H2 Agonist Impromidine Research Articles

Effects of histamine and related compounds on the differentiation of HL-60-Eo cells into eosinophils.

The effects of histamine and related compounds on the differentiation of HL-60-Eo cells into eosinophils were studied. The histamine and H2 agonists impromidine and 4-methylhistamine caused concentration-related increases in the number of differentiated cells. On the other hand, the H1 agonists 2-methylhistamine and 2-pyndylethylamine showed no such effect. Histamine-induced eosinophil differentiation was antagonized by the H2 antagonists cimetidine and ranitidine. Histamine and H2 agonists inhibited (3H)-thymidine uptake, suggesting that these compounds caused a decrease in proliferation. Histamine as well as the H2 agonists impromidine and 4-methythistamine caused increases in cAMP level, and this effect was antagonized by ranitidine. From these findings, we concluded that both the differentiation of HL-60-Eo cells into eosinophils and proliferation of HL-60-Eo cells were mediated via H2 receptors.

Effects of histamine agonists and antagonists on rat peritoneal mast cells.

histamine release from rat peritoneal mast cells (RPMC). Since inhibitory effects of these compounds could be reversed by thioperamide, but not by mepyramine or cimetidine, an H3-receptor dependent negative feedback mechanism on anaphylactic histamine release was proposed to exist in RPMC. However since dimaprit has no H3receptor stimulating activity in rat brain [3], these authors suggested that the postulated H3-receptors in mast cells are a subtype distinct from those in the brain. In contrast, Lau and Pearce [4] reported that dimaprit and another H2 agonist impromidine had no inhibitory activity on RPMC at concentrations <10 π5 M but instead induced histamine release at higher concentrations. Hence, we reinvestigated the effects of dimaprit and impromidine, and included the H3 agonist imetit for comparison. The effects of these three compounds on RPMC were further characterised with specific histamine receptor antagonists and benzalkonium chloride.

Dual Control of Human Interleukin-2 and Interferon-γ Gene Expression by Histamine: Activation and Suppression

Histamine is considered to be an activator of cells with suppressive capacity. In agreement with this concept, we show that histamine elicits a strong inhibition of the induced expression of interleukin-2 (IL-2) and interferon-γ (IFN-γ) genes. However, our experiments reveal a novel property of histamine: early in the induction process, it strongly stimulates expression of these two genes in cultured human peripheral blood mononuclear cells (PBMC). The histamine-mediated superinduction of IL-2 mRNA is seen also in a Th cell line, showing that such cells respond directly to histamine. In the course of mitogenic induction, a 20-fold stimulation by histamine is converted into an equally strong inhibition. The response of a PBMC population to histamine thus undergoes a remarkable change following T cell activation. The dual effect of histamine can be blocked by the H2 histamine receptor antagonist cimetidine, while the early activation by histamine is mimicked by the H2 agonist impromidine, showing that both activation and inhibition of IL-2 and IFN-γ gene expression by histamine are exerted via this receptor. These results support the concept that histamine, released during an immune response, exerts opposite regulatory effects by first activating cells able to express the IL-2 and IFN-γ genes and only then suppressive cells that become responsive to histamine more slowly, but once activated shut off the expression of these genes.

BENEFICIAL EFFECT OF H2−AGONISM AND H1−ANTAGONISM IN RAT ENDOTOXIC SHOCK

Although histamine release is generally considered harmful in endotoxic shock, several data exist to doubt this view. Own previous studies in rats let us assume a possible beneficial effect only with H1-antagonists, however a detrimental effect on survival with H2-antagonists. Consequently H1- and H2-agonists and antagonists were studied to prove the hypothesis of a beneficial H2-agonistic and H1-antagonistic effect. Two randomized studies were performed in a standardized rat endotoxic shock model (45 mg of Escherichia coli endotoxin/kg body weight (b.w.)). In both, methylprednisolone (50 mg/kg b.w.) and saline were used as positive and negative controls, respectively. Study I compared the effects of H1- and H2-agonists (betahistine, .1 mg/kg/h, and impromidine, 100 micrograms/kg/h) with H1- and H2-antagonists (astemizole and famotidine both 1 mg/kg b.w.; 20 rats/dose). Study II was performed to estimate the dose-response relationship of a new, highly potent H2-agonist with additional H1-antagonistic features (BU-E 75: .01, .1, 1.0, 10, and 100 micrograms/kg/h; 20 rats/dose). Animals receiving impromidine or BU-E 75 all received omeprazole (1 mumol/kg b.w.) to suppress gastric acid secretion. In study I impromidine significantly increased the survival-time and -course compared to famotidine treated animals (p = .01 and p < .05). Study II showed a positive dose-response relationship of BU-E 75 with an increase in survival rates from 30% (.01 microgram/kg/h) to 70% (100 micrograms/kg/h). These data strongly support the hypothesis of a beneficial effect of H2-agonism and H1-antagonism on survival parameters in rat endotoxic shock.

Effects of intracerebroventricular injection of histamine and related compounds on corticosterone release in rats.

1. The effects of intracerebroventricular (i.c.v.) injection of histamine and related compounds on plasma adrenocorticotrophic hormone (ACTH) and corticosterone concentrations were studied in conscious rats. 2. Histamine at doses of 5-20 micrograms kg-1 rapidly increased plasma ACTH and corticosterone concentrations almost simultaneously, and subsequent courses were also similar to each other. However, in the case of CRF-41 (i.v.), the plasma ACTH concentration first increased followed by an increase in plasma corticosterone concentration. Even in hypophysectomized rats, a significant increase in plasma corticosterone concentration was induced by histamine at doses of 20 and 50 micrograms kg-1. 3. Histamine at doses of 10 and 20 micrograms kg-1 elicited an increase in the amplitude of adrenal nerve activity, and electrical stimulation to the adrenal nerves resulted in an increase in plasma corticosterone concentration. 4. Both H1-agonist (2-methylhistamine) and H2-agonists (4-methylhistamine and impromidine) also induced similar effects to those of histamine. Pretreatment with pyrilamine caused an inhibition of histamine-induced increase in plasma ACTH and corticosterone concentrations, while both cimetidine and ranitidine failed to inhibit this effect. However, both H2-blockers were effective in inhibiting the 4-methylhistamine-induced elevation of plasma ACTH and corticosterone concentrations. 5. Neither (R)-alpha-methylhistamine nor thioperamide had a significant effect, indicating that the H3-receptor is not involved in the histamine-induced increase in plasma ACTH and corticosterone concentrations. 6. From these findings, it was concluded that (1) electrical signals transmitted from the brain to the adrenal gland through the neurones may be involved in the rapid corticosterone release induced by histamine, and (2) not only H1- but also H2-receptors are implicated in histamine-induced hormone secretions in rats, though the contribution of the H2-receptor is less important than that of the H1-receptor.

Cardiac electrophysiological effects of histamine, H1 and H2 agonists

The effects of histamine, H1 and H2 agonists on the transmembrane action potentials (APs) of electrically driven left auricle of guinea-pig were studied in Tyrode and in 25 mM K+ Tyrode solution. Under physiological conditions, histamine (10−7−10−5M) increased the amplitude and the plateau phase of AP. The H1 agonist pyridylethylamine (PEA; 10−5−10−4M) exerted similar effects as histamine while the H2-agonist impromidine (10−8−10−7M) decreased the duration of AP. PEA restored the abolished electromechanical activity in high K+ (25 mM)-depolarized atria. These slow APs were unaffected by the β-adrenergic blocker pindolol (5×10−7M) but were abolished by the H1 antagonist mepyramine (10−5M). Neither dimaprit nor impromidine was able to induce slow AP. Our results suggest that in guinea-pig left atria histamine enhances the slow inward Ca2+ current mediated by H1 receptors.

Role of prostaglandins in regulation of gastric mucosal blood flow and acid secretion.

The role of prostaglandins in the rat gastric mucosal vascular response to acid stimulation was studied. Blood flow was measured with laser-Doppler flowmetry (LDF) and with red blood cell velocity measurements in the superficial mucosa; acid secretion was determined by titration. Baseline acid output was calculated to be 0.026 +/- 0.011 mueq/min. Pentagastrin (20 and 40 micrograms.kg-1.h-1 iv) significantly increased acid output to 0.387 +/- 0.104 and 0.546 +/- 0.220 mueq/min and LDF to 119 +/- 10 and 132 +/- 13% of control, respectively. LDF was significantly reduced by 15% after indomethacin (3 mg/kg iv) and was not changed by pentagastrin, whereas acid secretion increased to similar levels as without indomethacin pretreatment. The H2-agonist impromidine (100 and 500 micrograms.kg-1.h-1 iv) induced a dose-dependent increase in acid secretion (0.178 +/- 0.068 and 0.330 +/- 0.072 mueq/min, respectively) while blood flow was unchanged. Despite a substantial blood flow reduction (-38%) by indomethacin, impromidine did not alter blood flow, and acid secretion was dose dependently increased to similar values as without indomethacin pretreatment. These results provide further evidence that there is not necessarily any correlation between blood flow and acid secretion and that the pentagastrin-induced blood flow increase depends on prostaglandin release.

The effect of lipophilic substituents on the H2-histaminergic activity of some close analogues of impromidine.

The cimetidine-like moiety of the potent H2-agonist impromidine (9a) and three closely related guanidines (10a, 11a, and 12a) which are modified in the imidazolylpropyl portion, has been replaced by 2-[(2-pyridyl)methylthio]ethyl, 2-(benzylthio)ethyl and 3,3-diphenylpropyl substituents. Guanidines 10-12 were obtained from acidic hydrolysis of corresponding N-benzoyl guanidines 7, 8, and 15, accessible by successive aminolysis of diphenyl N-benzoyl carbonimidate (2) according to known methods. Compared with leads 10a and 11a lipophilic substitution affords almost equipotent H2-agonists 10b-d and 11b-d, while substituents with increasing lipophilicity enhance both intrinsic activity and potency of the weak partial agonist 12a at guinea-pig atrial H2-receptors. Guanidines 10-12 are weak H1-antagonists on the isolated guinea-pig ileum.

Effects of platelet-activating factor on β- and H2-receptor-mediated increase of myocardial contractile force in isolated perfused guinea pig hearts

Platelet-activating factor (PAF) has been termed an important mediator of cardiovascular shock due to immunological reactions, including anaphylaxis and endotoxic reactions. Previous studies have shown that PAF is a potent cardiodepressive agent inducing a drastic coronary constriction and a sustained impairment of myocardial contractility. In this study, an attempt was made to further characterize the prolonged PAF effects on coronary circulation and myocardial contractile force in the isolated guinea pig heart perfused at constant pressure. An intracoronary PAF bolus (0.18 nmol, related to coronary flow rates of 1 ml/min) induced a precipitous decrease of coronary flow rates, left ventricular pressure, and left ventricular contraction (peak positive dP/dt), which was followed by a slow increase reaching new steady state after 15 min (-48%, -40%, -42% below baseline, respectively). If the specific PAF antagonist WEB 2086 (3.65 nmol/min, related to coronary flow rates of 1 ml/min) was infused 30 min after PAF administration, the prolonged PAF-mediated cardio-depressive effects were rapidly reversed. Several studies indicate that PAF induces a down regulation of beta-adrenoreceptors in different cell types, including human lung tissue. Therefore, a further objective of the study was to evaluate whether PAF selectively impairs the positive inotropic effects of beta-receptor agonists or also inhibits the contractile effects of inotropic drugs, which are known to enhance cardiac contractility independently of beta-receptors. In these experiments, the beta-agonist isoproterenol and the H2-agonist impromidine were administered as intracoronary boluses (0.35 nmol and 0.14 nmol, respectively, related to coronary flow rates of 1 ml/min) prior to PAF injection and 30 min after PAF.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of histamine H1‐, H2‐ and H3‐receptor selective drugs on the mechanical activity of guinea‐pig small and large intestine

1. In this study we have evaluated the possible contribution of acetylcholine release in histamine-induced contractions of guinea-pig large and small intestinal smooth muscle. Moreover, the presence of the histamine receptor types involved in smooth muscle relaxations and inhibition of electrically-induced twitches was studied by use of several selective agents. 2. Histamine-induced contractions appeared to be a pure H1-receptor-mediated effect. Responses were not attenuated by the presence of 0.1 microM atropine and were competitively and stereoselectively inhibited by the two enantiomers of chlorpheniramine with pA2 values of 6.73 +/- 0.08, 7.30 +/- 0.06, 6.93 +/- 0.03 and 7.19 +/- 0.04 for the L-isomer and 8.63 +/- 0.09, 8.85 +/- 0.09, 9.01 +/- 0.16 and 0.11 for the D-isomer in the duodenum, jejunum, ileum and colon, respectively. 3. There appeared to be a marked regional difference in sensitivity to histamine. In ileal and jejunal preparations pD2 values of 6.24 +/- 0.06 (n = 22) and 6.37 +/- 0.07 (n = 22) were found, whereas the pD2 values in the duodenum and colon were 5.55 +/- 0.05 (n = 36) and 5.68 +/- 0.06 (n = 31) respectively. 4. This regional difference in sensitivity to histamine was not due to variations in receptor affinity since pA2 values for the two enantiomers of chlorpheniramine did not differ markedly among the four tested preparations. Since a similar variation in sensitivity was found for methacholine, it is likely that the signal transfer mechanism in guinea-pig ileum and jejunum is more efficient than in the duodenum and colon. 5. The H2-agonists dimaprit and impromidine relaxed methacholine-precontracted (+/- 70% of maximum contraction) intestine at high concentrations (pD2 values of 3.79 + 0.03 and 4.44 + 0.09 for the jejunum). These relaxations could not be antagonized by 0.1 microM tiotidine, famotidine or mifentidine and were observed in all parts of the intestine investigated. 6. The dimaprit analogues nordimaprit and homodimaprit (inactive at H2-receptors) were equipotent in relaxing the methacholine-precontracted smooth muscle. Since several H2-antagonists were also able to produce relaxations, we do not consider these relaxations to be mediated by a H2-receptor subtype, but to be due to some nonspecific effects at the high concentrations used. 7. The histamine receptor involved in the inhibition of electrically-induced contractions in the presence of atropine could be classified as an H3-receptor effect. In all parts of the intestine the H3-agonist R-alpha-amethylhistamine inhibited the twitches with pD2 values ranging from 8.10 + 0.06 (ileum) to 8.27 + 0.03(colon). This effect was competitively antagonized with the selective H3-antagonist thioperamine (pA2 values are 8.09 + 0.07, 8.13 + 0.05, 8.15 + 0.04 and 8.36 + 0.04 in duodenum, jejunum, ileum and colon, respectively. 8. The guinea-pig intestine is a suitable preparation for the evaluation of either H1- or H3-receptor effects. H2-receptors, causing smooth muscle relaxation appear not to be present in our preparations. At high concentrations of H2-receptor agents (agonists and antagonists) relaxations might be observed, due to unknown nonspecific effects.

Characterization of central H2 receptors mediating cardiovascular activity by means of three histamine H2 receptor antagonists: MK-208, BMY-25368, and cimetidine in the rat

Stimulation of central histamine H1 and or H2 receptors with histaminergic drugs results in a dose-related pressor response and bradycardia in conscious, freely-moving rats. Two recently developed peripheral histamine H2 antagonists, MK-208 and BMY-26368, as well as cimetidine, were evaluated with respect to their ability to block the cardiovascular actions of central histamine H2 receptors. These drugs do not readily cross the blood brain barrier, therefore, they were administered intracerebroventricularly (i.c.v.). The ability of these agents to attenuate the cardiovascular effects of the H2 agonist impromidine was studied in conscious, freely-moving rats. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulae. All of the H2 antagonists tested induced a transient hypertensive response that lasted approximately 15 min. MK-208 (30 μg) partially blocked the central cardiovascular actions of impromidine. Unlike other histaminergic agents, MK-208 produced a tachycardia and a profound hyperactivity which slowly developed into seizures. BMY-25368 and cimetidine failed to antagonize the cardiovascular actions of impromidine. These results demonstrate that cimetidine and BMY-25368, established peripheral H2 antagonists, did not block central H2 receptors, suggesting that central and peripheral H2 receptors may be pharmacologically distinct.

Histamine Stimulation of Cyclic AMP Accumulation in Astrocyte‐Enriched and Neuronal Primary Cultures from Rat Brain

Histamine stimulates cyclic AMP accumulation in astrocyte-enriched and neuronal primary cultures from rat brain in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. The response in the astrocyte cultures (Emax = 304 +/- 44% over basal, EC50 = 43 +/- 5 microM) was much higher than in neuronal cultures (Emax = 24 +/- 2%, EC50 = 14 +/- 7 microM). The histamine effect in astrocytes was competitively inhibited by the H2 antagonists cimetidine (Ki = 1.1 +/- 0.2 microM) and ranitidine (Ki = 46 +/- 10 nM) but was insensitive to the H1 antagonist mepyramine (1 microM). The two selective H2 agonists impromidine and dimaprit behaved as partial agonists and showed relative potencies (139 and 0.5, respectively) consistent with an interaction with H2 receptors. The more selective H1 agonist 2-thiazolylethylamine (0.01-1 mM) did not potentiate the response to impromidine (10 microM). Thus, in contrast to what is generally observed in intact cell preparations from brain, the histamine-induced cyclic AMP accumulation in astroglial cells is mediated solely by H2 receptors. The small effect shown in neuronal cultures also appears to be mediated by H2 receptors.

Studies on the cardiovascular actions of central histamine H 1 and H 2 receptors : Poulakos JJ, Gertner SB: J Pharmacol Exp Ther 250:500–507, 1989

Histamine administered i.c.v. to conscious freely moving rats results in dose-related pressor responses and bradycardia. The selective H1 agonist pyridylethylamine (PEA) and the H2 agonist impromidine (IMP) were utilized to characterize the central receptor subtypes involved in the central cardiovascular actions of histamine. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulas. Central administration of PEA or IMP produced dose-dependent pressor responses and bradycardia. The H1 antagonist chlorpheniramine blocked the pressor response, but not the bradycardia produced by PEA. In contrast, the H2 antagonist BMY-25405 blocked both the increase in blood pressure and the bradycardia induced by IMP. Crossover experiments were carried out to examine the specificity of the antagonists' actions. Chlorpheniramine failed to block the actions of IMP and BMY-25405 likewise was ineffective in blocking the actions of PEA. These results suggest that both central H1 and H2 receptors mediate the central pressor effects of histamine, and that PEA and IMP are selectively acting at their respective receptors in the brain. The heart rate effects appear to be mediated directly by central H2 actions, as BMY-25405 was capable of blocking the heart rate changes. The finding that IMP is less potent in the central nervous system, compared to its known greater potency in the periphery, suggests that peripheral and central H2 receptors may be pharmacologically distinct.

Alteration of H2 receptor sensitivity in duodenal ulcer patients after maintenance treatment with an H2 receptor antagonist.

The effects of a specific H2 receptor agonist impromidine, on gastric acid secretion were measured in six patients with duodenal ulcer in clinical remission before and after three months treatment with ranitidine 150 mg nocte. After treatment basal acid output increased from 1.2 to 2.8 mmol/h and after maximal impromidine stimulation from 36.9 (4.7) to 44.2 (6.2) mmol/h (p less than 0.02). Intravenous ranitidine 50 mg was given at the end of the impromidine infusion on each study day; the antisecretory effect of intravenous ranitidine was accentuated after the treatment with ranitidine from a trough acid output of 8.5 (1.2) mmol/h before, to 3.8 (1.5) mmol/h (p less than 0.05) after, treatment. The increased response to the H2 agonist impromidine and the H2 antagonist ranitidine after treatment with ranitidine suggests an enhanced sensitivity of the H2 receptor. This might be explained on the basis of an increase in the number of H2 receptors ('up-regulation').

The use of molecular probes in the study of the action of histamine on macrophages.

The effect of histamine on the expression in vitro of C2, factor B and C3 genes in murine resident peritoneal macrophages was investigated. By measuring the levels of specific mRNA and the amount of the biosynthetically labelled gene products, we found that histamine decreases the biosynthesis of C2 and factor B. However, histamine had virtually no effect on the biosynthesis of C3 in the same cells. To clarify the mechanism of these effects, the H1 agonists (2-pyridylethylamine (PEA)and 2-methylhistamine), the H2-agonists (impromidine and 4-methyl-histamine), the H1-antagonist (chlorpheniramine) as well as the H2-antagonist (cimetidine) were also tested. We found that the inhibitory effect of histamine on C2 and factor B is produced only through H2 receptors. With the combination of histamine agonists and antagonists an inverse effect via H1- or H2-receptors was determined on the biosynthesis of C3. H1-receptor stimuli enhanced, and the stimulation of H2-receptors inhibited, C3 biosynthesis. All effects were pretranslational since the same results were obtained on mRNA and protein levels.

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

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 microM 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 microM. In contrast, the H1-agonist 2-pyridylethylamine did not affect the pathway. The H2-antagonist cimetidine (10 microM) but not the H1-antagonist mepyramine (10 microM) 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.

Evidence for Presynaptic Inhibitory Histamine (H2) Receptors in the Rat Hindquarter Vasculature

Histamine released within walls of resistance blood vessels is suggested to mediate an active portion of baroreceptor-mediated neurogenic vasodilatation in skeletal muscle vasculature. Studies were undertaken to examine the possibility that histamine-mediated active vasodilatation could be effected, in part, by an inhibitory presynaptic action of histamine on vascular sympathetic varicosities. All experiments were conducted in constant-flow autoperfused rat hindquarters in which vasoconstrictor responses were evoked by sympathetic chain (L2-4) stimulation at varying frequencies or intraarterial norepinephrine (0.5 microgram) administration. Intraarterial histamine infusion resulted in a significant inhibition of nerve-stimulated hindquarter vasoconstriction, with the greatest reduction (20%) occurring at the 82.5-ng/ml/min dose. The inhibitory effect of histamine was not stimulation frequency dependent, and occurred when the vasoconstrictor responses to intraarterial norepinephrine and dilator responses to intraarterial nitroglycerin (1 microgram) were unaltered by the histamine infusions. The H2 agonist impromidine produced a significant inhibition of nerve-stimulated hindquarter vasoconstrictor responses without altering perfusion pressure responsiveness to either intraarterial norepinephrine or nitroglycerin. The magnitude of this inhibition of nerve-stimulated vasoconstrictor response was equivalent to or greater than that produced by histamine. The alpha 2-agonist clonidine produced a significant inhibitory effect on neurogenic vasoconstrictor responses with a maximum of 54%. Cimetidine infusion (10 mg/kg i.a.) essentially abolished the inhibitory effect of histamine on nerve-stimulated hindquarter vasoconstriction. These results are consistent with the existence of inhibitory presynaptic histamine receptors on sympathetic varicosities in the hindquarter vascular bed. Furthermore, evidence supports these inhibitory receptors being of the H2 class and the possibility that histamine-mediated active vasodilatation in rat hindquarters involves inhibitory presynaptic histamine receptors.

H3 receptor assay in electrically-stimulated superfused slices of rat brain cortex; effects of Nα-alkylated histamines and impromidine analogues

The release of the putative neurotransmitter histamine (HA) from rat brain cortex slices is under negative feedback control by an HA autoreceptor. This autoreceptor has been postulated to belong to a new class of HA receptors, H3. To verify this hypothesis we have developed an assay using superfused rat brain cortex slices. The HA transmitter pool is labelled by incubation of the slices with the precursor 3H-histidine; 3H-HA is estimated after separation by column chromatography. Release of HA was found both after K+-induced depolarization and electrical field stimulation. The latter resulted in higher and more reproducible HA release. Electrically induced HA release could be fully inhibited in a concentration dependent way by exogenous HA in the superfusion buffer. N alpha-alkylated histamines also showed agonistic activity. The action of exogenous HA was totally blocked by the potent H2 agonist impromidine and some of its analogues.

Stimulated Pepsin Secretion after Omeprazole-Induced Acid Suppression in the Totally Isolated, Vascularly Perfused Rat Stomach

The effect of the H2 agonist impromidine, gastrin 1-17 (G1-17), pentagastrin, and the M1 agonist McN-A-343 on pepsin secretion in the acid-inhibited totally isolated, vascularly perfused rat stomach was studied. Omeprazole produced a 97-98% inhibition of stimulated acid outputs. Base-line pepsin output after omeprazole was 712 +/- 278 micrograms/h (mean +/- SEM) and, after stimulation with impromidine, 1528 +/- 164 micrograms/h; G1-17, 1520 +/- 180 micrograms/h; and pentagastrin, 2063 +/- 605 micrograms/h. Output after McN-A-343 was 534 +/- 69 micrograms/h. Pepsin secretion after impromidine, G1-17, and pentagastrin was significantly (p less than 0.01) higher than base-line output. McN-A-343 had no significant effect on pepsin output in this model. Pepsin secretion after impromidine, G1-17, and pentagastrin was considerably lower than found in the same model with uninhibited acid output. This could be caused by decreased tubular 'washout' after acid inhibition, and, accordingly, no conclusions can be drawn as to the possible stimulatory effect of acid on pepsin secretion. However, the present study indicates that pepsin secretion can be stimulated directly by impromidine and (penta)gastrin without concomitant acidification of the gastric glands.

Electrophysiological characterization of histamine receptor subtypes in mammalian heart preparations

Histamine-induced electrophysiological effects have been investigated in guinea-pig left atria, papillary muscles and rabbit AV-nodal preparations by means of intracellular recording of action potentials, slow responses in the presence of 27 mmol/l (K+)o and voltage clamp experiments. Differentiation of the H-receptor subtypes was performed by the use of the H2-selective agonists dimaprit and impromidine and the H1- and H2-selective antagonists dimetindene and cimetidine, respectively. The following results were obtained: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium. Histamine at concentrations less than 1 mumol/l leads to a small increase in APD30 and APD90, but to a marked decrease at concentrations greater than or equal to 1 mumol/l, whereas Vmax, resting potential and amplitude remain nearly unchanged. The effects on ADP are completely blocked by cimetidine and not changed by dimetindene. Changes in action potential may be explained by an increased in slow inward current and outward currents as shown by voltage clamp experiments. In left atria histamine increases APD30 and APD90, whereas there is only a minor increase in amplitude with no changes in Vmax and resting potential. These effects are completely reversed by the H1-antagonist dimetindene but not by cimetidine. IBMX decreases APD90 and does not potentiate the action of histamine. Vmax of slow responses is increased in left atria by stimulation of H1-receptors and in papillary muscles by stimulation of H2-receptors. The results suggest that stimulation of atrial H1-receptors directly causes an increase in Ca-channel conductance.(ABSTRACT TRUNCATED AT 250 WORDS)