Characterization of prostanoid relaxant/inhibitory receptors (psi) using a highly selective agonist, TR4979.

Abstract

TR4979, an analogue of prostaglandin E1 (PGE1) was evaluated on respiratory and non-respiratory isolated tissues known to contain heterogeneous or homogeneous populations of the two classes of prostanoid (prostaglandins and thromboxanes) receptors. These receptors are classified as 'chi' the contractant/stimulant receptor with 'chi 1,2,3' being three subdivisions and 'psi' the relaxant/inhibitory receptor(s). On a respiratory tissue (cat trachea) containing predominantly 'psi'-receptors, TR4979 was 26 times less potent than PGE1 or PGE2. On other respiratory tissues known to contain mixtures of the 'chi 1,2,3'- and 'psi'-receptors (guinea-pig trachea and lung strip, cat lung strip and human bronchial muscle), TR4979 consistently acted as a potent relaxant whereas PGE2 and to a lesser extent PGE1 had significant contractant activities. Human pregnant uterus, guinea-pig and rat pseudo-pregnant uteri, rat colon and fundic strips and chick ileum are known to contain one or more of the three subclasses of the 'chi'-receptor. TR4979 (10(-9) -10(-5) M) was inactive on all these tissues whereas all of the reference prostanoids were contractants of varying potencies. PGE1 and histamine-induced contractions of the guinea-pig isolated ileum were both non-competitively antagonized by increasing concentrations of TR4979 suggesting that 'psi'-receptors also exist on this tissue. TR4979 is a highly selective agonist of prostanoid 'psi' (relaxant/inhibitory)-receptors which at present have been demonstrated to exist mainly in the lung. This prostaglandin analogue is a useful new selective pharmacological tool for revealing as yet unidentified prostanoid 'psi'-receptors and actions in a wide range of non-respiratory tissues/organs such as the guinea-pig ileum.