Histamine receptors in the cat mesenteric circulation

Summary The distribution of histamine receptors was studied in the isolated perfused vascular bed of the cat terminal ileum. The results indicated that the depressor effect of histamine is mediated through the stimulation of metiamidesensitive H₂-receptors, while the pressor effect of the amine is mediated by the stimulation of mepyramine-sensitive H₁-receptors.The authors are indebted to Dr.W. A. M. Duncan, Research Institute, Smith Kline and French Laboratories, Welwyn Garden City, Hertfordshire, England, for his generous gift of metiamide. This work is supported in part by Eczacibasi Research Found. Levent, Istanbul, Turkey.     

Feeding induced by blockade of histamine H1-receptor in rat brain

Histamine antagonists were infused into the third ventricle of the cerebrum in rats. All the H1-, but none of the H2-antagonists tested, induced initial feeding during the early portion of the light phase when histamine level was highest. No periprandial drinking was observed. Ambulation increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early portion of the dark phase, or was decreased by alpha-fluoromethylhistidine. Hypothalamic neuronal histamine may suppress food intake through H1-receptors, and diurnal fluctuations of food intake may mirror neuronal histamine levels.     

Effect of dimethindene, an antihistaminic drug, on the transmembrane potentials of mammalian myocardium

Dimethindene (DMI) decreased the maximum rate of rise of action potential (AP) without changing the resting potential in cat ventricular myocardium. DMI abolished the histamine-induced slow APs in left atria but not in right ventricular papillary muscles of guinea-pig, suggesting that DMI blocked the histamine H1-receptors.     

Histamine binding to H2 receptors stimulates phospholipid methylation in mast cells

Summary Rat peritoneal mast cells incubated in vitro in the presence of L-[methyl-³H] methionine and exposed to histamine undergo a rapid but transient increase in phospholipid methylation. By using specific H₁- and H₂-receptor antagonists, and histamine analogues differing in their H₂-receptor agonist potency, it has been demonstrated that this metabolic event is dependent on histamine binding to H₂-receptors.We are grateful to Smith Kline and French Laboratories for the generous gift of histamine analogues.     

Relaxation of isolated rabbit veins mediated by latent histamine H2-receptors

Summary Isolated rabbit veins preconstricted by either norepinephrine, methoxamine or potassium were relaxed by histamine in the presence of mepyramine, a histamine H₁-antagonist. The relaxation was not antagonized by atropine, propranolol and indomethacin but by an H₂-antagonist cimetidine. It is likely that histamine relaxes the rabbit veins through H₂-receptors.     

Feeding induced by blockade of histamine H1-receptor in rat brain

Summary Histamine antagonists were infused into the third ventricle of the cerebrum in rats. All the H₁-, but none of the H₂-antagonists tested, induced initial feeding during the early portion of the light phase when histamine level was highest. No periprandial drinking was observed. Ambulation increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early portion of the dark phase, or was decreased by -fluoromethylhistidine. Hypothalamic neuronal histamine may suppress food intake through H₁-receptors, and diurnal fluctuations of food intake may mirror neuronal histamine levels.     

Pentagastrin activation of adenylate cyclase in human gastric biopsy specimens.

Adenylate cyclase activity of human fundic mucosa is log-normally distributed and equally stimulated by pentagastrin and histamine. Cimetidine inhibits the histamine, but not the pentagastrin effect, which is even intensified by H2-receptor blockade. The results indicate that pentagastrin and histamine activate adenylate cyclase via distinct receptors.     

Nitroglycerin inhibits the phosphorylation of intermediate filament proteins rather than myosin light chain on porcine coronary artery sustained contraction

The smooth muscle relaxation induced by nitroglycerin is hypothesized to be mediated by an increase in the cytoplasmic concentration of guanosine 3′,5′-monophosphate (cGMP) and subsequent dephosphorylation of the 20-kilodalton myosin light chain (MLC). We investigated this hypothesis in procine coronary arterial smooth muscle stimulated with histamine (3 μM) or K⁺ (30 mM). Stimulation of [³²P]Pi-labeled muscle with histamine or K⁺ for 2 min resulted in a four- or 6.2-fold increase, respectively, in the incorporation of³²P into MLC. After 48 min of exposure to histamine. MLC phosphorylation decreased to the basal level and the phosphorylation of desmin, synemin, and of three unidentified cytosolic proteins was increased. K⁺ stimulation resulted in a sustained increase of MLC phosphorylation but had no effect on the phosphorylation of desmin, synemin, or the three unidentified cytosolic proteins. Application of nitroglycerin (1 μM) 48 min after histamine stimulation inhibited the phosphorylation of desmin, synemin, and the three cytosolic proteins. The sustained phase of histamine-induced contraction was also inhibited to a greater extent then the acute phase of histamine-induced contraction and both the acute and sustained phases of K⁺-induced contraction. These results suggest that MLC phosphorylation is required for both phases of K⁺-induced contraction, whereas phosphorylation of intermediate filament proteins is required for the sustained phase of histamine-induced contraction. Intermediate filament proteins, rather than MLC, may also be the target for the relaxant action of nitroglycerin during histamine-induced sustained contraction.     

Occurrence of inhibitory histamine H2-receptors in isolated pulmonary blood vessels of dogs and rats

Summary Isolated, helically cut strips of pulmonary arteries and veins of dogs, and pulmonary arteries of rats, precontracted with norepinephrine or 5-HT exhibited potent concentration-dependent relaxations to impromidine and dimaprit (histamine H₂-agonists). The occurrence of inhibitory histamine H₂-receptors in the pulmonary vasculature could play a modulatory role in hypoxic pulmonary vasoconstriction.Supported by research grants NHLBI-18002, NHLBI-18015 and DA-02339 from the USPHS. We are grateful to Dr D.D.A. Owen of Smith, Kline & French Ltd, England for the generous supply of dimaprit and impromidine. Requests for reprints should be addressed to B.M. Altura.     

Influences of temperature change on the relaxation and amplitude inhibition by noradrenaline in the rabbit jejunum

Summary In the rabbit jejunum, the elevation of temperature within the range of 25–37°C diminished the sensitivity to noradrenaline (NA) for both the relaxation and amplitude inhibition. The relaxation by NA was mainly mediated via adrenergic -receptors at 25, 30 or 37°C. The amplitude inhibition was mediated via -receptors at 37°C, and both - and -receptors at 30 or 25°C.     

Stimulation of H+ ion secretion from the isolated mouse stomach by sodium fluoride

Summary The effect of sodium fluoride on H⁺ ion secretion was investigated in the isolated distended mouse stomach. It was found that sodium fluoride on its own caused dose-related stimulation of H⁺ ion secretion. Sodium fluoride did not inhibit H⁺ ion secretion induced by histamine. The possible mechanisms involved are discussed. It is considered that sodium fluoride might stimulate H⁺ ion secretion by causing histamine release and by increasing cyclic AMP formation in the intact gastric mucosa.     

Blood histamine and response of spleen cells to phytohemagglutinins during moderate magnesium deficiency in the rat]

Blood histamine and spleen cell stimulation index by PHA were determined in either magnesium deficient or control Rats. Between the 10th and 17th days of diet (hyperemia and dermatosis period), histaminemia was significantly higher in deficient animals (485 ng/ml) than in control ones (112 ng/ml), but at the 32nd day it came back to normal values. The mean spleen cell stimulation index by PHA was depressed in deficient animals mainly between the 10th and 17th day of the deficiency; 33% of control mean value. A negative correlation is found between histamine level and stimulation index.     

Modification of the action of pentagastrin on acid secretion by botulinum toxin.

I.v botulinum toxin after 60-90 min abolished the dose-response relationship between pentagastrin and gastric acid secretion in anesthetized rats and guinea-pigs. The toxin reduced but did not abolish the acid stimulatory effect of histamine. As expected, the acid response to vagal stimulation was abolished and that to methacholine in rats was unaltered by the toxin.     

Histamine-induced hypotension modified by H1 and H2 antagonists in the monkey (Macaca mulatta).

Blocking H2 receptors with burimamide in the dose used (20 mg/kg) approximately doubles the amount of histamine needed to produce the same effect as seen when H1 antagonists (chlorpheniramine or mepyramine) are used alone. The Kz ratios for chlorpheniramine-chlorpheniramine plus burimamide are 117-204 and for mepyramine-mepyramine phus burimamide are 200-478. H1 and H2 receptors, in the monkey, when stimulated, both cause cardiovascular responses in the same direction.     

Differential vascular effects of neuropeptide Y(NPY) selective receptor agonists

Neuropeptide Y (NPY) increases blood pressure either directly or indirectly by potentiating the effect of various vasoconstrictors. Only one (the Y₁-receptor) of two subtypes of receptors (Y₁ and Y₂) is thought to mediate the vascular smooth muscle contraction. To test this hypothesis we challenged isolated rat mesenteric arteries that had a functional endothelium with (1–36) NPY and with specific Y₁-receptor ([Leu³¹, Pro³⁴] NPY) and Y₂-receptor ([Ahx^5–24, -Glu²--Lys³⁰] NPY) agonists. The Y₁-receptor agonist elicited a contractile response similar to that of NPY, whereas the Y₂-receptor agonist had no effect on wall tension. We also found that the presence of a functional endothelium has no influence on the contractile response to NPY. From these data we conclude that the direct contractile effect of NPY in the mesenteric artery is mediated by stimulation of Y₁-receptors and is not endothelium-dependent.     

Effect of stimulation of vagus nerves on gastric tissue histamine concentration in albino rats.

2 different time schedules were applied in order to stimulate vagus nerves around the oesophagus at the region of the cardio-oesophageal junction. The result shows a significant reduction in gastric tissue histamine concentration following vagal stimulation, the reduction being more when the duration of stimulation was longer.     

Histamine receptor-mediated signaling during development and brain function in adulthood

Histamine might have an important role in brain development. However, most studies have focused on short-term effects of histamine receptor-mediated signaling on brain function in adulthood. Little is known about the potential long-term effects of histamine receptor-mediated signaling during development on brain function in adulthood. We hypothesize that increased postsynaptic histamine receptor-mediated signaling during development has detrimental effects on brain function in adulthood. Our data support this hypothesis. In the developing mouse brain, histamine H3 receptor blockade, which increases histamine release, has detrimental sex-dependent effects on object recognition, spatial learning in the water maze, and pre-pulse inhibition in adulthood. Our data also support the hypothesis that histamine mediates the detrimental long-term sex-dependent effects of methamphetamine exposure early in life on these brain functions in adulthood. Therefore, increased efforts are warranted to carefully evaluate the effects of drugs that directly or indirectly affect histamine receptor-mediated signaling during development on cognitive function later in life.     

A negative inotropic effect of acetylcholine in the presence of several phosphodiesterase inhibitors

The phosphodiesterase inhibitors papaverine, theophylline and 3-isobutyl-1-methylxanthine (IBMX) reveal a negative inotropic effect of acetylcholine in cat ventricular heart muscle. This effect in unrelated to beta-adrenoceptor stimulation and possibly mediated by the accumulation of cyclic GMP.     

The effects of dopamine on renin release in the isolated perfused rat kidney

Summary In the isolated and perfused kidney of the rat, the stimulant effect of dopamine on renin release is blocked by propanolol and not by haloperidol. This suggests that the release of renin induced by dopamine is due to the activation of \-receptors.     

Nitric oxide mediates histamine induced down-regulation of H<Subscript>2</Subscript> receptor mRNA and internalization of the receptor protein (R1)

During agonist-dependent long-term stimulation of cells, histamine receptor subtypes are frequently down-regulated. However, the mechanisms underlying the modulation of receptor expression during long-term histamine stimulation have yet to be resolved. Based on our recently reported results showing an H₁-mediated down-regulation of histamine H₂ receptor mRNA in endothelial cells, our aim was to characterize the mechanism controlling rapid and long-term histamine-mediated modulation of H₂ receptor expression in more detail. We were able to show that the histamine-induced down-regulation of H₂ receptor mRNA and cell surface expression lasting for 24 h was accompanied by augmentation of the receptor protein level in the cytoplasmatic fraction of endothelial cells for this time period. Furthermore, changes in receptor protein levels in whole-cell lysate were negligible, indicating that the rapid and prolonged modulation of cell surface H₂ receptor levels by histamine was regulated solely via internalization. The role of nitric oxide (NO) as a key mediator in histamine-stimulated cell responses was underlined by subsequent studies showing the attenuation of histamine-induced H₂ receptor mRNA down-regulation and protein trafficking following NO synthase isozyme inhibition.Received 11 March 2003; received after revision 11 June 2003; accepted 17 June 2003