An indirect sympathomimetic effect of burimamide on kitten isolated atria. (1/24)

1. Burimamide (34-1080 muM) caused a concentration-dependent increase in the force and frequency of contraction of kitten isolated atria. 2. Metiamide (467 muM) had no stimulant action on kitten atria and did not modify the effects of burimamide. 3. The atrial stimulation produced by burimamide was reduced by (-)propranolol (34-68 nM) and by cocaine (3 muM). 4. The atrial stimulant effect of burimamide was prevented by pretreatment of kittens with reserpine (1 mg/kg, 24 h before the experiment). 5. It is concluded that burimamide causes atrial stimulation by releasing catecholamines.  (+info)

Constitutive activity of histamine h(3) receptors stably expressed in SK-N-MC cells: display of agonism and inverse agonism by H(3) antagonists. (2/24)

Agonist-independent activity of G-protein-coupled receptor, also referred to as constitutive activity, is a well-documented phenomenon and has been reported recently for both the histamine H(1) and H(2) receptors. Using SK-N-MC cell lines stably expressing the human and rat H(3) receptors at physiological receptor densities (500-600 fmol/mg of protein), we show that both the rat and human H(3) receptors show a high degree of constitutive activity. The forskolin-mediated cAMP production in SK-N-MC cells is inhibited strongly upon expression of the G(i)-coupled H(3) receptor. The cAMP production can be further inhibited upon agonist stimulation of the H(3) receptor and can be enhanced by a variety of H(3) antagonists acting as inverse agonists at the H(3) receptor. Thioperamide, clobenpropit, and iodophenpropit raise the cAMP levels in SK-N-MC cells with potencies that match their receptor binding affinities. Surprisingly, impentamine and burimamide act as effective H(3) agonists. Modification of the amine group of impentamine dramatically affected the pharmacological activity of the ligand. Receptor affinity was reduced slightly for most impentamine analogs, but the functional activity of the ligands varied from agonist to neutral antagonist and inverse agonist, indicating that subtle changes in the chemical structures of impentamine analogs have major impact on the (de)activation steps of the H(3) receptor. In conclusion, upon stable expression of the rat and human H(3) receptor in SK-N-MC cells constitutive receptor activity is detected. In this experimental system, H(3) receptors ligands, previously identified as H(3) antagonists, cover the whole spectrum of pharmacological activities, ranging from full inverse agonists to agonists.  (+info)

The role of H1 and H2-receptors in the coronary vascular response to histamine of isolated perfused hearts of guinea-pigs and rabbits. (3/24)

1. The effects of histamine on the isolated perfused hearts of guinea-pigs and rabbits were examined. Records of contractile force, heart rate and coronary perfusion pressure were obtained. 2. Histamine exerted positive inotropic and chronotropic effects which were antagonized by burimamide and attributed to stimulation of H2-receptors. 3. The coronary vascular response to histamine differed between guinea-pigs and rabbits. In guinea-pig hearts, three phases were apparent: (a) An initial vasodilatation preceding any effects on heart force and rate was antagonized by mepyramine and therefore mediated by histamine H1-receptors in the coronary circulation. (b) A secondary vasoconstriction was attributed to the increased myocardial compression during the positive inotropic and chronotropic responses. (c) The final, more predominant, component was a prolonged vasodilatation probably associated with the increased metabolic activity of the heart. 4. The latter two components were abolished together with the myocardial responses by burimamide. The remaining coronary vascular response was biphasic, consisting of a vasodilatation immediately followed by vasoconstriction. Both were antagonized by mepyramine and therefore mediated by H1-receptors. 5. The coronary vascular response of rabbit hearts was similar but no direct vasodilatation was observed and it was concluded that histamine receptors in the coronary vasculature involve only vasoconstriction.  (+info)

Inhibition of sympathetic hypertensive responses in the guinea-pig by prejunctional histamine H3-receptors. (4/24)

1. The effect of (R)-alpha-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 microA) produced intensity-dependent increases in blood pressure and a more variable tachycardia. 2. (R)-alpha-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-alpha-methylhistamine was dose-dependent (10-300 micrograms kg-1, i.v.) and was not seen at high intensities of stimulation. 3. (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not attenuate the pressor response to adrenaline (1 and 3 micrograms kg-1, i.v.), indicating that the effect of (R)-alpha-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4. The inhibition of CNS-induced hypertension by (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-1, i.v.), impromidine (ID50 = 0.22 mg kg-1, i.v.) and burimamide (ID50 = 6 mg kg-1, i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 micrograms kg-1, i.v.) and cimetidine (3 mg kg-1, i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-alpha-methylhistamine. 5. These results suggest that (R)-alpha-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals. Furthermore, on the basis of the rank order potency to different H3-antagonists, it appears that the H3B-receptor subtype is involved with H3-receptor responses on vascular sympathetic nerves.  (+info)

Effects of the histamine H2-receptor blocking drugs burimamide and cimetidine on noradrenergic transmission in the isolated aorta of the rabbit and atria of the guinea-pig. (5/24)

1 In rabbit aortic strips, concentration-response curves to noradrenaline (NA) were shifted to the right in a parallel and concentration-dependent manner by the alpha-adrenoceptor blocking drug, phentolamine and also by the histamine H(2)-receptor blocking drugs, burimamide and cimetidine. Responses to 5-hydroxytryptamine were not affected by these drugs.2 Burimamide had the properties of a competitive antagonist of noradrenaline, possessing about one-hundredth the potency of phentolamine. Cimetidine was weaker than burimamide and did not fulfil the requirements for competitive antagonism of noradrenaline.3 In guinea-pig isolated atria, in which noradrenergic transmitter stores were labelled with [(3)H]-noradrenaline, phentolamine (3 muM), burimamide (30 muM) and cimetidine (30 muM), in decreasing order of effectiveness, each enhanced stimulation-induced efflux of [(3)H]-noradrenaline, indicating that their blocking effects on prejunctional alpha-adrenoceptors in this tissue are in the same order of relative potency as on postjunctional alpha-adrenoceptors in rabbit aortic strips.4 In the concentrations used (30 muM), neither burimamide nor cimetidine interfered with the neuronal uptake of noradrenaline. Burimamide, and to a much lesser extent, cimetidine, increased the resting efflux of [(3)H]-noradrenaline from guinea-pig atria.5 The effect of clonidine, a partial agonist on prejunctional alpha-adrenoceptors in guinea-pig atria, in increasing stimulation-induced efflux of [(3)H]-noradrenaline when stimulated with 150 pulses at 5 Hz was blocked by cimetidine (30 muM) and reversed by phentolamine (3 muM) and burimamide (30 muM).  (+info)

The effects of burimamide and metiamide on basal gastric function in the cat. (6/24)

1 Burimamide injected intravenously in the anaesthetized or conscious cat produced significant increases in gastric acid secretion: in the anaesthetized cat it produced increased gastric mucosal blood flow. 2 Metiamide, in doses which inhibited pentagastrin-stimulated acid secretion, produced no increase in gastric acid secretion in conscious animals, or gastric acid secretion or gastric mucosal blood flow in the anaesthetized cat. 3 Metiamide did not influence the amount of acid which diffused out of the stomach when instilled at pH values between 1.5 and 6.0. 4 The possible mode of action of burimamide in increasing basal gastric secretion is discussed.  (+info)

Interaction of histamine H1-and H2-receptor antagonists with histamine uptake and metabolism by guinea-pig isolated atrium and mouse neoplastic mast cells cells in vitro. (7/24)

1. Burimamide, metiamide, chlorpheniramine, triprolidine and cocaine, were tested as inhibitors of histamine uptake and metabolism in the guinea-pig atrium and in mouse neoplastic mast cells. 2. Cocaine did not affect the uptake and metabolism of histamine, either in the atrium or in the mast cells. All the antihistamines tested blocked the uptake and metabolism of histamine in both preparations. The order of potency was burimamide greater than chlorpheniramine greater than triprolidine greater than metiamide in the atrium; and burimamide greater than metiamide greater than triprolidine greater than chlorpheniramine, in the mase cells. 3. Comparison of the present results with the antihistamine activity of these blocking agents suggests that no correlation exists between the receptor blocking activity and the ability of these substances to act as inhibitors of histamine uptake and metabolism.  (+info)

The possible roles of histamine, 5-hydroxytryptamine and prostaglandin F2alpha as mediators of the acute pulmonary effects of endotoxin. (8/24)

1 In an attempt to investigate the possible role of released vasoactive substances in mediating the pulmonary pressor responses to E. coli endotoxin, cats were pretreated with histamine, 5-hydroxytryptamine (5-HT) or prostaglandin antagonists, with a histamine depleting agent (compound 48/80) or with an inhibitor of prostaglandin synthetase (sodium meclofenamate).2 The administration of endotoxin (2 mg/kg) resulted in a rapidly developing pulmonary hypertension (pressure twice normal after 2-3 min), increases in right atrial and intratracheal pressures, systemic hypotension and bradycardia. These effects were unaffected by methysergide in a dose sufficient to prevent the effects of intravenously administered 5-HT.3 Endotoxin responses were also unaffected by a combination of mepyramine and burimamide in doses sufficient to reduce markedly the effects of intravenously-administered histamine. In cats pretreated (chronically or acutely) with compound 48/80, endotoxin induced a transient pulmonary pressor response which was not maintained.4 The pulmonary and systemic responses to endotoxin were prevented by the prior administration of the prostaglandin antagonist, polyphloretin phosphate and by pretreatment with the prostaglandin synthetase inhibitor, sodium meclofenamate.5 It is concluded that a pulmonary vasoconstrictor prostaglandin is involved in the acute response to endotoxin in the cat.  (+info)

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