Histamine receptor-independent muscle relaxation elicited by a series of histamine H2-receptor agonists on the isolated guinea pig duodenum: a study into the mechanism of action.
1. The histamine H2 receptor agonists, dimaprit, impromidine, amthamine, and several dimaprit- and impromidine-analogues were investigated for their spasmolytic activity on the guinea pig duodenum, precontracted with acetylcholine or KCl. 2. Almost all the H2 receptor agonists exerted a histamine H2 receptor-independent muscle relaxation, which was more evident on acetylcholine- than on KCl-precontracted preparations. 3. The relaxing activity of these compounds was independent of inhibitory receptors, like beta-adrenergic, GABA-ergic, serotoninergic, etc. Similarly, modifications of cyclic nucleotide metabolism and nitric oxide production did not appear to be involved. 4. The behavior of histamine H2-receptor agonists was shared only by the Na+-blocker procaine, 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 inhibitory activity on the protein kinase C-dependent activation of the contractile machinery. 6. Finally, our findings suggest that the histamine H2 receptor-independent muscle relaxation is a general feature shown by H2 receptor agonists endowed with different chemical structure and the putative spasmolytic "receptor" prefers a (substituted) thiazole over a (substituted) imidazole.
Coruzzi
G
G
Institute of Pharmacology, University of Parma-School of Medicine, Italy.
Poli
E
E
Pozzoli
C
C
Bertaccini
G
G
Timmerman
H
H
D000818:Animals; D017259:Dimaprit / Q000032:analysis / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects; D004558:Electric Stimulation; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000494:pharmacology*; D017446:Impromidine / Q000032:analysis / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology
D017442:Histamine Agonists; D010276:Parasympatholytics; D013844:Thiazoles; C076207:amthamine; D017446:Impromidine; D017259:Dimaprit