INVERSE AGONISM OF HISTAMINE H-2 ANTAGONISTS ACCOUNTS FOR UP-REGULATION OF SPONTANEOUSLY ACTIVE HISTAMINE H-2 RECEPTORS

Histamine H-2 receptors transfected in Chinese hamster ovary (CHO) cel ls are time- and dose-dependently upregulated upon exposure to the H-2 antagonists cimetidine and ranitidine. This effect appears to be H-2 receptor-mediated as no change in receptor density was observed after H-1 or H-3 antagonist treatment or after incubation with the structura l analogue of cimetidine, VWF 8299, which has no H-2 antagonistic effe cts, Bq using transfected CRO cells expressing different densities of wild-type H-2 receptors or an uncoupled H(2)Leu(124)Ala receptor, the histamine H-2 receptor was found to display considerable agonist-indep endent H-2 receptor activity. Cimetidine and ranitidine, which both in duce H-2 receptor upregulation, actually functioned as inverse agonist s in those cell lines displaying spontaneous agonist-independent H-2 r eceptor activity, Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H-2 receptor upregu lation after long-term exposure, The displayed inverse agonism of H-2 antagonists appears to be a Mechanistic basis for the observed H-2 ant agonist-induced H-2 receptor upregulation in transfected CHO cells, Th ese observations shed new light on the pharmacological classification of the H-2 antagonists and mag offer a plausible explanation for the o bserved development of tolerance after prolonged clinical use.