Stimulation of gastric acid secretion by 5-methyl histamine in cat

5-Methyl histamine caused strong and long-lasting stimulation of gastric acid secretion in cats with gastric fistulas. After stopping intravenous infusion of high doses of 5-methyl histamine, secretion persisted at slowly decreasing levels for more than 6 hours. The calculated maximal response to 5-methyl histamine was not significantly different from that to histamine. The dose required for half maximal response was 1.8 times greater for histamine than for 5-methyl histamine.This work was supported by a Veterans Administration Senior Medical Investigatorship (Dr. Grossman) and by USPHS Grant AM 08354.     

Synthesis and analgesic activity of 4-(3-oxo-1,2-benzoisothiazoline-2-yl)phenylalkanoic derivatives

The synthesis of a new series of 4-(3-oxo-1,2-benzisothiazolin-2-yl)phenylalkanoic compounds and some of their functional derivatives is described. The compounds, on the basis of data obtained from 1,2-benzisothiazolin-3-one derivatives, were biologically examined mainly for their antiphlogistic and analgesic actions. Results obtained, in analyzing the relationship between structure and pharmacological actions, suggest that both 4-(3-oxo-1,2-benzisothiazolin-2-yl)-phenyalkanoic acids and o-sulphobenzimido alkanoic esters are endowed with pain-killing effects comparable in potency and efficacy with phenylbutazone.     

Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents

We hypothesized that proteinase-activated receptor-2 (PAR(2)) modulates intestinal injuries induced by ischemia/reperfusion. Ischemia (1 hour) plus reperfusion (6 hours) significantly delayed gastrointestinal transit (GIT) compared with sham operation. Intraduodenal injection of PAR(2)-activating peptide SLIGRL-NH(2) significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR(2)(-/-) mice compared with PAR(2)(+/+). SLIGRL-NH(2) significantly accelerated transit in ischemia/reperfusion in PAR(2)(+/+) but not in PAR(2)(-/-) mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP(8-37) and RP67580, respectively, abolished the SLIGRL-NH(2)-induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH(2); this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP(8-37). Intestinal PAR(2) mRNA levels were not affected by SLIGRL-NH(2) in ischemia/reperfusion. We propose that PAR(2) modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR(2) effect on transit might be mediated by CGRP and substance P, whereas the effect on tissue damage appears to involve substance P but not CGRP. PAR(2) might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion.     

Synthesis and local anesthetic activity of alkylaminoacyl derivatives of 3-amino-1,2-benzisothiazoles

Two series of new alkylaminoacylamino-1,2-benzisothiazoles were synthetized and assayed for anesthetic activity. The above-mentioned compounds were prepared by reaction between the appropriate amines and 3-(haloacyl)amino-1,2-benzisothiazoles, which had been obtained by acylation of a 3-amino-1,2-benzisothiazole with the required haloacylchloride. The local anesthetic activity of the compounds, isolated as hydrochlorides, was tested for surface, infiltration and trunkular anesthesia. Several compounds proved to be active in infiltration and trunkular anesthesia, whereas no compound showed local surface anesthesia. On the basis of the results obtained the structure-activity relationships were examined.     

The actions of caerulein on gastric secretion of the dog and the rat

1. Caerulein, as expected from its amino-acid composition and sequence, has a potent stimulant action on gastric secretion in the dog, the rat and the frog.2. In the denervated fundic pouch of the dog, caerulein increases the rate of flow of gastric juice and the outputs of acid and pepsin. Acid concentration and pepsin concentration in caerulein-produced juice are generally greater than in control juice. The threshold subcutaneous dose of caerulein is 0.15-0.5 mug/kg and the threshold rate of intravenous infusion 0.25-0.5 mug/kg per hr. Rapid intravenous injection is ineffective. On a molar basis, caerulein is approximately twice as active as human gastrin I on volume and acid output of the gastric pouch and 4 times as active on pepsin output.3. Sustained acid secretion of the fundic pouch produced by histamine infusion is inhibited by caerulein, administered either intravenously or subcutaneously. In turn, acid secretion elicited by caerulein is inhibited by atropine.4. In the rat, the activity ratio of caerulein to human gastrin I is 7-30, calculated on a molar basis, and is thus considerably greater than in the dog. Further, caerulein is 3 times more active than cholecystokinin-pancreozymin. Tested on the perfused stomach preparation of the rat, the threshold dose of caerulein by rapid intravenous injection is 25 ng/kg, by intravenous infusion 0.25 mug/kg per hr, and by subcutaneous injection 0.25 to 0.5 mug/kg.5. The activity of caerulein is sharply reduced by pretreatment of the rats with the histamine liberator 48/80 and potentiated by pretreatment with the diamine oxidase inhibitor aminoguanidine. When caerulein is given by rapid intravenous injection during a priming infusion of histamine its effect is enhanced and considerably prolonged.6. The isolated mucosa of the frog stomach is extremely sensitive to caerulein which, in a concentration of a few pg/ml., stimulates active transport of chloride.7. Qualitative and quantitative differences in the action of gastrin and caerulein are pointed out, and particular emphasis is laid on the importance of esterification of the tyrosyl residue for the biological activity of caerulein.     

R-alpha-methylhistamine-induced inhibition of gastric acid secretion in pylorus-ligated rats via central histamine H3 receptors.

1. The effect of central H3 histamine receptor activation on gastric acid and pepsin production has been investigated in pylorus-ligated rats. 2. Intracerebroventricular injections (i.c.v.) of the selective H3 agonist, R-alpha-methylhistamine (0.5-50 nmol per rat) caused a dose-dependent inhibition of gastric acid secretion while intravenous administration (5-500 nmol per rat) was completely ineffective. 3. I.c.v. microinjections of mepyramine, tiotidine and thioperamide (51 nmol per rat), selective antagonists at H1-, H2- and H3-sites respectively, failed to modify the acid secretory response to pylorus ligation. 4. The antisecretory effect of R-alpha-methylhistamine (5 nmol per rat, i.c.v.) was selectively prevented by the H3-blocker, thioperamide (51 nmol per rat, i.c.v.), mepyramine and tiotidine pretreatment being completely inactive. 5. Unlike acid secretion, pepsin production was not significantly affected by all the tested compounds. 6. These findings provide the first pharmacological evidence that the activation of central H3 histamine receptors exerts a negative control in the regulation of gastric acid secretion in conscious pylorus-ligated rats.     

Are histamine receptors involved in the stimulant activities of thiazolylethylamines supposed as cyclic models of dimaprit?

A representative group of 2-aminothiazolylethylamine derivatives, in which the gastric acid secretion stimulatingS-aminoalkylisothiourea moiety can be recognized, was tested. The quite different responses observed suggest thatin vivo but notin vitro some events mimicking an H₂-receptor agonist-like activity rather than a direct interaction with H₂-receptors could take place. On the basis of structure-activity relationships, it can be speculated that the active conformation of dimaprit is not that resembled by these compounds which have been considered as cyclic models of one of its possible conformations.