In Brazilian folk medicine, extracts from Piper species are used to reduce blood pressure. Previously, we demonstrated the vasodilatory activity of crude extracts from leaves of Piper truncatum explaining their possible use in the treatment of hypertension in traditional medicine. In the present study, we investigated the effects of eudesmin, a lignan isolated from hexane extract of leaves from Piper truncatum, on the contractility of rat aortas and the possible mechanisms involved in its vascular action. Eudesmin induced an intense concentration-dependent relaxation of aortic rings precontracted with phenylephrine. The concentration of eudesmin necessary to reduce phenylephrine-induced aortic contraction by 50%(IC(50)) was 10.69+/-0.67 microg/ml. Eudesmin-induced vasodilation required an intact endothelium since vascular relaxation was inhibited by mechanic removal of endothelium, and by pretreatment with nitric oxide synthase inhibitor and soluble guanylate cyclase inhibitor. Relaxation induced by eudesmin was also impaired in the presence of indomethacin and diphenhydramine, a cyclooxygenase inhibitor and an antagonist of type 1 histamine receptor (H(1)), respectively. IC(50) was increased to 18.1+/-1.8 and 18.1+/-2.6 microg/ml (P<0.05; n=6) after exposure to indomethacin and diphenhydramine, respectively. Atropine (muscarinic receptor antagonist), propranolol (beta-adrenoceptor antagonist) and glibenclamide (ATP-sensitive K(+) channel blocker) did not alter the effect of eudesmin. These results indicate that eudesmin-induced vascular relaxation in rat aorta is mediated by release of nitric oxide and prostanoid through the involvement of histamine receptor present in the endothelial cells.

In this article, we review the recent developments in the field of histamine research. Besides the description of pharmacological tools for the H1, H2 and H3 receptor, specific attention is paid to both the molecular aspects of the receptor proteins, including the recent cloning of the receptor genes, and their respective signal transduction mechanisms.

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT(2A) and 5-HT(2C) serotonin receptors, H(1)-histamine receptors, alpha(1)- and alpha(2)-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H(1)-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman rho=-0.72; p<0.01), as were affinities for alpha(1A) adrenergic (rho=-0.54; p<0.05), 5-HT(2C)(rho=-0.49; p<0.05) and 5-HT(6) receptors (rho=-0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H(1), alpha(2A), alpha(2B), 5-HT(2A), 5-HT(2C), and 5-HT(6) receptors were most highly correlated with the first principal component, and affinities for the D(2), 5-HT(1A), and 5-HT(7) receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H(1) and alpha(1A) receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H(1)-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H(1)-histamine receptor antagonists are known to induce weight gain with chronic use, and because H(1)-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H(1)-histamine receptors.

The TRPM subfamily of mammalian TRP channels displays unusually diverse activation mechanisms and selectivities. One member of this subfamily, TRPM5, functions in taste receptor cells and has been reported to be activated through G protein-coupled receptors linked to phospholipase C. However, the specific mechanisms regulating TRPM5 have not been described. Here, we demonstrate that TRPM5 is a monovalent-specific cation channel with a 23 pS unitary conductance. TRPM5 does not display constitutive activity. Rather, it is activated by stimulation of a receptor pathway coupled to phospholipase C and by IP(3)-mediated Ca(2+) release. Gating of TRPM5 was dependent on a rise in Ca(2+) because it was fully activated by Ca(2+). Unlike any previously described mammalian TRP channel, TRPM5 displayed voltage modulation and rapid activation and deactivation kinetics upon receptor stimulation. The most closely related protein, the Ca(2+)-activated monovalent-selective cation channel TRPM4b, also showed voltage modulation, although with slower relaxation kinetics than TRPM5. Taken together, the data demonstrate that TRPM5 and TRPM4b represent the first examples of voltage-modulated, Ca(2+)-activated, monovalent cation channels (VCAMs). The voltage modulation and rapid kinetics provide TRPM5 with an excellent set of properties for participating in signaling in taste receptors and other excitable cells.

From pharmacological studies using histamine antagonists and agonists, it has been demonstrated that histamine modulates many physiological functions of the hypothalamus, such as arousal state, locomotor activity, feeding, and drinking. Three kinds of receptors (H1, H2, and H3) mediate these actions. To define the contribution of the histamine H1 receptors (H1R) to behavior, mutant mice lacking the H1R were generated by homologous recombination. In brains of homozygous mutant mice, no specific binding of [3H]pyrilamine was seen.[3H]Doxepin has two saturable binding sites with higher and lower affinities in brains of wild-type mice, but H1R-deficient mice showed only the weak labeling of [3H]doxepin that corresponds to lower-affinity binding sites. Mutant mice develop normally, but absence of H1R significantly increased the ratio of ambulation during the light period to the total ambulation for 24 hr in an accustomed environment. In addition, mutant mice significantly reduced exploratory behavior of ambulation and rearings in a new environment. These results indicate that through H1R, histamine is involved in circadian rhythm of locomotor activity and exploratory behavior as a neurotransmitter.

Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (Kds) for 17 antidepressants and two of their metabolites at histamine H1, muscarinic, alpha 1-adrenergic, alpha 2-adrenergic, dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2 receptors. Several newer antidepressants were compared with older drugs. In addition, we studied some antimuscarinic, antiparkinson, antihistamine, and neuroleptic compounds at some of these receptors. For the antidepressants, classical tricyclic antidepressants were the most potent drugs at five of the seven receptors (all but alpha 2-adrenergic and 5-HT1A receptors). The chlorophenylpiperazine derivative antidepressants (etoperidone, nefazodone, trazodone) were the most potent antidepressants at alpha 2-adrenergic and 5-HT1A receptors. Of ten antihistamines tested, none was more potent than doxepin at histamine H1 receptors. At muscarinic receptors antidepressants and antihistamines had a range of potencies, which were mostly weaker than those for antimuscarinics. From the in vitro data, we expect adinazolam, bupropion, fluoxetine, sertraline, tomoxetine, and venlafaxine not to block any of these five receptors in vivo. An antidepressant's potency for blocking a specific receptor is predictive of certain side effects and drug-drug interactions. These studies can provide guidelines for the clinician in the choice of antidepressant.

The antihistamine [3H]mepyramine binds to H1 histamine receptors in mammalian brain membranes. Potencies of H1 antihistamines at the binding sites correlate with their pharmacological antihistamine effects in the guinea pig ileum. Specific [3H]mepyramine binding is saturable with a dissociation constant of about 4 nM in both equilibrium and kinetic experiments and a density of 10 pmol per gram of whole kinetic experiments and a density of 10 pmol per gram of whole brain. Some tricyclic antidepressants are potent inhibitors of specific [3H]mepyramine binding. Regional variations of [3H]mepyramine binding do not correlate with variations in endogeneous histamine and histidine decarboxylase activity.

To investigate the possible role of mast cells in blood vessel formation, rat mast cell granules were studied for their proliferative effect on human microvascular endothelial cells. It was found that granules had a marked proliferative effect and that most of this activity was restricted to a dialyzable fraction. The dialyzable mast cell granule constituent histamine was found to be mitogenic, an effect that was shown with the use of specific agonists and antagonists to be mediated through an H1 receptor. H1 antagonists reduced the proliferation caused by the untreated mast cell granules to the level of proliferation caused by dialyzed granules, suggesting that all the dialyzable mitogenic activity was due to histamine. Histamine was also shown to cause proliferation of cells that were growth arrested by serum deprivation, suggesting that it is an endothelial growth factor. The compound responsible for the undialyzable mitogenic activity could not be identified but was shown not to be mast cell heparin. This demonstration of mast cell granule-induced endothelial proliferation suggests that the mast cell may be of importance in the process of angiogenesis.

This review covers mechanisms of action, efficacy, side effects, and toxicity of various classes of antidepressants: tricyclic antidepressants, monoamine oxidase inhibitors, second-generation antidepressants including the selective inhibitors of serotonin reuptake, and novel drugs such as mirtazapine, nefazodone, and venlafaxine.

Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.

Although activation of muscarinic cholinergic receptors on 1321N1 human astrocytoma cells results in a linear accumulation of inositol phosphates for up to 60 min in the presence of LiCl [Masters, Quinn & Brown (1985) Mol. Pharmacol. 27, 325-332], activation of H1-histamine receptors resulted in an increase in total inositol phosphate formation that was maintained for less than 5 min. The effects of stimulation of these two receptors on accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], inositol 1,3,4-trisphosphate [Ins(1,3,4)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] were also examined. Incubation of 1321N1 cells with carbachol resulted in a rapid accumulation of all three inositol phosphates, reaching a maximum within 30 s; this elevated value was maintained for up to 60 min. The rate of disappearance of Ins(1,3,4)P3 from carbachol-treated cells after the addition of atropine paralleled or exceeded the rate of disappearance of Ins(1,4,5)P3. Although the initial rates of accumulation of Ins(1,4,5)P3, Ins(1,3,4)P3 and Ins(1,3,4,5)P4 in the presence of histamine were similar to that observed with carbachol, the amounts of these inositol phosphates had returned to control values within 5 min after the addition of histamine. The results indicate that, although the acute effects of muscarinic receptor and H1-histamine receptor stimulation on phosphoinositide hydrolysis are very similar, the histamine receptor is desensitized rapidly, whereas the muscarinic receptor is not. This effect on histamine-receptor function is apparently homologous, since preincubation of 1321N1 cells with histamine did not decrease the subsequent response to carbachol.