Evidence for and against Heterogeneity in the Histamine H&lt;sub&gt;2&lt;/sub&gt;-Receptor Population

1 The effect of lorglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic secretion and growth induced by caerulein and bombesin was studied in the rat. 2 Pancreatic exocrine secretion was studied both in vitro (isolated and perfused pancreatic segments) and in vivo (anaesthetized animals with cannulation of the common bile duct) whereas the trophic effect was investiged after short-term (5 days) administration of the peptides and/or lorglumide. 3 Both caerulein and bombesin stimulated amylase release from in vitro pancreatic segments in a concentration-dependent manner. Although the efficacy of both peptides was virtually identical, the potency of caerulein was higher than that of bombesin. Lorglumide displaced the concentrationresponse curves to caerulein to the right without affecting the maximum response, suggesting a competitive antagonism. The Schild plot analysis of data gave a straight line with a slope not significantly different from unity. The calculated pA2 for lorglumide was 7.31 + 0.45. The antagonist, however, was completely ineffective when tested against bombesin-induced amylase release. 4 In vivo experiments confirmed results from in vitro studies since lorglumide (5 and I0mgkg 1) significantly reduced pancreatic exocrine secretion induced by caerulein without affecting the response to bombesin. 5 Administration of either peptide increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Lorglumide (10mgkg-1), administered together with caerulein, reduced the peptide-induced increase in pancreatic weight, protein and enzyme content. On the contrary, when lorglumide was given together with bombesin, all the parameters that were examined were not altered by concomitant administration of the antagonist. 6 These results have demonstrated the ability of lorglumide to antagonize the effects on the pancreas of a CCK-analogue, caerulein, and its inability to affect bombesin-induced pancreatic secretion and growth, suggesting that lorglumide is a potent and selective antagonist of CCK-receptors in the pancreas.

Section: Discussionsupporting

confidence: 82%

Effect of a new potent CCK antagonist, lorglumide, on caerulein‐ and bombesin‐induced pancreatic secretion and growth in the rat

Scarpignato

Varga

Dobronyi

et al. 1989

“…This could be due to the high concentrations which had to be used (lower concentrations were absolutely inactive) with the consequent possible appearance of non-specific, effects of the compound. Non-specific effects of all the available H2-receptor antagonists of the older and the newer types have already been reported (Domschke & Domschke, 1980;Bertaccini & Dobrilla, 1980;Bertaccini & Coruzzi, 1981). The fact that similar results were obtained in the whole ileum and in the longitudinal muscle strip preparation tends to minimize the possible role of the circular smooth muscle in all the observed phenomena.…”

Section: Resultssupporting

confidence: 58%

“…As for the histamine receptors, the experiments by Kenakin et al (1974) were not convincing: the authors used only histamine and one H2-antagonist (metiamide) and they did not pay any attention to the possible effects of H2 selective agonists. The recent availability of new very potent and selective H2-and HI-agonists and antagonists and our specific interest in the field of histamine receptors because of the possible heterogeneity in this population (Bertaccini, 1981;Bertaccini & Coruzzi, 1981) prompted us to re-investigate the problem of the temperature-dependent interconversion. Our aim was to throw new light on this interesting experimental situation.…”

Section: Introductionmentioning

confidence: 99%

Evidence against the temperature‐dependent interconversion of histamine H₁‐ and H₂‐receptors in the guinea‐pig ileum

Bertaccini

Zappia

1983

1The possible temperature-dependent interconversion of histamine Hl-and H2-receptors in the guinea-pig ileum suggested from previous studies was re-investigated by use of new and selective H2-receptor agonists and antagonists. 2 Chlorpheniramine, an H1-blocker, caused a rightward shift of the cumulative histamine doseresponse curve at both 37°C and 12°C. Conversely cimetidine and tiotidine, two H2-receptor blockers, were ineffective at both temperatures. Metiamide behaved as a non competitive antagonist at 12°C but only in very high concentrations. 3 Dimaprit and impromidine, two selective H2-receptor agonists, were inactive at both 37°C and 12°C when given alone, whereas at both temperatures they elicited the already described relaxation of the contractions induced by histamine. 4 Similar results were obtained on the guinea-pig whole ileum and on the longitudinal muscle strip: this indicates a lack of interference of the circular smooth muscle. 5 Our results allow us to conclude that no temperature-dependent interconversion of histamine H1-and H2-receptors occurs in the guinea-pig ileum.

“…There is currently considerable controversy as to whether or not the histamine H2-receptor is a homogeneous entity between different tissues and different species. The existence of H2-receptor sub-types has been postulated (Bertaccini & Coruzzi, 1981), though this subdivision is far from widely accepted. If, however, such a subdivision were justified, it is possible that the present findings reflect strain differences in relative proportions of the putative H2-receptor sub-types.…”

Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity of histamine H₂‐receptors in the mouse vas deferens

Calvete

Donegan

et al. 1984

1 The ability of histamine to inhibit the overall contractile ('twitch') response of the isolated vas deferens of the mouse to electrical field stimulation (64 V pulse, 1 ms pulse width, frequency 0.2 Hz) was studied in nine inbred mouse strains. The strains were also characterized in terms of the potency of the histamine H2-receptor antagonist cimetidine in its inhibition of histamine-mediated effects. An apparently bimodal inter-strain variation (8-10 fold) in both characteristics was encountered, with three strains (SWR, A2G and C57BL/1OScSn) relatively sensitive (S) to both agonist and antagonist actions, and six (C3H, A, C57/BL6, DBA/2, Balb/C and 129/Sv) relatively insensitive (IS). 2 These strain differences were independent of extracellular calcium concentration in the range 1.25 -5 mM, and also independent of the frequency of tissue stimulation over the range 0.2 -6.4 Hz.3 Representative S (SWR and A2G) and IS (DBA/2 and C3H) mouse vasa were also characterized in terms of their sensitivity to the agonist actions of dimaprit and the antagonist actions of tiotidine. In the S strain tissues, dimaprit produced 50% inhibition of the twitch response at 4.6-1.8pM (mean+s.d.) and was able to elicit complete inhibition of the twitch response at concentrations greater than 100 JM, whereas 48.7 ± 11.9 JIM dimaprit was required to produce 50% inhibition of the twitch response in tissues from IS mice. In addition, the agonist actions of dimaprit were incomplete in the latter tissues, the drug eliciting no more than 75% inhibition of the twitch response at concentrations in the range 300-1000 JIM. Tiotidine produced competitive antagonism of the actions of both histamine and dimaprit, the strain differences being of the same magnitude as those observed for cimetidine.4 Mating of a representative S (SWR) and IS (129/Sv) strain produced F, mice with intermediate histamine and cimetidine sensitivities relative to the parental strains. A backcross of male F1 to female IS mice produced progeny displaying a range of histamine and cimetidine sensitivities representative of those seen in tissues from F1 and IS parental animals, however, the data were not bimodal. Thus, the backcross data provided no evidence to support single gene inheritance of histamine sensitivity and might suggest that more than one gene is responsible for these differences between S and IS mice.