Characterization of the effects of histamine on the transmembrane electrical activity of guinea-pig and rabbit SA- and AV-node cells

Summary The effects of histamine on the transmembrane electrical activity of cells of small preparations (0.5 × 0.5 mm) of guinea-pig and rabbit sinoatrial- and atrioventricular-nodes were studied. Histamine at concentrations above 10^–7 mol/l increased the firing rate, the rate of diastolic depolarization, the maximum diastolic potential, the amplitude and the maximum rate of depolarization of the action potential of pacemaker cells of rabbit and guineapig sinoatrial cells and rabbit atrioventricular cells. These effects were antagonized by the HZ-receptor blocker cimetidine (2.5 × 10^–6 mol/1) but they were not modified by the H₁-receptor blocker chlorphenamine (2.5 and 5×10^–6 mol/1). Small preparations of guinea-pig atrioventricular node did not exhibit spontaneous activity, but it was induced by histamine and blocked by cimetidine. Histamine increased the maximum upstroke velocity of propagated action potential of cells of the central part of complete atrioventricular node in both species studied. These effects were blocked by cimetidine, but not by chlorphenamine. It is concluded that the increase in automaticity induced by histamine in guinea-pig and rabbit sinoatrial and atrioventricular nodes was due to stimulation of H₂receptors. Histamine did not depress electrical activity of atrioventricular node cells, but rather increased it. This effect was due to H₂-receptor stimulation. Send offprint requests to: J. Sanchez-Chapula at the above address     

Modulation of the delayed K+ current by histamine in guinea pig ventricular myocytes

Summary The effects of histamine on delayed K⁺ current (I_K) were investigated in patch-clamped single guinea pig ventricular myocytes. Histamine increased I_K with a maximal fractional response of 2.7 and a k_d of 9.4 × 10^–7 mol/l. At a concentration of 10^–8 mol/l, histamine did not increase I_K significantly, but increased I_Ca by 52% ± 12%. The voltage-dependence of I_K activation, the reversal potential and the time course of the I_K tail decay were not changed by histamine. Under pretreatment with 10^–4 mol/l of ranitidine, neither histamine (10^–6 mol/l) nor 2-pyridylethylamine (10^–4 mol/l) caused any sizable increase in I_K. When the cell was pretreated with a saturating dose of isoproterenol (10^–6 mol/l), histamine did not additively enhance I_K. The I_K enhancement by 3 × 10^–7 mol/l histamine was partially antagonized by concurrent exposure to 5 × 10^–6 mol/l carbachol. Whereas, use of a higher concentration of histamine (10^–6 mol/l) obscured the inhibitory effect of carbachol. It is concluded that histaminergic action of I_K is attributed exclusively to H₂ receptor-mediated reactions involving G_s protein and adenylate cyclase. Send offprint requests to Y. Habuchi at the above address     

Adenylate cyclase of the dog gastric mucosa: Stimulation by histamine and inhibition by metiamide

Summary The activity of the non-stimulated, basal adenylate cyclase of the dog gastric mucosa is reduced by the histamine H₂-receptor antagonist metiamide but not by the histamine H₁-receptor antagonist mepyramine. Histamine activates the adenylate cyclase only slightly. In the presence of 10^–5 M metiamide a concentration-dependent stimulation of the enzyme by histamine was found. These data indicate that endogenous histamine in dog gastric mucosal homogenate is contributing at least in part to what is measured as basal adenylate cyclase activity. This effect is mediated by H₂-receptor excitation and in earlier studies has prevented the demonstration of a stimulatory effect of exogenous histamine on this enzyme.Supported by a grant from the Deutsche Forschungsgemeinschaft     

Effect of some new histamine H2-receptor antagonists on the guinea-pig papillary muscle

Summary Several histamine H₂-receptor antagonists (cimetidine, ranitidine, oxmetidine and tiotidine) were tested for their activity on the papillary muscle of the guinea pig stimulated by histamine. All of the compounds exerted a competitive antagonism against histamine the order of potency being tiotidine > oxmetidine > ranitidine > cimetidine. Oxmetidine was the only drug which at high concentrations (10^–6 M) decreased the maximum response of histamine probably because of non specific effects of the molecule already described in the literature. As it was expected, the H₁-receptor antagonist, mepyramine, exerted a non-competitive antagonism.     

Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine

Summary Human neutrophils possess an NADPH oxidase which catalyzes superoxide (O _inf2 ^sup– ) formation and is activated by chemotactic peptides. Histamine inhibits O _inf2 ^sup–1 formation via H₂-receptors (Burde et al. 1989). We characterized the neutrophil H₂-receptor with a series of new guanidine-type H₂-agonists structurally derived from impromidine. Histamine inhibited O _inf2 ^sup– formation with an IC₅₀ value of 6.7 ± 1.2 M. Five aryloxy- and arylthioalkylguanidines were less potent and effective than histamine. Several arpromidine-like phenyl(pyridylalkyl)guanidines were either full or partial H₂-agonists. Some guanidines possess a three-membered carbon chain connecting the aromatic rings and the guanidine group; they were similarly potent and effective as histamine. Shortening or elongation of the carbon chain substantially decreased the potency and intrinsic activity of the guanidines. Halogenation of the phenyl ring did not substantially affect the potency and intrinsic activity of the compounds in comparison to the non-substituted parent compound. The H₂-antagonist, famotidine, competitively antagonized inhibition of O _inf2 ^sup– formation caused by the guanidine, arpromidine, with a pA₂ value of 6.84. The H₂-antagonist, cimetidine, differentially counteracted inhibition caused by partial and full H₂-agonists. Partial H₂-agonists antagonized the effects of histamine. The inhibitor of phosphodiesterases, 3-isobutyl-lmethylxanthine, additively enhanced the inhibitory effects of histamine and guanidines. The properties of the neutrophil H₂-receptor were compared with literature data concerning properties of the H₂-receptor of the guinea pig atrium. In the latter system, guanidines are full H₂-agonists with potencies of up to 125-fold of that of histamine. Our data indicate that guanidines inhibit O _inf2 ^sup– formation in human neutrophils via H₂-receptors. The structure/activity relationship for the neutrophil H₂-receptor substantially differs from the one for the H₂-receptor in the guinea pig atrium, suggesting that the neutrophil H₂-receptor has cell type-specific properties. Other possibilities to explain the differences between H₂-receptors in these systems are discussed. Send offprint requests to R. Seifert at the above address     

Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

Summary We have studied the effect of histamine and H₁- or H₂-receptor antagonists on cutaneous blood flow and catecholamine release in man.Histamine was infused alone or in combination with mepyramine, an H₁-antagonist or cimetidine, an H₂-antagonist for 2 h. Cutaneous blood flow was measured continously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min.The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no effect on the sustained response. The Concomitant infusion of cimetidine was without effect on the immediate vasodilatation, but abolished the sustained response. Infusion of the antagonists alone had no effect on cutaneous blood flow.Histamine caused a rapid and sustained increase in plasma noradrenaline, while the increase during concomitant H₁-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H₂-receptor blockade was small and transient. The rise in plasma adrenaline was not significant.These findings suggest that histamine causes an immediate cutaneous vasodilatation through H₁-receptors and a more sustained response through H₂-receptors. The vasodilatation is accompanied by an increase in plasma catecholamine concentrations. Despite the continuous infusion of histamine, blood flow decreased during the last hour of histamine infusion, while the plasma noradrenaline concentration was still elevated.     

Regulation of sterol synthesis by histamine in human mononuclear leukocytes: Roles of H1- and H2-receptors

Summary The effect of histamine on sterol synthesis has been investigated in freshly isolated human mononuclear leukocytes from healthy subjects.Incubation of cells for 6 h in a medium containing lipid depleted serum led to a threefold increase in the incorporation of (¹⁴C)-acetate or tritiated water into sterols. Histamine 0.3 µM added to the incubation medium at zero time inhibited this induction by 35% with a sigmoidal log dose-effect curve.The receptors mediating this action were characterised pharmacologically by using selective H₁- and H₂-agonists and -antagonists. The H₂-agonists impromidine and 4-methylhistamine mimicked the effect of histamine on sterol synthesis, the suppression being 42% and 31%, respectively, at a concentration of 1 µM. In contrast, the H₁-agonist 2-pyridylethylamine did not affect the pathway. The H₂-antagonist cimetidine (10 µM) but not the H₁-antagonist mepyramine (10 µM) totally reversed the inhibition of sterol synthesis by histamine.The results provide evidence that sterol synthesis in human mononuclear leukocytes is regulated by histamine, which appears to act predominantly via H₂-receptors.     

Long-term increase of hippocampal excitability by histamine and cyclic AMP

The action of histamine (HA) on rat hippocampal CA1 pyramidal cells in vitro was investigated in slices perfused with solution containing 0.2 mM Ca²⁺/4.0 mM Mg²⁺. Extracellular recordings of the spontaneous discharges occurring under these conditions revealed that HA caused a long-lasting increase in cell firing. The HA-effects were dose-dependent, in that low concentrations of HA (0.1–0.5 μM) exhibited an initial transient depression of cell firing and practically no long-lasting action, whereas higher concentrations of HA (1–10 μM) exerted strong, non-declining increases. The H₁-receptor antagonist mepyramine (1 μM) blocked the initial depression of firing and attenuated the long-lasting HA-mediated excitation. Pure H₁-receptor activation, tested with the H₁-receptor agonist 2-(3-fluorphenyl)histamine (1–10 μM) depressed cell firing, similar to the low dose effects of HA. HA-induced excitations were prevented by the H₂-receptor antagonist cimetidine (10–50 μM), and mimicked by the very potent H₂-receptor agonist impromidine (1 or 3 μM) which was, however, less effective compared to equal concentrations of HA. H₃-receptor activation by R-α-methylhistamine had no significant effect on cell firing. Thus, histamine H₁ and H₂ receptors seem to cooperate in producing this long-lasting augmentation of excitability. 8-Bromo-cyclic AMP monophosphate (8-Br-cAMP, 50–100 μM) mimicked the long-term excitation, whereas the adenylyl-cyclase inhibitor 9-tetrahydro-2-furyladenine (THFA, 100–500 μM) or the PKA-inhibitor Rp-adenosine-3′5′-cyclic monophosphate (Rp-cAMPS, 10 μM) blocked it, indicating that the HA-mediated increase of excitability in the hippocampus is dependent on the adenylate cyclase/PKA-signal transduction cascade. -2-Amino-5-phosphonopentanoic acid (APV, 50 μM) significantly attenuated the magnitude of the HA-induced enhancement, indicating an NMDA receptor-dependent component. Other biogenic amines, acting through receptors positively coupled to adenylyl cyclase, elicited similar responses as HA, indicating common mechanisms by which these substances modulate excitability in CA1 pyramidal cells.     

Effect of Cimetidine on the Pharmacokinetics and Pharmacodynamics of Chlorpheniramine and Diphenhydramine in Rabbits

Purpose. The effects of concomitant administration of the H₂-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H₁-receptor antagonists chlorpheniramine and diphenhydramine were studied in rabbits. Methods. A single dose of chlorpheniramine 10 mg (Group A) or diphenhydramine 10 mg (Group B) was given intravenously on three different study days as follows: 2 weeks before cimetidine administration, after giving cimetidine 100 mg/kg intravenously every 12 hours for one week, and two weeks after discontinuing the cimetidine. Serum chlorpheniramine and diphenhydramine concentrations were measured by HPLC. Histamine H₁-blockade was assessed by measuring suppression of the histamine-induced wheals in the skin. Results. The chlorpheniramine and diphenhydramine terminal elimination half-life values and area under the curve values were significantly increased, and the systemic clearance rates were significantly decreased, during concomitant administration of cimetidine. For each H₁-receptor antagonist, pharmacokinetic parameters were similar before cimetidine was co-administered and two weeks after cimetidine was discontinued. Wheal suppression produced by chlorpheniramine or diphenhydramine was increased and prolonged when cimetidine was administered concomitantly. Conclusions. Any enhanced peripheral H₁-blockade observed could be attributed, at least in part, to a pharmacokinetic interaction.     

N-methyl-d-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors

In superfused rat brain cortex slices and synaptosomes preincubated with [³H]noradrenaline the effect of agonists or antagonists at presynaptic H₃ receptors on NMDA-evoked [³H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H₃ receptor agonist R-(–)--methylhistamine inhibited NMDA-evoked tritium overflow (IC₂₀ values 0.27 mol/l or 0.032 mol/l, respectively); S-(+)--methylhistamine (up to 10 mol/l) as well as the selective H₁ receptor agonist (2-(2-thiazolyl)ethylamine) and the selective H₂ receptor agonist dimaprit (each up to 10 mol/l) were ineffective. The H₃ receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H₁ receptor antagonist dimetindene and the preferential H₂ receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(–)--methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of -conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(–)--methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H₃ receptors. NMDA receptors and H₃ receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H₃ receptor stimulation. Correspondence to: M. Göthert at the above address     

Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects

Summary Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H₂-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study.No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r=0.983). The apparent plasma clearance was 38.11·h^–1, 31.01·h^–1, and 47.41·h^–1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion.The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H₂-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.     

Effects of cimetidine on adenylate cyclase activity of guinea pig gastric mucosa stimulated by histamine,sodium fluoride and 5′-guanylylimidodiphosphate

Summary Cimetidine, a recently developed histamine H₂-receptor blocking agent has been shown to be a potent inhibitor of histamine-stimulated gastric acid secretion in rat, cat, dog and man. To study the mode of action of cimetidine the modification of the stimulatory effects of histamine, sodium fluoride and 5-guanylylimidodiphosphate by cimetidine on the adenylate cyclase activity of guinea pig gastric mucosa was studied. The effect of cimetidine was also compared to that of metiamide, an older histamine H₂-receptor antagonist. The effect of cimetidine was qualitatively similar to that of metiamide, i.e. a selective blockade of histamine H₂-receptors. Quantitatively cimetidine was about 10-fold more potent than metiamide.     

Functional pharmacology of H1 histamine receptors expressed in mouse preoptic/anterior hypothalamic neurons

BACKGROUND AND PURPOSE

Histamine H₁ receptors are highly expressed in hypothalamic neurons and mediate histaminergic modulation of several brain-controlled physiological functions, such as sleep, feeding and thermoregulation. In spite of the fact that the mouse is used as an experimental model for studying histaminergic signalling, the pharmacological characteristics of mouse H₁ receptors have not been studied. In particular, selective and potent H₁ receptor agonists have not been identified.

EXPERIMENTAL APPROACH

Ca²⁺ imaging using fura-2 fluorescence signals and whole-cell patch-clamp recordings were carried out in mouse preoptic/anterior hypothalamic neurons in culture.

KEY RESULTS

The H₁ receptor antagonists mepyramine and trans-triprolidine potently antagonized the activation by histamine of these receptors with IC₅₀ values of 0.02 and 0.2 μM respectively. All H₁ receptor agonists studied had relatively low potency at the H₁ receptors expressed by these neurons. Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine had full-agonist activity with potencies similar to that of histamine. In contrast, 2-pyridylethylamine and betahistine showed only partial agonist activity and lower potency than histamine. The histamine receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT) had no agonist activity at the H₁ receptors H1 receptors expressed by mouse preoptic/anterior hypothalamic neurons but displayed antagonist activity.

CONCLUSIONS AND IMPLICATIONS

Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine were identified as full agonists of mouse H₁ receptors. These results also indicated that histamine H₁ receptors in mice exhibited a pharmacological profile in terms of agonism, significantly different from those of H₁ receptors expressed in other species.     

Effect of a new potent H2-receptor antagonist 3[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-N2-sulfamoylpropionamidine (YM-11170) on gastric mucosal histamine-sensitive adenylate cyclase from guinea pig

The effect of 3[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-N²-sulfamoylpro-pionamidine (YM-11170), a new thiazole H₂-receptor antagonist bearing propionamidine at the terminus of a side chain, on histamine-sensitive adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] of gastric mucosa from the guinea pig was studied and compared with that of cimetidine. YM-11170 displaced the concentration-stimulation curve of histamine-sensitive adenylate cyclase to the right with a pA₂ of 7.65 (K_i, = 2.25 × 10^?8M). Stimulation of gastric adenylate cyclase by 0.1 mM histamine was competitively inhibited by YM-11170 and cimetidine in a dose-dependent manner, with ic₅₀ values of 5.9 × 10^?7M and 1.4 × 10^?5M respectively. Hippocampal histamine-sensitive adenylate cyclase in the presence of 0.1 mM histamine was also competitively inhibited by YM-11170 with an ic₅₀ of 1.1 × 10^?7 M. YM-11170 did not affect Gpp(NH)p-, NaF-, PGE₂-stimulated or basal activity of the gastric adenylate cyclase. These data, together with other results, indicate that YM-11170 is a highly selective and potent H₂-receptor antagonist which competes with histamine at the receptor site on the histamine-sensitive adenylate cyclase.     

Histamine H1- and H2-receptors in the gastrointestinal circulation

Summary Evidence for the presence of specific histamine H₁- and H₂-receptors in the gastrointestinal circulation was obtained using histamine, 2-methylhistamine (a specific H₁-agonist), 4-methylhistamine (a specific H₂-agonist), and selective H₁- and H₂-receptor antagonists in the anesthetized dog. Histamine and 2-methylhistamine increased conductance in the vascular beds of the superior mesenteric artery, the left gastric artery and the common hepatic artery, whereas 4-methylhistamine mainly enhanced conductance in the vascular beds of the left gastric artery and the common hepatic artery. All three agents depressed systemic arterial blood pressure. The vasodilatory effect of histamine and 2-methylhistamine on the superior mesenteric artery bed occurred earlier and was of shorter duration than their effect on the two other vessels. The H₁-receptor antagonists mepyramine and clemastine blocked the response of the superior mesenteric artery bed to histamine, but had a lesser inhibitory effect on the histamine response of the common hepatic artery and the left gastric artery. The addition of the H₂-receptor antagonist cimetidine to mepyramine blockade augmented the inhibiting effect of mepyramine on the common hepatic artery. Cimetidine bolus injections prevented enhancement of vascular conductance by 4-methylhistamine, but did not influence conductance enhancement by histamine or 2-methylhistamine. These data demonstrate there are separable histamine H₁- and H₂-receptors in the gastrointestinal circulation which are distinguished by anatomic location, temporal relationships of receptor response, and response to specific histamine H₁- and H₂-agonists and antagonists.     

Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction

Background and purpose:

Post-transplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays important roles in the genesis of diabetic complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T-cells, reducing allograft survival. Out of four distinct AGE subtypes (AGE-2, AGE-3, AGE-4 and AGE-5), only AGE-2 and AGE-3 induced expression of intercellular adhesion molecules (ICAMs), output of cytokines and proliferation of lymphocytes, during the mixed lymphocyte reaction (MLR). Here we have assessed the role of histamine in the actions of AGEs during the MLR.

Experimental approach:

Human peripheral blood cells were used in these experiments. Flow cytometry was used to examine the expression of the ICAM-1, B7.1, B7.2 and CD40. Production of the cytokine interferon-γ, and levels of cAMP were determined by elisa. Lymphocyte proliferation was determined by [³H]-thymidine uptake.

Key results:

Histamine concentration dependently inhibited the action of AGE-2 and AGE-3. The actions of histamine were antagonized by an H₂-receptor antagonist, famotidine, and mimicked by H₂/H₄-receptor agonists, dimaprit and 4-methylhistamine. The effects of histamine were reversed by a protein kinase A (PKA) inhibitor, H89, and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin.

Conclusions and implications:

Histamine down-regulated AGE-2- and AGE-3-induced expression of adhesion molecules, cytokine production and lymphocyte proliferation via histamine H₂ receptors and the cAMP/PKA pathway.     

Calcium dependency of the AT1-receptor mediated effects in the rat portal vein: influence of calcium antagonists

The calcium dependency of AT₁-receptor mediated contractions was studied in isolated rat portal vein preparations.The spontaneous phasic contractile force of the rat portal vein was increased (ED₅₀ = 1.76 mmol/l) and the frequency of contractions decreased by raising the extracellular calcium concentration. The Ang 11-induced rise in phasic contractile force (mediated by AT₁-receptors, Zhang et al. 1993) proved most pronounced at 0.9 mmol/l of calcium chloride, but it was weaker at either lower or higher calcium concentrations. The maximal increases in the phasic contractile force induced by Ang II were 2.4±0.4, 14.8±0.9 and 5±0.5 mN at calcium concentrations of 0.5, 0.9 and 2.5 mmol/l, respectively. Calcium antagonists reduced at the lower and abolished at the higher concentrations (nifedipine 2×10^–8 or 10^–7 mol/l; verapamil 10^–7 or 5 × 10^–7 mol/l; diltiazem 3 × 10^–7 or 10–6 mol/l) the spontaneous contractile force. All of these calcium antagonists caused a strong inhibition or suppression of the phasic contractions induced by Ang II.The rank order of potency was nifedipine >verapamil > diltiazem. Ang II (10^–6 mol/l) elicited a tonic contraction which was abolished by the AT₁-receptor antagonist losartan 10-6 mol/l but not by the AT₂-receptor antagonist PD 123177 (10–5 mol/l). Very high concentrations of nifedipine (10–6 mol/l), verapamil (5 × 10-6 mol/l) and diltiazem (5 × 10^–6 mol/l) almost suppressed the tonic effect evoked by the activation of AT₁-receptors.In a nominally Ca²⁺ free, EGTA-containing solution, a single supra-maximal concentration of Ang II (10^–6 mol/l) caused a transient contraction, also mediated by AT₁-receptors. This finding suggests the existence of Ang II-sensitive intracellular calcium stores in this preparation. The depletion of such stores proved complete after 4–6 min of perfusion in a Ca²⁺ free, EGTA-containing solution.In conclusion, various types of contractions (a transient contraction in a Ca²⁺-free medium, phasic and tonic contractions) induced by Ang II in the rat portal vein proved to be mediated by AT₁-receptors. These contractions were clearly modified by changes in the availability of extra- and possibly intracellular calcium ions. The calcium movements elicited by stimulation of AT₁-receptors in a calcium containing solution were inhibited by the three calcium antagonists investigated. Correspondence to: J. S. Zhang at the above address     

Inhibition of pentagastrin-stimulated gastric acid secretion and plasma levels of the new histamine H2-receptor antagonist ramixotidine dihydrochloride (CM 57755) in human volunteers

Summary The new competitive histamine H₂-receptor antagonist, ramixotidine 2 HCl (CM 57755), has been tested in healthy male volunteers for its ability to inhibit pentagastrin-stimulated gastric acid secretion. In the first study, in 8 subjects, pentagastrin 6 µg·kg^–1 was injected s.c., 90 min after the following 4 oral treatments given in random order at weekly intervals: placebo, 100, 200 and 400 mg CM 57755. Gastric contents were collected over 15-min periods during the 2 h after pentagastrin stimulation. In a second, similar study, 8 subjects received placebo, 0.5 and 1.0 g CM 57755 and 800 mg cimetidine, 120 min before a 2 h i.v. infusion of 6 µg·kg^–1·h^–1 pentagastrin. Cumulative gastric secretion in placebo-treated subjects was 46±14 and 62±11 mmol H⁺·2 h^–1 (mean±SD), respectively, in the first and second studies. It was significantly reduced only after 400 mg CM 57755 in the first study. In the second study either dose of CM 57755 and cimetidine caused a significant reduction in gastric acid secretion. Average plasma levels of ramixotidine were dose-related after 0.2 and 1.0 g and ranged from 0.3 and 1.6 µg/ml, respectively, at 60 min to 0.5 and 3.7 µg/ml at 180 min. The peak cimetidine level averaged 3.6 µg/ml at 150 min. Individual CM 57755 plasma levels throughout the test period were fairly consistent with the inhibition of cumulative gastric acid secretion scored concurrently in each subject. No subjective side-effects attributable to the treatments were reported, and no abnormal findings were seen in the ECG or in laboratory tests.     

Intragastric and intraoesophagel pH monitoring in duodenal ulcer patients: effect of the new histamine H2-receptor antagonist ramixotidine

Summary The effect of the new histamine H₂-receptor antagonist ramixotidine 750 mg p.o., administered at 22.00 h, on intragastric and intraoesophageal pH monitored from 22.00 h to 08.00 h, was studied in a double-blind cross-over trial in 11 duodenal ulcer patients. Placebo and ramixotidine were given to each patient on 2 consecutive days in a randomized sequence. Three patients were excluded from the intragastric pH analysis as the records on the second study day were technically inadequate.No significant carry-over or sequence effect was noted. Intragastric hydrogen ion activity was significantly lower (p=0.01) after ramixotidine than after placebo: median (range) 24 (9–100) vs 97 (27–188) mmol/l. The percentage of time with intraoesophageal pH <4 was less than 5% in all but three recordings, with a maximum value of 12%, and it was not significantly different after the two treatments.