Selectivity of 4-methylhistamine at H1- and H2-receptors in the guinea-pig isolated ileum

The selectivity of 4-methylhistamine (4-MH) as an agonist at histamine H1- and H2-receptors has been evaluated in the guinea-pig isolated ileum. The EC50 values of 4-MH on H1- and H2-receptors that mediate contractile responses were determined. The EC50 at H1-receptors was estimated after selective blockade of H2-receptors by tiotidine and the EC50 at H2-receptors estimated after selective blockade of H1-receptors by mepyramine. The -log EC50 values at H1- and at H2-receptors were 4.57 and 5.23, respectively. The dissociation constants for the interaction of 4-MH with H1- and H2-receptors were determined. The -log KD values at H1- and H2-receptors were 3.55 and 4.27, respectively. These results suggest that 4-MH is only about 5 times as potent at H2- as it is at H1-receptors in the guinea-pig ileum and that 4-MH should be used with caution to discriminate between H1- and H2-receptors.     

Characterization of histamine H3-receptors in guinea-pig ileum with H3-selective ligands.

1. The effect of the selective histamine H3-receptor agonist R-(alpha)-methylhistamine has been investigated on the contractile responses of the longitudinal smooth muscle of guinea-pig ileum elicited by electrical field stimulation of acetylcholine release from myenteric nerve endings. 2. R-(alpha)-methylhistamine produced a concentration-dependent (EC50 = 1.4 +/- 0.2 x 10(-8) M) inhibition of the response to electrical field stimulation which was insensitive to inhibition by mepyramine (1 microM) and tiotidine (2.4 microM). 3. This response to R-(alpha)-methylhistamine could be inhibited in a competitive fashion by a range of H3-receptor antagonists including thioperamide (KB = 1.1 nM), impromidine (KB = 65 nM), norburimamide (KB = 380 nM) and SKF 91486 (KB = 34 nM). Burimamide was also a potent inhibitor of this response but the Schild slope obtained (1.3) was significantly greater than unity. 4. The estimated KB values were all within a factor of three of those values reported for the histamine H3-receptor mediating inhibition of histamine release in rat cerebral cortex. 5. These data suggest that the histamine receptor mediating inhibition of cholinergic neurotransmission by R-(alpha)-methylhistamine in guinea-pig ileum is the same as the H3-receptor present in rat cerebral cortex.     

Evidence that histamine homologues discriminate between H3-receptors in guinea-pig cerebral cortex and ileum longitudinal muscle myenteric plexus.

1. The binding of the selective histamine H3-receptor agonist ([3H]-R-alpha-methylhistamine) to sites in guinea-pig cerebral cortex and ileum longitudinal muscle myenteric plexus has been characterized and a comparison made of the apparent affinities of a series of H3-receptor ligands. 2. Saturation analysis suggested that [3H]-R-alpha-methylhistamine labelled a homogeneous population of histamine H3-receptors in guinea-pig cerebral cortex (pKD=9.91+/-0. 07; nH=1.07+/-0.03; n=5) and ileum longitudinal muscle myenteric plexus (pKD=9.75+/-0.21; nH=0.97+/-0.02; n=5). There was no significant difference in the estimated affinity of [3H]-R-alpha-methylhistamine in the two tissues. The cerebral cortex had a significantly higher receptor density (3.91+/-0.37 fmol mg-1 tissue) than the ileum longitudinal muscle myenteric plexus (0. 39+/-0.11 fmol mg-1). 3. Overall, the apparent affinities of compounds, classified as H3-receptor ligands, in cerebral cortex and ileum longitudinal muscle myenteric plexus were well correlated (r=0. 91, P<0.0001) and consistent with the cerebral cortex and ileum longitudinal muscle myenteric plexus expressing histamine H3-receptor population(s) that are pharmacologically indistinguishable by the majority of histamine H3-receptor ligands. However, it was evident that the homologues of histamine within this group of compounds could discriminate between the receptor populations in the two tissues. Thus, the estimated affinity of five imidazole unbranched alkylamines (histamine, homohistamine, VUF4701, VUF4732 and impentamine) were significantly higher in the guinea-pig cerebral cortex than in the ileum longitudinal muscle myenteric plexus assay.     

The role of histamine H1- and H2-receptors in the generation of thromboxane A2 in perfused guinea-pig lungs.

1. When isolated perfused lungs from normal and ovalbumin sensitized guinea-pigs were challenged with histamine and 2-methylhistamine (agonists for H1-receptor), a release of thromboxane A2-like substance was observed. The effect of histamine on production of thromboxane A2 (TXA2) in sensitized lungs, was more pronounced than in normal lungs (P less than 0.01). 2. Specific activation of histamine H2-receptors in normal lungs with large doses (100 micrograms) of dimaprit and 4-methylhistamine, does not produce thromboxane-like or prostaglandin-like substances. 3. Perfusion of the lungs with pyrilamine (10 micrograms/ml) inhibited the release of arachidonate metabolites induced by histamine H1-receptor stimulation, whereas cimetidine (5 micrograms/ml) was ineffective. 4. It is concluded that only the stimulation of histamine H1-receptors appears to be responsible for generation of thromboxane A2 and other prostaglandin-like substances in normal guinea-pig lungs. In sensitized lungs, an increased ability of histamine to release TXA2 could be due to a possible interconversion of H2 into H1-receptors.     

Evidence for both histamine H1- and H2-receptors in the gastric vasculature of the cat

1 Experiments have been done to study the gastric vascular response to histamine given intra-arterially in the cat.2 In experiments utilising pump perfusion of the stomach at constant flow rates, rapid intra-arterial injections of histamine elicited dose-dependent vasodilatation. The dose-response curve to histamine was displaced to the right by mepyramine and further to the right by mepyramine plus cimetidine. Cimetidine alone did not displace the histamine dose-response curve. This interaction between histamine and histamine antagonists is very similar to the interaction observed in other vascular beds.3 Intra-arterial infusions of histamine also caused vasodilatation with increased gastric blood flow, measured with an electromagnetic flow probe. Mepyramine reduced the immediate increase in blood flow during each infusion, although responses in the later stages of the infusions were unaltered. Cimetidine had no effect on the immediate response but reduced sustained responses to histamine. Treatment with mepyramine and cimetidine was required to abolish histamine responses.4 Infusions of 2-(2-aminoethyl) pyridine and dimaprit also increased gastric blood flow.5 These results indicate the involvement of both H(1)- and H(2)-receptors in histamine-induced gastric vasodilatation. There appears to be a time-base in the interaction between histamine and vascular histamine receptors; H(1)-receptor responses preceding H(2)-receptor responses.     

Regional variation in the sensitivity of longitudinal smooth muscle to histamine at H1-receptors in guinea-pig ileum and colon.

The sensitivity of the distal ileum, proximal colon, medial colon, and distal colon of the guinea-pig to histamine has been evaluated. The rank order of sensitivity was ileum greater than medial colon greater than proximal colon approximately equal to distal colon. The mean -logEC50 values at receptors in the ileum, medial, proximal, and distal colon were 6.74, 6.18, 5.79, and 5.72, respectively. The apparent dissociation constant for the interaction of histamine with receptors in the various regions was determined. The -log Kd values at receptors in the ileum, proximal colon, medial colon, and distal colon were 4.68, 4.65, 4.62, and 4.44, respectively. The mean apparent -log Kd values for the antagonism of histamine by mepyramine were 9.0, 9.0, 9.1, and 8.9 for receptors on the ileum, proximal, medial, and distal colon, respectively. The results of these experiments provide no evidence that histamine receptors in the colon are distinguishable from H1-receptors as characterized on the ileum. The differences in sensitivity to histamine in the various regions of the intestine may be due to differences in the density of H1-receptors.     

Involvement of histamine H1- and H2-receptors in induced asthmas in dogs.

Participation of histamine H1- and H2-receptors in both asthmas, i.e. experimentally induced bronchoconstriction and bronchosecretion, with ascaris suum and histamine in anesthetized dogs was investigated. Dogs given 0.2% histamine solution or ascaris antigen (3 mg protein) by inhalation showed increases in respiratory resistance (Rrs) and respiratory rate to 2.5-5.0 fold. Airway secretion volume was also significantly increased 3-4 fold. The increase in Rrs by histamine inhalation was effectively inhibited or abolished by a histamine H1-receptor antagonist, chlorpheniramine (0.3-1 mg/kg i.v.), but not by a H2-receptor antagonist, cimetidine (1-3 mg/kg i.v.). The increase in Rrs by antigen inhalation was reduced by relatively high doses of chlorpheniramine (1-3 mg/kg i.v.), and not by cimetidine. In contrast, hypersecretion of tracheobronchial fluid in both asthmas was significantly prevented by either chlorpheniramine or cimetidine. Combinations of both antagonists abolished the hypersecretion. Atropine (2 mg/kg i.v.) significantly inhibited the occurrence of responses in both asthmas. The results suggest that histamine is involved in the allergic asthma produced by ascaris suum and that histamine directly evokes airway constriction through H1-receptors and hypersecretion of tracheobronchial fluid through H1- and H2-receptors, and, in part, indirectly activates the cholinergic pathway.     

Cardiovascular effects of histamine mediated by H1- and H2-receptors

Histamine was found to suppress the myocardial contractile function, to decrease systemic arterial blood pressure and to exert a positive chronotropic effect in unanesthetized dogs. A preliminary blockade of H1-receptors prevented the hypotensive effect of histamine, blockade of H2-receptors prevented the development of the positive chronotropic effect.     

Differentiation of the roles of histamine H1- and H2-receptors in the mediation of the effects of histamine in the isolated working heart of the guinea-pig.

1 Differentiation of the roles of histamine H1- and H2-receptors in the mediation of the effects of histamine on the isolated working heart of the guinea-pig was achieved through the use of histamine and selective histamine receptor agonists and antagonists. 2 Histamine over the dose range 10(-9) mol to 10(-6) mol produced dose-related increases in sinus rate, left intraventricular pressure (LVP)max, LVdP/dtmax, coronary flow, aortic flow, total cardiac output and external pressure-volume work. 3 Dimaprit, a selective histamine H2-receptor agonist, produced very similar responses to histamine. 4 2-Pyridylethylamine, a selective histamine H1-receptor agonist, had little effect on cardiac function unless large doses were administered. Such doses produced increases in all measured parameters. 5 Cimetidine, a selective histamine H2-receptor antagonist, antagonized the effects of histamine and dimaprit and some but not all effects of 2-pyridylethylamine. In the presence of cimetidine a decrease in all parameters with the exception of sinus rate was observed with both histamine and 2-pyridylethylamine. 6 The selective histamine H1-receptor antagonist, mepyramine, had little effect on responses to all three agonists. However, the depressant effects observed with histamine and 2-pyridylethylamine in the presence of cimetidine were antagonized by mepyramine. 7 The results indicate the important role of the histamine H2-receptor in the mediation of the gross cardiac effects of histamine and also indicate that histamine H1-receptors can mediate cardiac depression.     

Pressor response mediated via histamine H1-receptors of the guinea-pig sympathetic ganglia

In pithed guinea-pigs, the general characteristics and origin of the pressor response to intravenous injection of histamine were examined. Histamine (5–80 μg/kg) produced a rapid, short-lasting, constant, prominent and dose-dependent pressor response, followed by a secondary slight and prolonged depressor response. The vascular response to histamine was accompanied by a marked tachycardia. The pressor effect of histamine (30 μg/kg) was strongly reduced or abolished in animals pretreated with nicotine, reserpine, bretylium or 6-hydroxydopamine. Furthermore, pyralamine, a histamine H₁-receptor antagonist, antagonized in a dose-dependent manner the pressor response to histamine. On the contrary, metiamide, a histamine H₂-receptor antagonist, as well as hexamethonium and atropine, cholinergic antagonists, did not suppress the pressor effect of histamine. The present experiments provide evidence that in guinea-pigs, the pressor component of the vascular response to histamine results predominantly from the activation of histamine H₁-receptors in the sympathetic ganglia with consequent release of noradrenaline at postganglionic sympathetic nerve terminals.     

Evaluation of the role of Histamine H1- and H2-receptors in cutaneous inflammation in the guinea-pig produced by histamine and mast cell degranulation.

1 The role of histamine H1- and H2-receptors in mediating the cutaneous inflammatory response produced by exogenous histamine and the release of endogenous histamine from mast cells has been investigated by a method which permits simultaneous, quantitative measurement of vasodilatation, vascular permeability and oedema formation. 2 Histamine and the selective H1-receptor agonist, 2-(2-aminoethyl) pyridine, both produced vasodilatation, increased vascular permeability and oedema formation whereas the selective H2-receptor agonist, dimaprit, produced only vasodilatation. 3 Mepyramine and cimetidine both reduced the vasodilatation response to histamine, the combination of antagonists being superior to either antagonist alone. Mepyramine (but not cimetidine) virtually abolished extravascular albumin accumulation and oedema formation. 4 Mepyramine and cimetidine both reduced the vasodilatation response produced by active cutaneous anaphylaxis and compound 48/80. However, mepyramine was less effective in reducing the vascular permeability response to mast cell degranulation than to histamine. 5 In conclusion, the vasodilator response to histamine is mediated by both H1- and H2-receptors; the permeability response to histamine is mediated solely by H1-receptors. A combination of H1- and H2-receptor antagonists appears to be more effective than either antagonist alone in reducing cutaneous inflammatory reactions involving histamine.     

The role of central histamine H1- and H2-receptors in hypothermia induced by histamine in the rat

Histamine administered intraventricularly or into the anterior hypothalamic preoptic region induced dose-dependent hypothermia in rats with chronic i.c.v. cannula. This hypothermia was almost totally abolished by both the histamine H1- and H2-receptor antagonists, mepyramine or chloropyramine and metiamide or cimetidine, respectively, give i.c.v. prior to histamine. In behavioural thermoregulation studies histamine considerably diminished the mean duration of dwelling of the rat under the heat lamp. This effect was abolished by histamine H1- but not by H2-receptor antagonists. It is concluded that histamine induces hypothermia by lowering the set point of the hypothalamic thermostat by means of H1-receptors. Histamine H2-receptor blockers antagonized the increase in tail skin temperature after histamine administration, suggesting that h2-receptors are involved in a heat loss mechanism.