Receptors for substance P. II. Classification by agonist fragments and homologues

Abstract

Substance P (SP), a series of C-terminal fragments, SP-(2–11), SP-(3–11), SP-(4–11), SP-(5–11), SP-(6–11), SP-(7–11) and the homologues physalaemin, eledoisin and kassinin were used to measure the order of potency of agonists in five pharmacological preparations. These are: the guinea pig ileum, the guinea pig trachae, the rabbit mesenteric vein, the dog common carotid artery and the rabbit aorta. Apparent affinities (pD 2) and relative activities of SP-related peptides were measured in the absence and presence of antagonists (a mixture of atropine, indomethacin and diphenhydramine) in the guinea pig ileum and the rabbit mesenteric vein, in the absence and presence of indomethacin in the guinea pig trachea and in tissues with intact endothelium (the dog carotid artery and the the rabbit aorta). The orders of potency measured in the absence and presence of antagonists in the guinea pig ileum were different, while no major changes were noted in two other preparations, namely the guinea pig trachea and the rabbit mesenteric vein. The order of potency of agonists determined with homologues revealed the existence of three major patterns namely: kassinin > eledoisin > physalaemin = SP in the guinea pig trachea and the rabbit mesenteric vein, SP = physalaemin > eledoisin > kassinineledoisin > kassininin the arterial smooth muscle of the dog carotid artery and the rabbit aorta and physalaemin > kassinin > eledoisin > SP in the guinea pig ileum treated th antagonists. Three major patterns emerged from studies with the fragments: (a) a pattern favouring the long sequences SP to SP-(4–11) in the arterial smooth muscles and in the vein (vascular receptors), (b) the opposite pattern favouring the shorter fragment sequences in the guinea pig trachea and (c) the pattern of the guinea pig ileum treated with antagonist in which the octapeptide SP-(4–11) is definitely more potent than all other fragments. These findings have been interpreted as indicative of the existence of different receptor subtypes for substance P.