogen‐dependent as well as dependent on the mechanism of action of the relaxant drug. Thus, relaxant drugs, whether of interest for their airway or vascular effects, should be tested against a full range of spasmogens of likely pathophysiological importance.