Histamine H2 receptor antagonists and the cardiovascular system.
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Animals↗
Biomedical subjects
G Bertaccini
Publications and source records attributed to G Bertaccini.
The new potent and selective histamine H2 receptor agonist amthamine as a tool to study gastric secretion.
The new histamine H2 receptor agonist amthamine, [2-amino-5-(2-aminoethyl)-4-methylthiazole], was tested for its activity on gastric acid secretion in different in vivo and in vitro experimental models. Amthamine induced a dose-related increase in acid secretion both in conscious cats with a gastric fistula (ED50 = 0.069 mumol/kg/h) and in anaesthetized rats with a lumen-perfused stomach (ED50 = 11.69 mumol/kg i.v.). In this last preparation the efficacy of amthamine was significantly higher than that of histamine and dimaprit. Amthamine was an effective secretagogue also in the rat isolated gastric fundus, behaving as a full agonist (EC50 = 18.9 mumol/l). In all the experimental models amthamine was more potent than dimaprit (from 3 to 10 fold) and approximately equipotent with histamine, and its effect was competitively antagonized by the histamine H2 receptor antagonists famotidine or ranitidine. Experiments with H1 and H3 receptor antagonists indicated that amthamine is devoid of stimulatory activity at H1 and H3 receptors. The present data indicate that amthamine is a full agonist at histamine H2 receptors and, being more effective and selective than the other compounds of the family, it may represent a good alternative to the other available histamine H2 receptor agonists for the study of gastric acid secretion.
Animals↗
Histamine H3 receptor-mediated inhibition of gastric acid secretion in conscious dogs.
The effect of (R)alpha-methylhistamine (MH) and thioperamide (selective agonist and antagonist respectively of histamine H3 receptors) was examined in conscious gastric fistula dogs to investigate the role of histamine H3 receptors in the control of basal and stimulated gastric acid secretion. Intravenous infusion of MH at 0.3 and 0.6 mumol/kg/h caused a significant reduction of the 2-deoxy-D-glucose (2-DG)-stimulated acid output, maximal inhibition being 60%. The inhibitory effect of MH was counteracted by thioperamide (0.1 mumol/kg/h), which, by itself, did not modify the 2-DG-induced acid secretion. The increase in plasma gastrin levels induced by 2-DG was not significantly affected either by MH or by thioperamide. Under basal conditions MH (0.3 mumol/kg/h) did not induce any significant change in acid secretion and in plasma gastrin levels; by contrast, thioperamide (0.1 mumol/kg/h) produced a significant increase both in acid output and in plasma gastrin. These results suggest that activation of H3 receptors can exert a negative control in stimulated acid secretion in conscious dogs, when cholinergic pathways to acid secretion are activated by 2-DG; moreover, the slight, but significant, stimulatory effect of thioperamide on basal acid output and basal plasma gastrin may be suggestive for a tonic inhibitory role of H3 receptors in the regulation of basal acid secretion, however, a nonspecific effect of this drug cannot be excluded.
Animals↗
In vitro cardiac pharmacology of the new histamine H2-receptor agonist amthamine: comparisons with histamine and dimaprit.
The cardiac activity of the novel histamine H2-receptor agonist amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD2 = 6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD2 = 6.17) and of the human atrium (pD2 = 5.38). In all these systems, amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of amthamine were competitively antagonized by ranitidine which had pA2 values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta amthamine was devoid of H1-mediated activities up to 3 x 10(-4) M. These results indicate that amthamine is a potent and selective histamine H2-receptor agonist which can be considered a valuable tool for investigating H2-receptor mediated effects in cardiac tissues.
Animals↗
Histamine H3-receptor-induced inhibition of duodenal cholinergic transmission is independent of intracellular cyclic AMP and GMP.
1. The inhibitory effect of the histamine H3-receptor agonist (R) alpha-methylhistamine on cholinergic neurotransmission was studied in the isolated guinea pig duodenum in the presence of different compounds which alter intracellular levels of cyclic nucleotides and of the G proteins blocker pertussis toxin. 2. The action of (R) alpha-methylhistamine on electrically-evoked contractions was not modified either by forskolin and isobutylmethylxanthine (which increase cyclic AMP) or by zaprinast and methylene blue (which increase and decrease, respectively intracellular cyclic GMP). Drugs affecting cyclic nucleotide levels were also ineffective against the inhibitory effect of the alpha 2 adrenergic agonist clonidine. 3. Pertussis toxin significantly reduced the maximum inhibition induced by (R) alpha-methylhistamine and clonidine, without influencing the effect of low concentrations of the above compounds; conversely it shifted to the right in a parallel way the inhibitory effect of adenosine. 4. These data suggest that H3-receptor-mediated inhibition of cholinergic transmission in the guinea pig duodenum is not linked to intracellular nucleotide changes. Moreover the signal transducing mechanism activated by (R) alpha-methylhistamine involves pertussis toxin both sensitive and insensitive G proteins.
1-Methyl-3-isobutylxanthine↗
Antimuscarinic activity of telenzepine on isolated human urinary bladder: no role for M1-muscarinic receptors.
1. The antimuscarinic activity of the selective M1-blocking drug, telenzepine, was investigated on the isolated human urinary bladder, contracted with exogenous muscarinic agonists and with field stimulation. 2. Telenzepine (3 x 10(-8)-10(-5) M) concentration-dependently shifted to the right the dose-response curves of bethanechol, acetylcholine and McN-A343, and partially depressed the electrically-evoked twitch responses. 3. pA2 values of telenzepine against bethanechol and McN-A343 were very close. 4. McN-A343 did not modify twitch responses elicited by field stimulation up to 10(-5) M. 5. The lack of muscarinic M1 receptors in human detrusor muscle is confirmed.
Adult↗
Histamine H3 receptors are not involved in the regulation of rat gastric secretion.
The effects of histamine H3 receptor activation [(R)alpha-methylhistamine] and blockade (thioperamide) on rat gastric secretion were determined in vivo and in vitro. (R)alpha-Methylhistamine (0.1-5 mumol/kg i.p.) did not modify secretory volume and acidity in pylorus-ligated rats; it did not affect basal acid secretion and the secretion stimulated by histamine, pentagastrin and 2-deoxy-D-glucose in the lumen-perfused stomach of anaesthetized rats, when administered by continuous infusion (0.01-1 mumol/kg/h) or bolus injection (0.05-25 mumol/kg). In this preparation, the H3 agonist increased acid secretion at doses of 3-25 mumol/kg i.v., the effect being antagonized by famotidine. In the isolated gastric fundus from immature rats both (R)alpha-methylhistamine (0.01-10 mumol/l) and thioperamide (0.01-1 mumol/l) were totally ineffective against both spontaneous and stimulated gastric secretion. These results suggest that histamine H3 receptors are unlikely to have a role in regulating gastric acid secretion in the rat.
Animals↗
Furan and thiophene analogues of omeprazole.
Synthesis and structure of some analogs of the omeprazole containing furan and thiophene rings are reported. Their effects on the basal and the histamine-stimulated secretion were evaluated on the isolated rat stomach.
Animals↗
Untoward reactions to gastric antisecretory drugs.
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Anti-Ulcer Agents↗
Histamine receptors in isolated guinea pig duodenal muscle: H3 receptors inhibit cholinergic neurotransmission.
A series of histamine H3 receptor agonists and the H3 receptor antagonist thioperamide were tested in the isolated guinea pig duodenum, to investigate the role of this new receptor subtype in the intestinal contractility. At the same time the selectivity of the different compounds for the various histamine receptor subtypes was investigated. In the presence of famotidine (10(-6) M) and thioperamide (10(-5) M), histamine, N alpha-methylhistamine (NMH) and (R)-alpha-methylhistamine (alpha-MH) exerted a concentration-dependent contractile effect through activation of H1 receptors; the ratio of potency was histamine = NMH greater than alpha-MH (this last compound was approximately 500 times less potent). In the presence of pyrilamine (10(-6) M) and thioperamide (10(-5) M), histamine, dimaprit and impromidine caused a slight contractile effect, showing a high degree of tachyphylaxis; this effect was abolished by tetrodotoxin (10(-6) M) and by famotidine (10(-6) M). alpha-MH was ineffective up to 10(-4) M. The H2 receptor agonists dimaprit (10(-4) to 10(-3) M) and impromidine (10(-6) to 10(-5) M) caused a relaxant effect on the contraction elicited by acetylcholine (ACh), BaCl2 and electrical stimulation. This effect, which was unaffected by famotidine, was not mimicked by alpha-MH and not reversed by thioperamide (10(-5) M). In the presence of pyrilamine (109-6) M) and famotidine (10(-6) M), histamine, NMH and alpha-MH inhibited the twitch responses to electrical stimulation, with EC50 values of 1.17 x 10(-7), 6.76 x 10(-8) and 2.45 x 10(-8) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of substance P and related neurokinins on gastric acid secretion.
Substance P and a series of related neurokinins having various degrees of selectivity for tachykinin receptors have been studied for their effects on gastric acid secretion both "in vitro" and "in vivo". In the isolated gastric fundus from immature rats, substance P, the C-terminal heptapeptide of neurokinin A, NKA (4-10), [Arg]NKB and two synthetic analogues of NKA (4-10), namely, [beta-Ala8]NKA (4-10) and [Ala5]NKA (4-10) (compounds marked Men 10210 and Men 10209, respectively) had no effect on spontaneous secretion but enhanced the secretory response to histamine. All the different neurokinins were effective in the range of concentrations 10(-7) - 10(-6) M. In the conscious cat with gastric fistula, substance P dose-dependently increased basal acid secretion, whereas Men 10210 was absolutely ineffective. Men 10209 caused a slight increase in acid output which, however, was only 10% of that induced by dimaprit or pentagastrin. The secretory effect of dimaprit and pentagastrin was not affected by the different neurokinins, conversely the response to 2-Deoxy-D-glucose was slightly reduced by Men 10210 (10 nmol/kg/h). The above data suggest that the natural and synthetic neurokinins studied have negligible effects on gastric acid secretion, thus the gastro-protective effect observed in some experimental conditions is unlikely to be related to an antisecretory effect of these compounds.
Amino Acid Sequence↗
Evidence that histamine H3 receptors are involved in the control of gastric acid secretion in the conscious cat.
In an attempt to assess the role of histamine H3 receptors in the control of gastric acid secretion, the effects of the selective histamine H3 receptor agonist, (R) alpha-methylhistamine and antagonist, thioperamide were evaluated in the conscious gastric fistula cat under basal conditions and against different stimuli. (R) alpha-methylhistamine (0.05-0.2 mumol/kg/h) was ineffective against spontaneous and dimaprit-induced acid secretion; it also did not reduce significantly pentagastrin-induced acid output, but caused a dose-dependent (0.05-0.1 mumol/kg/h) and significant inhibition of the acid response to 2-deoxy-D-glucose. Thioperamide (0.02-0.04 mumol/kg/h) did not modify spontaneous acid secretion, whereas it evoked a significant enhancement of the acid response to submaximal doses (50 mg/kg i.v.) of 2-deoxy-D-glucose. Thioperamide completely reversed the inhibitory effect of (R) alpha-methylhistamine against 2-deoxy-D-glucose-induced secretion, while leaving unaffected the inhibition induced by somatostatin. These data suggest that histamine H3 receptors may be involved in the control of acid secretion stimulated by indirectly acting secretagogues.
Animals↗
Histamine H3-receptor activation inhibits acetylcholine release from the guinea pig myenteric plexus.
The role of histamine H3-receptors in the control of acetylcholine release from peripheral cholinergic neurons was evaluated in the isolated guinea pig ileum, previously loaded with 3H-choline. When tested in the presence of H1- and H2-blockade, histamine (0.1-100 mumol/l) and (R) alpha-methylhistamine (0.01-1 mumol/l) dose-dependently reduced the electrically-evoked choline outflow, with (R) alpha-methylhistamine being a partial agonist. Selective H3-receptor blocking drugs, thioperamide (0.1 mumol/l) and impromidine (0.1 mumol/l) reversed the histamine-induced inhibitory effect. These data suggest that intestinal cholinergic nerves are endowed with histamine H3-receptors whose activation produces an inhibitory effect upon acetylcholine release. The practical implications of these findings are obvious.
Acetylcholine↗
Histamine H3 receptors regulate acetylcholine release from the guinea pig ileum myenteric plexus.
The effect of selective histamine H3-receptor agonists and antagonists on the acetylcholine release from peripheral nerves was evaluated in the guinea pig longitudinal muscle-myenteric plexus preparations, preloaded with (3H)choline. In the presence of H1 and H2 blockade, histamine (10(-7)-10(-4) M) and (R)-alpha-methylhistamine (10(-8)-10(-6) M) inhibited the electrically-evoked acetylcholine release, being (R)-alpha-methylhistamine more active than histamine, but behaving as a partial agonist. The effect of histamine was completely reversed by selective H3-blocking drugs, thioperamide and impromidine, while only submaximal doses of (R)-alpha-methylhistamine were antagonized. Furthermore, thioperamide and impromidine enhanced the electrically-evoked acetylcholine release. On the contrary, the new H3-blocker, HST-7, was found substantially ineffective, both as histamine antagonist and as acetylcholine overflow enhancer. These data suggest that histamine exerts an inhibitory control on the acetylcholine release from intestinal cholinergic nerves through the activation of H3 receptors.
Acetylcholine↗
Review article: the histamine H3-receptor: a novel prejunctional receptor regulating gastrointestinal function.
This review examines the evidence for the existence in the gastrointestinal tract of a new subtype (H3) of histamine receptors, previously described in the central nervous system. Study of these receptors is facilitated by the availability of the highly selective agonist (R) alpha-methylhistamine and the selective antagonist, thioperamide. H3-receptors seem to exert negative control on gastric acid secretion evoked by indirect cholinergic stimuli: their localization is unclear but it seems to be outside the parietal cell. H3-receptors also seem to be located on cholinergic and non-adrenergic non-cholinergic (NANC) neurones of the myenteric plexus, where they negatively control the release of neurotransmitters.
Animals↗
Positive inotropic effect of endothelin-2 on human atrium preparations in vitro.
The inotropic effect of endothelin-2 was investigated on isolated preparations of human atrium taken from patients undergoing cardiac surgery. Pectinate muscle fragments were set up in isolated organ chambers under isometric conditions and electrically stimulated through two ring platinum electrodes. Endothelin-2 (10(-11)-10(-8) M) increased both the force and velocity of contraction in a concentration-dependent manner, giving a maximum response of about 70% of that attainable with histamine or epinephrine. The putative endothelin B receptor agonist, the C-terminal hexapeptide endothelin-(16-21), did not affect inotropic activity. The action of endothelin-2 was not modified by indomethacin and propranolol, thus excluding an involvement of endogenous prostaglandins or catecholamines. The adenylate-cyclase activator, forskolin, and the calcium agonist, Bay K 8644, at concentrations able to enhance the inotropic effect induced by histamine and epinephrine, did not modify the action of endothelin-2. The data show that endothelin-2 has a strong positive inotropic effect on the isolated human myocardium. The effect seems to be independent of the sympathetic system and is unlikely to involve slow channel conductance or cyclic AMP. The lack of activity of endothelin fragment suggests that an endothelin receptor subtype, similar to that found in rat aorta, is present on human atrium.
Endothelins↗
Effect of histamine on gastric acid secretion "in vitro": interference with endogenous prostaglandins.
The interference between histamine and endogenous prostaglandins (PGs) was investigated in the isolated gastric fundus from immature rats by evaluating the effect of nonsteroidal antiinflammatory agents (NSAIDs) on the acid response to histamine and the effect of histamine on PGs production by the gastric mucosa. Indomethacin (10(-5) M) and diclofenac (10(-5) M) caused a dose-dependent enhancement of the response to histamine, dimaprit and DBcAMP, but did not affect bethanechol-, isoprenaline- and forskolin-induced acid production. The enhancing effect of indomethacin was abolished in low Ca2+ medium. PGE2 and 6-keto PGF1 alpha levels in the mucosal solution were not modified by histamine, while being reduced by indomethacin. From these data it is concluded that endogenous PGs may negatively modulate the secretory response to histamine. However, a direct effect of the amine on cyclooxygenase to increase PGs synthesis seems to be excluded since histamine did not modify PGs levels in the mucosal solution.
Animals↗
Ranitidine but not famotidine releases acetylcholine from the guinea pig myenteric plexus.
The effects of the histamine H2-receptor antagonists ranitidine and famotidine on acetylcholine release have been studied in the guinea pig myenteric plexus longitudinal muscle preparation incubated with [3H]-choline. Ranitidine (3 x 10(-5)-3 x 10(-4) M) dose-dependently increased the resting release of acetylcholine and that evoked by electrical stimulation. The effect was present only in strips perfused with 10(-5) M physostigmine. The effect of ranitidine was inhibited by tetrodotoxin and hexamethonium. Famotidine (10(-5)-3 x 10(-4) M) was totally ineffective in modifying both the resting release and that evoked by field stimulation. Ranitidine did not antagonize the inhibitory effect of oxotremorine, which specifically activates negative feedback mechanisms via presynaptic muscarinic receptors.
Acetylcholine↗