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

Abstract

1 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 ‘χ’ the contractant/stimulant receptor with ‘χ_1,2,3’ being three subdivisions and ‘ψ’ the relaxant/inhibitory receptor(s). 2 On a respiratory tissue (cat trachea) containing predominantly ‘ψ’-receptors, TR4979 was 26 times less potent than PGE₁ or PGE₂. 3 On other respiratory tissues known to contain mixtures of the ‘χ_1,2.3’- and ‘ψ’-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. 4 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 ‘χ’-receptor. TR4979 (10⁻⁹ − 10⁻⁵ M) was inactive on all these tissues whereas all of the reference prostanoids were contractants of varying potencies. 5 PGE, and histamine-induced contractions of the guinea-pig isolated ileum were both noncompetitively antagonized by increasing concentrations of TR4979 suggesting that ‘ψ’-receptors also exist on this tissue. 6 TR4979 is a highly selective agonist of prostanoid ‘ψ’ (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 ‘ψ’-receptors and actions in a wide range of non-respiratory tissues/organs such as the guinea-pig ileum.