Biological activities of a new specific stimulant of histamine H2 receptors.

Compound N-methyl-2-(5-methyl-4-imidazolyl)ethylamine (5-methyl-N-methylhistamine) was submitted to a thorough pharmacological examination and was found to be a potent stimulant of H2 receptors, devoid of any appreciable effect on H1 receptors. Because of its high degree of specificity it therefore seems to represent an interesting drug to be used in clinical gastric secretory tests and an useful tool for the study of histamine H2 receptors.     

A possible physiological role of histamine H2-receptors in rat mesenteric circulation

Dose-response curves of histamine were studied on the mesenteric circulation of the anaesthetized rat. The vasodilation produced by small doses of histamine was prevailingly H2-receptor-dependent, as shown by its inhibition by cimetidine but not by mepyramine, and by its reproducibility by some H2-receptor agonists, but not by specific H1-receptor agonists. The vasodilation produced by high doses of histamine was mainly due to stimulation of H1-receptors, as shown by its 70% inhibition by mepyramine. Mepyramine and cimetidine given simultaneously nearly completely inhibited the vasodilating action of high doses of histamine. Certain H2-receptor agonists, administered at high doses, induced a paradoxical vasoconstriction. It is suggested that a small number of H2-receptors is present in rat mesenteric arterioles, and that these receptors may play a physiological role in the control of mesenteric circulation.     

Activity of 2-(5-methyl-4-imidazolyl)-ethylamine (5-methylhistamine) on the gastric secretion of different laboratory animals and of man

The compound 2-(5-methyl-4-imidazolyl)-ethylamine, namely 5-methylhistamine3(5-MeH), was compared to histamine for its stimulant activity on gastric secretion in Heidenhain pouch dogs, cats, rats and also on gastric secretion of human volunteers.In dogs and cats 5-MeH had approximately the same activity as histamine, both as regards threshold doses and peak secretory effects, when given by subcutaneous injection or by intravenous infusion.In the rat 5-MeH was 60% less active than histamine when given by either i.v. injection or infusion.In the preliminary experiments carried out in man, 5-MeH and histamine given at the same doses had approximately the same effect as regards volume, acidity of the gastric juice and also persistence of effect. 5-MeH was tolerated in all the subjects whereas histamine was not tolerated in 1 out of 5 subjects.The results obtained suggest that this new methyl derivative could reprent a good alternative to thmmon stimulants used in the clinical gastric secretory tests.     

Structure and pharmacological actions of phyllocaerulein, a caerulein-like nonapeptide: Its occurrence in extracts of the skin of Phyllomedusa sauvagei and related Phyllomedusa species

1. The South American amphibian Phyllomedusa sauvagei contains in its skin large amounts of a polypeptide closely resembling caerulein in its pharmacological actions. This polypeptide, called phyllocaerulein, was obtained in a pure form, and upon acid hydrolysis, enzymic digestion and end-group determination experiments it proved to be a nonapeptide of the following composition Pyr-Glu-Tyr(SO(3)H)-Thr-Gly-Trp-Met-Asp-Phe-NH(2)It may be seen that caerulein and phyllocaerulein have in common the C-terminal heptapeptide and the N-terminal pyroglutamyl residue.2. Phyllocaerulein is indistinguishable from caerulein even in parallel bioassay. However, the former polypeptide seems to be somewhat more potent than the latter on all the preparations tested.3. In different batches of Phyllomedusa sauvagei skin the phyllocaerulein content ranged between 150 and 600 mug/g of fresh tissue.Phyllocaerulein or similar polypeptides occur also in the skin of several other Phyllomedusa species, among which are Phyll. burmeisteri, Phyll. dachnicolor, Phyll, helenae, Phyll. annae, Phyll. callidryas and Phyll. bicolor.4. The qualitative identification and quantitative estimation of caerulein-like polypeptides in crude skin extracts may be complicated by the concomitant occurrence of other active polypeptides. These, however, are poorly effective on some test preparations which seem to respond selectively to caerulein.5. Like that of caerulein, the biological significance of phyllocaerulein is completely obscure.     

Inhibitory effect of fentonium on gastric acid secretion in different laboratory animals.

The influence of fentonium, a new derivative of hyoscyamine, on the gastric secretion has been evaluated in rats, cats and dogs. The compound appeared to be able to markedly reduce the gastric hypersecretion produced by pentagastrin, caerulein and bethanechol; its antagonizing activity against histamine stimulation was poor.     

Synthesis of new derivatives of 3-benzyl-1,2-benzisothiazole and a study of analgesic activity in mice

This paper describes the synthesis of 3-benzyl-1,2-benzisothiazole derivatives, structurally related to benzylisoquinolines, and their analgesic activity studied using writhing technique in the mouse. The presence of lipophilic substituents in position 3, 4 of the benzyl group give substances with analgesic activity, although their "potency" is lower than that shown by papaverine.     

Action of bombesin on the motility of the stomach

1. The tetradecapeptide bombesin was tested for its activity on the stomach in rats, dogs and men. On the rat stomach bombesin displayed a striking spasmogenic activity apparently independent from the autonomic nervous system. 2. In the dog the peptide was spasmogenic on the denervated Heidenhain pouch and the antrum. The inhibitory activity predominated on the innervated stomach and body fundus. 3. In man the peptide exerted a contracting effect on the antrum and the pylorus and an inhibitory effect on the stomach body and the fundus. In vitro studies performed on human stomach isolated strips showed a constant stimulant effect. 4. Apparently bombesin has a direct effect on the in situ rat stomach and on the isolated preparations, whereas it has an indirect effect on the other in situ innervated preparations.