Interaction between the central histaminergic and the muscarinic cholinergic systems

Histamine (HA) was given intracerebroventricularly (icv) to rats anaesthetized with pentobarbital. During the first minute after administration, HA alone elicited a small fall in blood pressure (BP) and a decrease in heart rate (HR), followed by a distinct increase in those parameters. Pretreatment with naloxone (Nx) in a dose of 0.1 g icv significantly decreased the rise in BP and augmented the increase in HR. When the rats were premedicated with atropine methyl bromide (ATMB), 15 min before histamine, higher doses of ATMB (100 g icv or 25 g ip) significantly inhibited the histamine induced BP rise. However, a very small dose (0.1 g) of ATMB stimulated the hypertensive response, but only after its peripheral and not central application. These changes were significantly reversed by icv pretreatment with Nx. HA-induced changes in HR, in contrast to BP, were not significantly modified by ATMB.     

Central antinociceptive action of histamine: Behavioural and electrophysiological studies

The effects of intracerebroventricular (i.c.v.) injection of histamine (HA), an H₁-agonist (2-pyridylethylamine, 2PEA) and an H₁-antagonist (pyrilamine, PYR) on hot-plate latency in rats were examined. HA (40 or 80 g/rat) significantly enhanced the pain threshold whereas 2PEA (80 or 160 g/rat) and PYR (20 g/rat) had no effect. Moreover, PYR did not modify HA antinociception. These results indicate that HA-H₁ receptors are not involved in the inhibition by HA of the hot-plate response. To characterize the neural pathways involved in the antinociceptive action of HA, the effect of HA (40 g/rat, i.c.v.) on the firing of thalamic neurons in arthritic rats evoked by peripheral noxious stimuli was recorded by electrophysiological techniques. HA markedly depressed the neuronal firing evoked by ankle mobilization, suggesting that the thalamus is one important area involved in modulation of pain by HA.     

Pharmacological characterization of histamine receptors in the mouse seminal vesicle: Sensitivity to H1- and H2-receptor agonists and antagonists

Neither histamine nor the more specific H₁- or H₂-receptor agonists (0.2–220 M) produced a contraction of the mouse seminal vesicle. However, all these agonists decreased resting tone and caused a dose-related inhibition of the electrically evoked twitch responses in these concentrations. The slopes of the percentage response versus log molar concentration curves for all agonists did not differ significantly from that of histamine. The rank order and relative potency of the compounds tested were: histamine (100%)>dimaprit (65%)4-methylhistamine (36%)>2-methylhistamine (4.5%)>2-(2-thiazolyl) ethylamine (1.7%). Inhibition of the twitch response by histamine was antagonized by cimetidine (3.5–140 M) but not by mepyramine (0.1–1.0 M). The slopes of Schild plots for cimetidine against histamine and dimaprit did not differ from unity, and the calculated pA₂ values of cimetidine were 5.70 and 5.55, respectively. Histamine (2.2 and 6.5 M) inhibited the contraction elicited by a submaximal concentration of exogenous noradrenaline (1 M); this inhibition could also be selectively antagonized by cimetidine. These results demonstrate that histamine and selective H₁- and H₂-receptor agonists have an inhibitory action on the mouse seminal vesicle, and that this action is mediated via a post-junctional H₂-receptor. The calculated pA₂ values of cimetidine against histamine and dimaprit also suggest that the receptor in the mouse seminal vesicle is of the conventional H₂-type. The results further indicate that an H₁-receptor is absent in the mouse seminal vesicle.     

Cyclic AMP generating systems in vertebrate retina: Effects of histamine and an established retinal modulator,dopamine

Histamine (HA), 1–1000 M, significantly stimulated both basal and forskolin-activated cAMP generation in chicken and adult hen retina. The action of HA was reproduced by the selective H₂-receptor agonists dimaprit and 4-methyl-histamine, but not by the selective H₁-receptor agonist 2-thiazolylethylamine, and it was antagonized by the specific H₂-receptor blockers cimetidine and tiotidine, but not by the H₁-receptor blocker mepyramine. In parallel experiments, dopamine, an established retinal neuromodulator acting through the D1-type of receptor, also stimulated basal and forskolin-driven adenylate cyclase activity in homogenate of chicken retina. It is suggested that chicken retina contains HA H₂-receptors which are positively coupled to the adenylate cyclase system.     

Dimaprit — induced neurotoxicity

The neurotoxicity of the histamine H₂ agonist dimaprit was characterized. Dimaprit (100 g administered into the lateral cerebral ventricle) induced a large area of brain necrosis 1–3 days later which was uniformly lethal. Lower doses caused dose — related effects on survival, gross brain pathology and body weight. Experiments with other H₂ agonists and H₂ antagonists, together with studies by others demonstrating a similar toxicity of the congener homodimaprit suggest that the neurotoxicity of dimaprit is independent of brain H₂ receptors. Although dimaprit is a useful tool for the characterization of H₂ receptor responses, the present results show that this agent must be used with caution, if at all, in classifying brain H₂-receptor mediated events.     

Antagonistic action of naloxone on central histamine receptors-stimulated corticosterone secretion in rats under stress

In rats under a mild stress of restraint the interaction between central opioid receptors and histaminergic stimulation of the pituitary-adrenocortical activity was investigated indirectly through corticosterone secretion. In order to avoid a possible direct action on adrenal glands, all the tested drugs were administered intracerebroventricularly (icv). Naloxone an opioid antagonist and cimetidine, a H₂- and mepyramine a H₁-receptor antagonists were given 15 min before histamine and histamine agonists. One hour after histaminergic drug injection the rats were restrained for 10 min and decapitated. Histamine, 2-pyridylethylamine (PEA), a histamine H₁-receptor agonist, and 4-methylhistamine (MeHA) and dimaprit, H₂-receptor agonists, significantly intensified the stress-induced increase in serum corticosterone levels. Naloxone, given alone icv or ip, did not substantially alter the stress-induced corticosterone response. Like mepyramine naloxone abolished the corticosterone response to PEA in stressed rats. Naloxone also decreased significantly, though not totally, the corticosterone response to MeHA, dimaprit and histamine, its efficiency being similar to that of cimetidine, a H₂-receptor antagonist. These results suggest that in stressed rats central opioid receptors are considerably involved in the histamine H₁-receptor — and, to a lesser degree, in the H₂-recepor stimulation of the hypothalamo-pituitary-adrenocortical axis.     

Naloxone antagonizes a central histaminergic stimulation of corticosterone secretion in rats

The interaction of central opioid receptors with histaminergic stimulation of the hypothalamo-pituitary-adrenocortical axis, evaluated indirectly through corticosterone secretion, was investigated in conscious unstressed rats. To avoid any possible direct action on the adrenal cortex, all drugs were given intracerebroventricularly (i.c.v.). Histamine, 2-pyridylethylamine (PEA), a histamine H₁-receptor agonist, and 4-methyl-histamine (MeHA) and dimaprit, the H₂-receptor agonists, considerably increased the serum corticosterone levels 1 h after adminstration. Naloxone, an opioid receptor antagonist, almost abolished the corticosterone response to PEA and considerably reduced the responses to MeHA, dimaprit and histamine. The maximum inhibitory effects of naloxone on corticosterone responses induced by histamine and histamine agonists were comparable with those of the H₁-and H₂-receptor antagonists, mepyramine and cimetidine.These results strongly suggest that a major part of the histaminergic stimulation of the hypothalamopituitary-adrenal axis is mediated by central opioid receptorsThe study was supported by the Polish Academy of Sciences, grant No 06.03.     

Responses to histamine and selective H2-receptor agonists in lung parenchymal strips from normal and sensitized guinea-pigs

Histamine produces concentration-dependent contractions of lung parenchyma strips obtained from normal and sensitized guinea-pigs. The responsiveness of the sensitized lung strips to histamine was significantly increased compared to normal tissues. Clemizole (0.1 M) was equally effective as an H₁-antagonist in normal (dose-ratio 9.12) and sensitized (dose-ratio 9.77) tissues.The concentration-response curves to histamine were displaced to the left by cimetidine (0.1 M to 0.1 mM) with similar dose-ratios in normal and sensitized tissues. Cimetidine enhanced maximal responses to histamine only in normal lung strips. The effects of submaximal equieffective concentrations of histamine were augmented to the same extent by cimetidine (0.1 mM) in normal and sensitized tissues. The responses to histamine were not modified by indomethacin (5 M).The responsiveness and sensitivity of sensitized lung strips to isoprenaline, impromidine, 4-methylhistamine and dimaprit were not different from those of normal tissues. Cimetidine yielded, as antagonist of dimaprit, similar pA₂ values in normal and sensitized tissues.In conclusion, there is no experimental evidence in favour of the existence of an impairment of H₂-receptor activity in sensitized airways. Hyperreactivity to histamine is probably due to differences between normal and sensitized tissues with respect to Ca²⁺ entry and/or intracellular Ca²⁺ release in response to H₁-receptor activation.     

Plasma vasopressin levels after I.C.V. infusion of histamine agonists in the conscious goat

Histamine H₁-agonists 2-pyridylethylamine (2-PEA) and 2-methylhistamine and H₂-agonists 4-methylhistamine, dimaprit and impromidine were given i.c.v. to conscious goats and the release of arginine vasopressin (AVP) was measured. 2-PEA at very low doses (9 and 27 moles/animal, equivalent to H₁-activity of about 0.5 and 1.5 moles histamine, resp.)_significantly increased plasma AVP. The H₂-agonists did not cause consistent changes in AVP even if their relative doses were higher. It is concluded that the vasopressin releasing effect of histamine is due to H₁-receptor activation.     

Inhibitory effect of famotidine on cat gastric secretion

The inhibitory effect of the novel H2 receptor antagonist famotidine was studied in conscious gastric fistula cats against dimaprit-induced hypersecretion, in comparison with ranitidine. On the secretory plateau induced by dimaprit (2 mol kg^–1 h^–1) famotidine (0.05–0.2 mol kg^–1 i.v.) exerted a dose-dependent inhibitory effect, being approximately 4.5 times as potent as ranitidine (ID₅₀ values were 0.067±0.015 and 0.30±0.025 mol kg^–1 for famotidine and ranitidine, respectively). No significant differences were found between the two drugs, as for the time-course of the inhibitory effect. Famotidine (0.01–0.32 mol kg^–1 h^–1) caused a parallel displacement of the dose-response curve to dimaprit to the right, without reducing the maximum response to the stimulant, thus behaving as a competitive antagonist, like ranitidine. pA₂ values for famotidine and ranitidine were 7.95 and 6.92, respectively. In the same range of doses famotidine dose-dependently reduced also the secretory response to histamine. From these data it was concluded that famotidine is a potent histamine H2 receptor antagonist in the cat gastric mucosa; moreover, conversely from in vitro data, the antagonism was surmountable even at the highest doses tested. In vivo experiment, therefore, did not reveal any particular feature of this compound, apart from the undoubtedly high potency, in comparison with other members of the family.     

Biphasic short-circuit current response to noradrenaline mediated by Ca2+ and cAMP in cultured rat epididymal epithelium

A study was carried out to investigate the short-circuit current (I _sc) response to noradrenaline (NA) and the signal transduction mechanisms involved in cultured rat cauda epididymal epithelium. In normal Krebs-Henseleit solution, NA (10 mol · l^–1) added basolaterally elicited a biphasic I _sc response consisting of a transient spike followed by a second sustained response. The biphasic response was almost abolished by removing ambient Cl^–. Preloading the tissues witha cell-permeant Ca²⁺ chelator, 1,2-bis(2-aminophenoxy) eth-ane-N,N,N,N,-tetraacetic acid acetoxymethyl ester (BAPTA/AM), or pretreating them with thapsigargin (Tg), a microsomal adenosine triphosphatase inhibitor abolished the initial spike in the I _sc response to NA, but had little effect on the second component. Pretreating the tissues with a non-selective -antagonist, nadolol, reduced the second I _sc response in a dose-dependent fashion but the initial spike was not affected. Microfluorimetric studies showed that NA (100 mol · l^–1) elicited single Ca²⁺ spikes in isolated epididymal cells, which could be abolished by prior treatment with Tg. Biochemical assays showed that NA (10 mol · l^–1) increased intracellular cyclic adenosine monophosphate concentration ([cAMP]_i) and the response was abolished by prior treatment with nadolol (50 mol · l^–1). The results showed that NA elicited a biphasic I _sc response mediated by a rise in intracellular Ca²⁺ concentration ([Ca²⁺]_i) followed by a rise in [cAMP]_i. The Ca²⁺-mediated I _sc response had a faster onset and more transient action than the cAMP counterpart. It is suggested that NA released from noradrenergic nerve endings regulates transepithelial Cl^– secretion in the epididymis thereby providing the specialized millieu vital for sperm storage and maturation.     

Chronotropic cardiac effects of histamine in the conscious dog with chronic atrioventricular block: interactions with the autonomic nervous system

Chronotropic effects of histamine and dimaprit were studied in the conscious dog with chronic atrioventricular block. Histamine at 0.2–5 g/kg and dimaprit at equimolar doses (i. e. 0.25–6.25 g/kg) increased atrial rate dose-relatedly. Blockade of muscarinic receptors reduced these effects and simultaneous blockade of muscarinic and beta-adrenergic receptors abolished them. Histamine and dimaprit moderately increased ventricular rate. Blockade of muscarinic receptors did not modify these effects, suppressed them. After blockade of beta-adrenoceptors, histamine and more rarely dimaprit sometimes decreased atrial and ventricular rates. These effects were prevented by additional muscarinic blockade. Histamine and dimaprit lowered mean blood pressure to the same degree before and after each antagonist. The positive chronotropic effects of histamine and dimaprit, at these doses, are probably reflex responses to their hypotensive effects. The negative chronotropic effects of histamine after pindolol are due to muscarinic receptor activation. No evidence was found to implicate histamine-specific receptors in any of the chronotropic effects of histamine and dimaprit.     

Histamine-induced microvascular permeability increases in hamster skin: a response predominantly mediated by H2-receptors

The pharmacology of histamine-induced increases in cutaneous microvascular permeability was investigated in the hamster by (a) examining the effects of cimetidine and pyrilamine on the increase in microvascular permeability evoked by graded doses of intradermally-injected histamine, and (b) comparing the cutaneous microvascular permeability responses to graded doses of impromidine (0.1–100 g), dimaprit (1–100 g) and -histine (0.1–100 g). Pretreatment with pyrilamine (0.1 mg/kg i.v. bolus injection) did not reduce the increase in microvascular permeability produced by any dose of histamine. In contrast, cimetidine (0.5 mg/kg/min i.v. infusion) significantly inhibited the microvascular permeability responses to 10 and 100 g histamine. Although neither cimetidine nor pyrilamine significantly altered the microvascular permeability response to 0.1 and 1g histamine, inhibition was afforded by a cimetidine-pyrilamine combination. These results suggest a predominantly H₂-receptor mediated phenomenon with a minor H₁-receptor mediated component. Studies with the H₂-receptor agonists impromidine and dimaprit and the H₁-receptor agonist -histine provide further support for this contention. Dimaprit and impromidine caused a dose-dependent increase in cutaneous microvascular permeability, but betahistine produced only a relatively modest response. In other laboratory species, increased cutaneous microvascular permeability appears to be mediated solely by H₁-receptors. Therefore, the hamster skin appears unique with respect to the pronounced H₂-receptor involvement in histamine-induced microvascular permeability changes.     

Central effects of histamine H2-receptor agonists and antagonists on nociception in the rat

The effects of intracerebroventricular injection of histamine H₂-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H₂-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SK&F 91487 on hot-plate latency in rats were examined. Both DIM (0.4–0.8 mol/rat) and 4-MeH (0.4–0.8 mol/rat) significantly enhanced the pain threshold, whereas SF&F 91487 (0.8 mol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H₂-antagonists CIM (0.8 mol/rat) and RAN (0.6 mol/rat) also enhanced the pain threshold, while FAM (0.03 mol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H₂-receptors and that the activation of HA-H₂-receptors is inhibitory to nociception.     

Effects of the H2-receptor agonist dimaprit on lymphocyte responsivenessin vitro

The histamine H₂-agonist dimaprit was found to increase the response of rat spleen cells to the T-cell mitogen Concanavalin A, when present at concentrations of 10^–5 and 10^–4 M. Higher concentrations of dimaprit were cytotoxic. The enhanced response seemed to be associated with an inhibitory effect of dimaprit on T-suppressor cell activity rather than with a direct mitogen-like stimulation of lymphocyte proliferation or with an interference with monocyte/macrophage functions. The stimulatory effects of dimaprit were not reversed by the H₂-receptor antagonist, cimetidine, nor by the -receptor antagonists metoprolol and H 35/25. Addition of the H₁-receptor antagonist, mepyramine, further increased the stimulatory effect of dimaprit on lymphocyte responsiveness.     

Interference of clonidine and α-methyl-p-tyrosine with stress and central histaminergic stimulation of the corticosterone response in rats

In conscious rats clonidine given intracerebroventricularly 1 h prior to a mild stress of immobilization intensified the stress-induced increase of pituitary-adrenocortical response, measured indirectly through corticosterone concentration in blood serum. The corticosterone response to clonidine was abolished by i.c.v. pretreatment of rats with yohimbine, an ₂-adrenergic antagonist, and was antagonized by pretreatment with phenoxybenzamine, an ₁-adrenergic antagonist. Clonidine intensified also the corticosterone response induced in stressed rats by i.c.v. injected histamine, 2-pyridylethylamine (PEA), a H₁-receptor agonist, and dimaprit, a H₂-receptor agonist.The depletion of brain catecholamines by -methyl-p-tyrosine (-MT) considerably increased the corticosterone response to stress but did not substantially change the response to histamine, PEA and dimaprit in stressed rats.These results suggest that clonidine increases the corticosterone secretion induced by a mild stress and histamine and histamine H₁ and H₂ agonists mainly through the activation of central ₁-adrenoceptors. The increase by -MT of the stress-induced corticosterone response may indicate the inhibitory role of central catecholamines in the pituitary-adrenocortical response to stress in rats.     

Electrophysiological characterization of histamine receptor subtypes in sheep cardiac Purkinje fibers

The histamine-receptor-subtype-mediated effects on action potentials of electrically driven and spontaneously active isolated sheep cardiac Purkinje fibers were investigated using H₁-and H₂-selective agonists and antagonists.In electrically stimulated Purkinje fibers, histamine (3 mol/l) increased the action potential plateau height, decreased the action potential duration measured at a repolarization level of –60 mV and enhanced the pacemaker activity. These effects were abolished by the H₂-selective antagonist cimetidine (30 mol/l), but were not impaired by the H₁-selective antagonist dimetindene (0.3 mol/l).In spontaneously active Purkinje fibers, histamine (10 mol/l) increased the spontaneous rate by 24%, the slope of diastolic depolarization by 45% and shortened the duration of the diastole by 32% of the respective control measurements. These effects were blocked by 30 mol/l cimetidine, but remained unchanged in the presence of 0.3 mol/l dimetindene.Concentration-response curves of histamine were shifted to the right by approximately 2 logarithmic units in the presence of 30 mol/l cimetidine, but were not influenced in the presence of 0.3 mol/l dimetindene. The H₂-selective agonist impromidine (0.001–0.3 mol/l) had similar actions as histamine on spontaneously active Purkinje fibers, while the H₁-selective agonist 2-(2-pyridyl-)ethylamine was ineffective. It is concluded that the pronounced stimulatory action of histamine on spontaneous activity in sheep cardiac Purkinje fibers is exclusively mediated by H₂ receptors.Dedicated to Prof. Dr. E. Mutschler on the occasion of his 60th birthday.Supported by Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen, Projekt-Nr. 40008786.     

Central histaminergic stimulation of corticosterone and hyperlipemic responses after chronic ethanol consumption in rats

The consumption of ethanol in a 10% solution for 3 weeks produced a negligible increase in corticosterone secretion in the rat but raised the levels of free fatty acid (FFA) in the serum. Mepyramine insignificantly antagonized and cimetidine intensified the corticosterone response. Histamine and the H₁- and H₂-receptor agonists, 2-pyridylethylamine (PEA) and dimaprit significantly raised the serum corticosterone levels in chronically alcoholized rats. Mepyramine antagonized and cimetidine increased the ethanol-induced hyperlipemia. Histamine, PEA and dimaprit considerably increased the serum FFA levels in alcoholized rats. After withdrawal of ethanol, histamine and dimaprit induced a marked hyperlipemic effect, whereas PEA did not increase the serum FFA concentration.These results indicate that in chronically alcoholized rats the central histaminergic system interacts with ethanol in regulation of the serum FFA level. After the ethanol withdrawal central H₁-receptors do not respond to H₁-agonist stimulation.     

Gastric and cardiovascular effects of histamine in the dog

The H-2 receptor stimulation of gastric acid secretion and of heart rate by histamine, a mixed H-1–H-2 agonist, given in 45-min successive step doses 2–150 g base/kg.h and 4(Me)histamine, (4(Me)H), 1.4 to 210 g base/kg.h, a specific H-2 agonist, in five conscious gastric fistula dogs showed no difference between the agonists in ED₅₀s or in maximal responses. The ED₅₀ for acid was lower (15–16 g/kg.h) than for cardiac chronotropism (25 to 27 g/kg.h). Both effects were competitively antagonized by the H-2 antagonist cimetidine, 0.5 to 1 mg/kg.h. Background infusions of diphenhydramine, 2 mg/kg.h, raised the maximum heart rate increase caused by histamine from +108 to +149 beats/min (p<0.05) but not that of 4(Me)H; acid outputs were not augmented. Diphenhydramine 2 mg/kg.h alone caused no significant change in heart rate or blood pressure. Histamine reduced systolic blood pressure (SBP) by 48 mmHg and with diphenhydramine background by 61 mmHg (p<0.05). 4(Me)H at a top dose of 210 g base/kg.h reduced SBP by 81 mmHg (p<0.05). To test whether the effects of added diphenhydramine could be interpreted as an H-1 receptor effect of histamine, the H-1 agonist 2-pyridylethylamine (PEA) was given alone (2–150 g/kg.h in 45-min steps) or as a 100 g/kg bolus during the infusion of 4(Me)H 50 g/kg.h. There was no effect of PEA on gastric acid, heart rate or blood pressure. Even though diphenhydramine augments the effect of histamine on heart rate and blood pressure, the lack of PEA effect would indicate that there is not a direct H-1 receptor mediated effect on gastric acid, heart rate or systolic blood pressure in the conscious dog. This contrasts with published data obtained in anesthetized animals. After a single dose of 4(Me)H, 50 g/kg.h had been infused i.v. for 45 min, acid output had reached 70% of the maximum seen at 90 min, heart rate had increased by 65% of its maximum response but SBP had not yet changed. Cimetidine blocked 4(Me)H-induced hypotension completely but blocked the heart rate increase only partially and competitively. We conclude that in the intact animal there is evidence for a direct H-2 mediated stimulation of heart rate in the conscious dog with kinetics similar to the H-2 stimulation of gastric acid secretion.Supported by Research Grant No. AM09260 from the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health and by the Medical Research Service of the Veterans Administration.     

Low level antigen responses in guinea-pig lung strip

Guinea-pigs were sensitized either by i.p. administration or by a novel procedure involving inhalation of ovalbumin (2, 0.2 and 0.002%) on days 0, 5 and 19 respectively. Lung strips from these guinea-pigs were challenged with both low (0.02 g/ml) and high (10 g/ml) concentrations of ovalbumin and the responses compared. Whereas the low level antigen gave consistent contractions following aerosol sensitization, no response was observed from the i.p. sensitized guinea-pig lung strips. Marked differences were also observed following the high ovalbumin challenge, where the aerosol sensitized lungs gave almost twice the response as tissue from the i.p. sensitized guinea-pigs, the former being approximately 140% of that observed with acetyl--methyl choline (1 mM). Furthermore, the response elicited in the lungs from aerosol sensitized guinea-pigs were not modified by the addition of high concentrations of the H₁-antagonist diphenhydramine (100 M), before or subsequent to challenge. The data suggest that the aerosol sensitization procedure gives rise to a contractile response in guinea-pig lung strips which contains no observable histamine component.