HISTAMINE RECEPTOR-INDEPENDENT MUSCLE-RELAXATION ELICITED BY A SERIESOF HISTAMINE H-2-RECEPTOR AGONISTS ON THE ISOLATED GUINEA-PIG DUODENUM - A STUDY INTO THE MECHANISM OF ACTION

1. The histamine H-2 receptor agonists, dimaprit, impromidine, amthami ne, and several dimaprit and impromidine analogues were investigated f or their spasmolytic activity on the guinea pig duodenum, precontracte d with acetylcholine or KCI. 2. Almost all the H-2 receptor agonists e xerted a histamine Hz receptor-independent muscle relaxation, which wa s more evident on acetylcholine- than on KC1-precontracted preparation s. 3. The relaxing activity of these compounds was independent of inhi bitory receptors, like beta-adrenergic, GABA-ergic, serotoninergic, et c. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of hi stamine H-2-receptor agonists was shared only by the Nai blocker proca ine, the intracellular Ca2+ antagonist ruthenium red and, at least in terms of efficacy, by the protein kinase C inhibitor, chelerithrine. 5 . This spasmolytic effect is probably due to an impairment of receptor -mediated depolarization at the plasma membrane level and/or an inhibi tory activity on the protein kinase C dependent activation of the cont ractile machinery. 6. Finally, our findings suggest that the histamine H-2 receptor-independent muscle relaxation is a general feature shown by HL receptor agonists endowed with different chemical structure and the putative spasmolytic ''receptor'' prefers a (substituted) thiazol e over a (substituted) imidazole. (C) 1998 Elsevier Science Inc.