Pharmacological characterization of cardiac histamine receptors: sensitivity to H1-receptor antagonists

The ability of five prototypic antihistamines (diphenhydramine, promethazine, cyclizine, chlorpheniramine and tripelennamine) to modify the cardiac actions of histamine was studied in order to determine the reactivity of cardiac histamine receptors. Histamine, as a function of dose, increases the rate, the force of contraction, the coronary flow and the time of atrioventricular conduction of the isolated guinea pig heart. Each of the five prototypic antihistamines failed to inhibit histamine-induced stimulation of cardiac rate and contractility. at the same time these antihistamines did inhibit the negative dromotropic effect of histamine. Chlorpheniramine and diphenhydramine antagonized the coronary dilating effect of histamine.These results suggest that two types of histamine receptors may be present in the guinea pig heart: H₁-receptors, at the atrioventricular node and coronary vessels; H₂-receptors at the sinoatrial node and on the ventricular fibers. The activity of these prototypic antihistamines is consistent with their action exclusively on H₁-receptors.     

Peripheral Cardiovascular Effects in Rats after Central Administration of Histamine and Antihistamines

1. Vascularly isolated but nervously intact rat right hind limbs were perfused with blood at a constant flow rate and changes in perfusion pressure (proportional to vascular resistance), heart rate and blood pressure were monitored. 2. Histamine administered into the right lateral cerebral ventricle (Lev.) through guide cannulae, induced dose-dependent increases in perfusion pressure, heart rate and blood pressure. 3. Prior i.c.v. or i.v. administration of metiamide (an H₂-antagonist) did not prevent the cardiovascular responses to i.c.v. histamine but rather prolonged them. Following i.c.v. or i.v. administration of chlorpheniramine (an H_rantagonist), however, changes in vascular resistance, heart rate and blood pressure were not significant. 4. Metiamide administration appeared to have some agonist activity on its own. Thus the role of H₂-receptors in cardiovascular responses to centrally administered histamine remains unclear. 5. The work shows that in rats increases in nervous discharge to at least the hind limb vascular bed occur following central administration of histamine and confirms that increases occur in heart rate and blood pressure. These responses appear likely to be mediated through stimulation of central H₁ receptors.     

EFFECTS OF HISTAMINE BOLUS INJECTIONS AND CONTINUOUS INFUSIONS ON THE H1- AND H2-RECEPTORS IN THE HINDLIMB VESSELS OF THE RABBIT

1. Hindlimb vascular resistance (HVR) was continuously measured after pharmacological block of the autonomic effectors in unanaesthetized rabbits with previously implanted Doppler ultrasonic flowmeters. 2. Histamine bolus injections caused a dose-related short lived fall in HVR followed by a more sustained rise. The fall was due to H₂-receptor stimulation (blocked by burimamide or metiamide) and the rise to H₁-receptor stimulation (blocked by mepyramine). At the doses of histamine tested the magnitude of the H₁-mediated vasocoiistriction had a larger peak effect than the H₂-mediated vasodilatation. 3. Histamine infusions up to 200 μg kg^?1 min^?1 did not alter HVR significantly but both increases and decreases in HVR were observed after giving H₂- or H₁-antagonists, respectively. 4. From the double reciprocal plots of 1/peak HVR change and 1/dose of histamine the magnitude of the predicted H₁- and H₂-mediated peak HVR effects at large doses were the same. This suggested that the number of H₁-_- and H₂-receptors were similar in the hindlimb vascular bed, in agreement with the infusion data.     

Regional vascular resistance and heart rate responses mediated through H1- and H2-histamine receptors in the unanaesthetised rabbit

The effects of histamine infusions (10—100 μg/kg/min) on heart rate and hindlimb, carotid, mesenteric and renal vascular resistance were investigated in unanaesthetised rabbits after “total” autonomic effector block to abolish reflex effects. Histamine caused a rise in heart rate that was predominately due to stimulation of H₂-receptors (blocked by metiamide). Hindlimb and carotid vascular resistance did not change significantly during histamine infusion. However, after blocking H₂-receptors with metiamide histamine infusions produced dose-related vasoconstriction in these beds while after H₁-receptor block with mepyramine histamine caused dose-related vasodilatation indicating that H₁- and H₂-receptors mediated opposite vascular effects which were of similar magnitude. By contrast, histamine infusion caused vasodilatation in both the mesenteric and renal vasculature before giving antagonists. This dilatation was mediated by both H₁- and H₂-receptors as either receptor antagonist attenuated the response. These studies suggest that H₁-receptors in the same species mediate vasoconstriction in some beds and vasodilatation in others while H₂-receptors mediate vasodilatation in all the beds studied and also account for most of the increase in heart rate.     

Histamine receptors in the vasculature of the rabbit ear

Summary Histamine has a dual action on the isolated perfused ear preparation of the rabbit. The amine induced a dose-dependent rise in perfusion pressure when the preparation was perfused with Krebs' solution. This pressor response was reversed to a depressor effect when mepyramine was added to the perfusion fluid. This depressor effect of the amine was also dose-related. Metiamide competitively inhibited the depressor effect of histamine. Prior treatment of the ear vessels with metiamide alone caused an increase in histamine-induced perfusion pressure.From these results it was concluded that the predominant pressor effect of histamine on the vascular bed of the rabbit ear is mediated through the H₁-receptors and the depressor effect of the amine through histamine H₂-receptors.     

Possible Regulatory Role of Histamine in Human Platelet Function Examined by Thrombin-induced Serotonin Release

Abstract: The influence of histamine on human platelet function was studied by thrombin-induced serotonin release. The thrombin-induced ³H-serotonin release was confirmed to be a rapid process which does not require external calcium. Histamine was found to reduce the release of serotonin and the inhibition was abolished when H₁-plus H₂-antagonists were added together with histamine. H₁- and H₂-receptor stimulation was examined in two ways, by a combination of histamine with cimetidine or diphenhydramine and by the selective agonists 2-(2-pyridyl)-ethylamine and impromidine. In both instances H₁- and H₂-stimulation was found to reduce the platelet serotonin release. These results suggest a regulatory role of histamine in the platelet function by stimulation of platelet H₁- and H₂-receptors.     

Studies on the Effect of Histamine in Isolated Human Pulmonary Arteries and Veins

Abstract: The effect of histamine (0.01–200 μM) was studied in isolated human pulmonary vessels. Histamine induced concentration dependent contractions in both arteries and veins. In veins the maximal response to histamine was lower than in arteries. Histamine and 2-methyl-histamine had a dual action in both arteries and veins clearly demonstrated in vessels precontracted with potassium. In these vessels histamine and 2-methyl-histamine induced relaxation at low concentrations and contractions at high concentrations. Veins were more sensitive to the relaxant effect of histamine than arteries. Mepyramine eliminated the dual action of 2-methyl-histamine and histamine and unveiled a mepyramine resistant relaxation at the highest histamine concentrations used which was resistant to the effect of cimetidine and metiamide. The H₂ receptor agonist dimaprit (10–400 μM) induced a slight relaxation in both arteries and veins that could be eliminated by metiamide (100 μM). The results show that histamine has a dual action in human pulmonary vessels which includes a contractile effect mediated via H₁ receptors and a relaxant response partly mediated through H₁ receptors and partly via unspecific mechanisms. However, an H₂ mediated relaxant effect cannot be excluded.     

Synthesis and Pharmacology of Combined Histamine H1-/H2-Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

The classical histamine H₁-receptor antagonists diphenhydramine ( 3a ) and cyproheptadine ( 9 ) and their derivatives ( 3b—d, 10 ) were connected with a 2-guanidinothiazole containing structure ( 28 ) derived from the H₂-receptor antagonist tiotidine in order to obtain combined H₁-/H₂-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H₁- and H₂-receptor antagonist activity at the isolated guinea-pig ileum (H₁) and the isolated guinea-pig right atrium (H₂), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H₁-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative ( 30–32, 34 ), however, cause a decrease of H₂-receptor antagonist potency compared to the diphenhydramines ( 29a—d, 33a—d ). Using nitroethenediamine as the polar group is apparently more favourable to H₁- and H₂-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H₁-receptor antagonist moiety ( 29c, d ) display the most potent H₁- and H₂-receptor antagonist effects. The presented concept is a very promising way to combine H₁- and H₂-receptor antagonist properties in one molecule.     

The Cardiovascular Effects of Thyrotropin-Releasing Hormone (TRH) are Attenuated by Cimetidine in Rats

Abstract: The modulation of cardioventilator effects of thyrotropin-releasing hormone (TRH) by histaminergic mechanisms was studied in anaesthetized rats pretreated with histamine receptor antagonists. TRH (1–10. nmol/kg) into the lateral cerebral ventricle dose-dependently elevated mean arterial pressure, heart rate and stimulated respiration. The respiratory stimulating effect of TRH remained unchanged after pretreatments with histamine H₁-receptor antagonist diphenhydramine or H₂-receptor antagonists cimetidine and ranitidine, while the TRH-induced hypertension and tachycardia were attenuated by cimetidine. This antagonism was not due to an interation between TRH and cimetidine at their central binding sites, since there was no displacement of [³H]MeTRH binding in the presence of cimetidine nor did TRH displace [³H]cimetidine in rat brain homogenates. Inability of diphenhydramine to modify the cardiovascular effects of TRH indicates that these effects are not due to histamine liberation, as cardiovascular stimulation after central administration of histamine is mainly mediated via H₁-receptors. The antagonism of the cardiovascular responses to TRH by cimetidine was not due to blockade of H₂-receptors, since another potent H₂-receptor antagonist ranitidine was unable to affect the cardiovascular effects of TRH. Therefore, we suggest that cimetidine exerted antagonism of TRH by some non-specific action.     

Pulmonary and hemodynamic effects of histamine in the pig. In vitro and in vivo studies

The purpose of this study was: (1) to investigate the distribution of H₁- and H₂- histaminergic receptors in the pulmonary artery and vein of the pig, and (2) to observe the hemodynamic and respiratory effects induced by 10 min of i.v. infusion of histamine in the anesthetized pig. D-chlorpheniramine and cimetidine were used as H₁- and H₂-receptor antagonists. Our results demonstrate a contractile response of the isolated pulmonary vein and artery (i.d. from 2.0 to 2.5 mm) which is mediated by H₁-receptors. The i.v. infusion of histamine was followed by an early significant increase of heart rate (HR) and mean pulmonary artery pressure. Subsequently a significant fall of cardiac output (CO) and dynamic pulmonary compliance were observed in association with hypoxia and hemoconcentration. After d-chlorpheniramine the infusion of histamine induced a marked pulmonary and systemic vasodilatation, hypotension and an increase in HR and CO. These effects could be dependent on a direct stimulation of H₂-receptors possibly present in the smallest pulmonary vessels. Most of the effects observed during the infusion of histamine alone persisted after cimetidine administration. Moreover an increase of the pulmonary dynamic compliance was observed during H₁-receptor stimulation. The combined blockade of H₁- and H₂-receptors prevented all the described effects.     

Histamine-induced excitation of spontaneously active medullary neurones in the rat brain is mediated by H2-receptors : A microiontophoretic study using H1 and H2-agonists and antagonists

The effects of histamine, applied by microiontophoresis onto spontaneously-active medullary neurones were investigated in the rat. Histamine caused current-dependent excitation of these neurones, an action that is at variance with previous studies in the cat. The nature of the receptor mediating these effects was examined using a number of agonists with differing potencies at peripheral H₁- and H₂-receptors. The precursor of histamine, l-histidine and the metabolite, N-telemethylhistamine did not mimic the effects of histamine while the H₂-agonist, 4-methylhistamine caused similar but weaker excitation. The extent of excitations produced by the H₁-agonists, 2-pyridylethylamine, 2-methylhistamine and 2-thiazolylethylamine could be related to their activity at H₂-receptors. Metiamide was ineffective in antagonising responses to histamine and related agonists as was mepyramine. The H₂-antagonist ranitidine, however, proved a good antagonist of responses to histamine and the H₁- and H₂-agonists, despite an unrelated excitatory action which may be linked to inhibition of cholinesterase. It is concluded that the excitatory effects of microiontophoretically-applied histamine and the agonists on medullary neurones in the rat is probably a result of activation of H₂-receptors.     

Pharmacological analysis of histamine receptors in musculature and vasculature of the dog trachea in situ.

1 The role of histamine H1- and H2-receptors in the musculature and vasculature of the dog trachea was investigated in the blood-perfused trachea in situ. 2 Histamine and acetylcholine caused increases in blood flow (tracheal, vasodilatation) and in intraluminal pressure (tracheal constriction) in a dose-dependent manner. Histamine was almost equipotent to acetylcholine in causing tracheal vasodilatation but was about 30 times less potent in causing tracheal constriction. 3 The histamine H2-receptor agonist, dimaprit, caused a dose-dependent increase in tracheal blood flow but failed to cause tracheal constriction. 4 The tracheal constriction produced by histamine was inhibited strongly by diphenhydramine but not modifed by metiamide. The tracheal vasodilatation produced by histamine was antagonized by both diphenhydramine and metiamide; diphenhydramine was more effective than metiamide. 5 It is concluded that in the tracheal musculature, histamine receptors are exclusively of the H1-type and mediate constriction, whereas in the tracheal vasculature, both histamine H1- and H2-receptors mediate vasodilatation but histamine H1-receptors are predominant.     

Further evidence for central histamine H2-receptor involvement in the hypotensive effect of clonidine in the rat

In urethane-anaesthetised rats, the administration of the specific histamine H₂-receptor antagonist metiamide intracerebroventricularly (i.c.v.) raised the blood pressure and increased the heart rate. Metiamide (i.c.v.) antagonised the hypotensive effect of clonidine (i.c.v.) in an apparently competitive manner. 4-Methylhistamine i.c.v. did not significantly change the blood pressure. The results are consistent with the concept that the hypotensive effect of clonidine is at least partly due to a stimulation of cerebral H₂-receptors. The existence of cerebral H₂-receptors mediating hypotensive effects is supported by the hypertensive effect of metiamide but not by the lack of hypotensive effects of 4-methylhistamine.     

The effects of histamine on responses of the rabbit ear artery to electrical stimulation and to exogenous noradrenaline

1 The effects of a subconstrictor dose of histamine (9 × 10^-7 mol/l) on the responses of the isolated perfused ear artery of the rabbit to electrical stimulation (E.S.) and to exogenous noradrenaline (NA) were investigated.

2 Both intraluminal (I/L) and extraluminal (E/L) histamine potentiated responses to E.S. and to I/L NA to the same extent.

3 Mepyramine alone (2.5 × 10^-6 mol/l) had no effect on the response of the ear artery to either stimulus, but in the presence of this concentration of mepyramine, the potentiation by histamine of the response to I/L NA was significantly decreased and that to E.S. was replaced by inhibition.

4 The H₁-receptor agonist, 2(2-pyridyl) ethylamine, applied I/L potentiated responses to I/L NA at both concentrations used (5.1 and 51 × 10^-7 mol/l), but only potentiated the effects of E.S. at the higher concentration.

5 The H₂-receptor antagonist, metiamide (4 × 10^-6 mol/l), alone did not alter the extent of potentiation of responses to either E.S. or I/L NA by histamine. This suggests relatively weak H₂-receptor activity in the rabbit ear artery. In the presence, but not the absence of metiamide, the potentiation by histamine of the I/L NA response was reversible, an observation suggesting an interaction between metiamide and the non-reversible component of the potentiating effect of histamine.

6 These results are interpreted in terms of postsynaptic H₁-receptors which potentiate and presynaptic H₂-receptors which inhibit contractile responses in the ear artery.

     

HISTAMINE ENHANCES HYPOXIA-INDUCED VENTRICULAR ARRHYTHMIAS IN ISOLATED RAT HEARTS

1. The effects of hypoxia, histamine-receptor agonist perfusion, and their combination on cardiac rhythm were studied in isolated rat hearts. 2. While hypoxia induced a high incidence of ventricular tachycardia or fibrillation, only a few preparations developed ventricular arrhythmias in response to perfusion with high concentration of histamine, 2-pyridylethylamine or impromidine. 3. The times of onset of hypoxia-induced ventricular arrhythmias were significantly shortened by perfusion with either histamine, 2-pyridylethylamine or impromidine. The accelerated occurrence of hypoxia-induced ventricular arrhythmias by histamine was significantly abolished by pretreatment with either diphenhydramine or cimetidine. 4. The results indicate that hypoxia and histamine can increase ventricular vulnerability of the rat heart to each other. It is also suggested that the arrhythmogenic actions of histamine in hypoxic rat hearts are mediated by both histamine H1-and H2-receptors.     

Mechanism of action of histamine in the estrogen-primed rat uterus

Histamine produced a dose-dependent relaxation of uterine strips obtained from the estrogen-primed rat uterus. The responses to histamine were blocked competitively by metiamide (10^?8 ?10^?8M), a specific H₂-receptor antagonist. Propranolol, a selective β-receptor blocker also produced competitive antagonism of the responses to histamine in the same dose range (10^?8?10^?6 M). The pA₂ value obtained for metiamide (8.9) was not significantly different from that obtained for propranolol (8.6). Nialamide (2.2 × 10^?6 M), the monoamine oxidase inhibitor, and cocaine (4.3 × 10^?6 M), the selective noradrenaline uptake blocker, potentiated the responses to histamine. However bretylium (2.4 × 10^?5 M), an adrenergic neuron blocker inhibited the responses to histamine. The combined effect of tyramine and histamine was found to be additive. Our data suggest that the histamine-induced relaxation of rat uterus may be produced through the stimulation of presynaptic H₂-receptors which causes the release of noradrenaline. The released noradrenaline acts on the postsynaptic β-receptors and produces relaxation of the rat uterus.     

Histamine H1- and H2-receptors in the mesenteric vascular bed of the pig

In order to study whether both histamine H₁- and H₂-receptors are present in the pig mesenteric vascular bed, natural histamine, 2-(2-pyridyl) ethylamine and 4-methylhistamine, as well as mepyramine and metiamide, were infused directly into the superior mesenteric artery. The results indicate that histamine H₁- and H₂-receptors, both inducing vasodilation, are present in the mesenteric circulation of the pig. Jejunal motility proved to be influenced by H₁-receptor stimulation only.     

Histamine receptors in the heart—Molecular characteristics,physiology and pharmacology

Histamine is a normal constituent of mammalian heart. It affects cardiac function mainly through stimulating histamine H1- and H2-receptor subtypes. The simultaneous activation of H1- and H2-receptors in the heart results in: a positive inotropic and chronotropic effect, a negative dromotropic effect, increased automaticity and increased coronary blood flow. H1- and H2-receptors have already been cloned from different, but not yet from cardiac, tissue. They are two independent molecular entities differing in the length of their amino acid sequence, pathways of transmembrane and intracellular signalling, characteristics of their binding sites and selectivity for the specific agonists and/or antagonists. Our results of radioligand binding studies show the presence in the heart of a high-affinity (K _D 0.4 nmol/L andB _max 100 fmol/mg of protein) and a low-affinity (K _D 4.5 nmol/L,B _max 466 fmol/mg of protein) H1-receptor-binding site and only a single population of less-abundant high-affinity H2-receptor binding sites (K _D 1.0 nmol/L andB _max 27 fmol/mg of protein). The role of the histamine in cardiac pathophysiology is well established but the physiological role is unclear. The only proposed physiological role of histamine in the heart is the modulation of noradrenaline release from sympathetic nerve terminals, where H3-receptor subtypes might be involved.     

Cardiovascular studies with impromidine (SK&F 92676), a new very potent and specific histamine H2-receptor agonist

Impromidine (SK & F 92676) has recently been identified as a potent and specific histamine H₂-receptor agonist. The present paper describes some cardiovascular studies with the drug. Impromidine lowers blood pressure in cats and rats by interaction with H₂-receptors. During continuous intravenous infusions of impromidine, the fall in blood pressure is due to a reduction in total peripheral resistance; cardiac output increases during hypotension. The responses to impromidine are similar to responses to histamine in mepyramine-treated cats. Impromidine administered intra-arterially also causes vasodilatation in the femoral and mesenteric vasculature by interaction with H₂-receptors. Impromidine stimulates all measured parameters including coronary flow in the isolated working heart of the guinea-pig. Dose-response curves to impromidine were displaced to the right in the presence of cimetidine.     

Histamine H1- and H2-receptors in the gastric vasculature of the rabbit

The histamine receptors in the rabbit blood perfused gastric vasculature were analysed pharmacologically. Histamine elicited a monophasic increase in perfusion pressure which was antagonized by mepyramine and enhanced by metiamide. The maximum observed response was enhanced by metiamide to that produce by a specific H₁-receptor agonist. It is concluded that the gastric vasculature responds to histamine with an H₁-receptor mediated vasoconstriction and an H₂-receptor mediated dilation. In this preparation the H₁-effect predominates in response to injection of histamine.