The increase in central histamine concentrations after inhibition of histamine N-methyltransferase (HNMT) activity is associated with the reversal of critical haemorrhagic hypotension, therefore the ...present study examines cardiac and regional haemodynamic effects of HNMT inhibitor metoprine in haemorrhage-shocked rats.
Cardiovascular parameters were measured in 72 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine.
Metoprine (5, 15 mg/kg) was administered intraperitoneally to normotensive and critically-hypotensive rats with mean arterial pressure (MAP) 20-25 mmHg. Haemorrhage-shocked rats were pre-treated intracerebroventricularly with histamine H(3) receptor agonist R(-)-alpha-methylhistamine (10 microg) or saline.
MAP, heart rate (HR) and cardiac and regional haemodynamics were monitored within 2 h after treatment, or to death if it occurred earlier. Histamine concentrations were measured using enzyme immunoassay. ANOVA followed by Neuman-Keules test, and Fisher's exact test were used to compare the results.
Bleeding resulted in an extreme decrease in cardiac index (CI), an increase in total peripheral resistance index (TPRI) and the death of control animals within 30 min. Metoprine induced increases in MAP and HR which were significantly higher in hypotensive than in normotensive animals. The resuscitating effect of metoprine (15 mg/kg) was associated with a rise in CI, a decrease in TPRI, and a 100% survival at 2 h. TPRI changes resulted from decreased renal, hindquarters and mesenteric vascular resistance. R(-)-alpha-methylhistamine inhibited metoprine-induced increases in endogenous histamine concentrations in the cerebral cortex (0.89 +/- 0.12 vs. 1.25 +/- 0.29 nmol/g of wet tissue; P < 0.05), hypothalamus (4.37 +/- 0.42 vs. 5.74 +/- 0.47 nmol/g of wet tissue; P < 0.01) and medulla oblongata (0.39 +/- 0.07 vs. 0.65 +/- 0.28 nmol/g of wet tissue; P < 0.05), diminished haemodynamic effects and decreased the survival rate at 2 h to 33% (P < 0.05 vs. the saline-pre-treated group).
The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension.
An increase in endogenous central histamine concentrations, after loading with histamine precursor L-histidine or inhibition of histamine N-methyltransferase (HNMT) activity, produces the reversal of ...critical hypotension with improvement in survival of haemorrhage-shocked rats. In the present study, the involvement of proopiomelanocortin (POMC)-derived peptides in central histamine-induced resuscitating action was examined in male anaesthetised Wistar rats subjected to a haemorrhagic hypotension of 20-25 mmHg resulting in the death of all control animals within 30 min. HNMT inhibitor metoprine (20 microg) administered intracerebroventricularly (i.c.v.) at 5 min of critical hypotension produced a long-lasting pressor effect with a 100% survival rate at 2 h. The action was accompanied by 34.5% and 28.9% higher plasma concentrations of ACTH and alpha-MSH, respectively, in comparison to concentrations in the saline-injected group as measured 20 min after treatment. Melanocortin type 4 (MC(4)) receptor antagonist HS014 (5 microg; i.c.v.) inhibited metoprine-induced increase in mean arterial pressure, which resulted from decreased regional vascular resistance, however, it did not affect the heart rate and the survival at 2 h. On the other hand, glucocorticoid type II receptor blocker mifepristone (30 mg/kg; sc) had no effect. In conclusion, POMC-derived peptides, acting centrally via MC(4) receptors, participate in endogenous central histamine-induced resuscitating effect in rats.
Metoprine elevates brain histamine content by blocking the conversion of histamine to methylhistamine. It suppresses food intake, increases water intake. and induces diuresis in rats. In the present ...experiment, to study which receptors were involved in these metoprine-induced changes, H1, H2, and H3 receptor blockers were administered to metoprine (10 mg/kg IP)-treated rats. The food and water consumption and urine excretion were measured at 10 and 24 h after the drug administration. It was found that systemic administration of the H3 receptor antagonist, thioperamide (5 mg/kg IP), supplemented the feeding suppressive effect of metoprine. In addition to this, the H1 receptor antagonist mepyramine (20 mg/kg IP) antagonized the suppression of feeding in metoprine-treated rats, whereas the H2 receptor antagonist, ranitidine (100 mg/kg IP), had no effect. Mepyramine also decreased the diuretic response to metoprine, whereas ranitidine or thioperamide were virtually without effect. The present results show that elevation of brain histamine content by inhibiting the catabolism of histamine suppresses food intake, and this effect of metoprine can be abolished by pretreatment with antihistamines. Although the blockade of H1 receptors also attenuates the diuretic response to metoprine, further studies are needed to understand the mechanisms that mediate the effects of metoprine on water balance.
The effect of clobenpropit on regional cerebral blood flow (rCBF) was investigated in the rat hippocampus.
rCBF was determined in the hippocampus by the hydrogen clearance method. The blood pressure ...was measured by a tail-cuff plethysmograph.
Intracerebroventricular (icv) injection of clobenpropit (20, 50 microg), a representative H3-antagonist, dose-dependently and significantly increased rCBF in the hippocampus. The increase of rCBF induced by clobenpropit was enhanced by metoprine (1, 2 mg/kg), a selective histamine N-methyltransferase inhibitor; however, was antagonized by an H3-agonist, (R)-alpha-methylhistamine (5 microg), an H(1)-antagonist, mepyramine (5-10 mg/kg), and an H2-antagonist, zolantidine (10 mg/kg). Clobenpropit caused no apparent effects on blood pressure even at a high dose of 50 microg.
These results suggest that brain endogenous histamine may contribute to increase rCBF in the rat hippocampus via both the post-synaptic H1-, H2-receptors and the pre-synaptic H3-receptor.
: In brain, the precursor of imidazoleacetic acid (IAA), a GABAA agonist but a GABAC antagonist, is not known. In the periphery, IAA derives from oxidation of histamine. But in brain, histamine is ...thought to be metabolized solely by histamine methyltransferase (HMT), forming tele‐methylhistamine (t‐MH) and tele‐methylimidazoleacetic acid (t‐MIAA). We showed that 3Hhistamine (intracerebroventricularly) could be converted to IAA in brains of rats, a process increased by inhibition of HMT. This demonstrated that brain can oxidize histamine and suggested that endogenous histamine might also be oxidized if HMT activity were reduced. We examined, in rat cerebral cortex, effects of the following HMT inhibitors (mg/kg i.p.): metoprine (10), tacrine (10), velnacrine (10, 30), and physostigmine (1, 2). Tacrine was a potent inhibitor (Ki∼ 22 nM). To measure histamine in tissue that contained HMT inhibitors, we developed a gas chromatography‐mass spectrometry method. After 2 h, all drugs reduced endogenous levels of t‐MH and t‐MIAA and increased levels of histamine and IAA. Our results show that inhibition of HMT promotes oxidation of histamine in brain, probably by shunting histamine to an alternative metabolic pathway. Formation of IAA provides a novel interaction between histaminergic and GABAergic systems in brain. Accumulation of IAA should be considered when inhibitors of HMT are used to probe brain histamine function.
Our previous results demonstrate the occurrence of presynaptic inhibitory histamine H3 receptors on sympathetic neurons innervating resistance vessels of the pithed rat. The present study, in which ...new H3 receptor ligands with increased potency and selectivity (imetit, clobenpropit) were used, was designed to further explore the role of H3 receptors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endogenous histamine and whether they are detectable in an experimental model of hypertension. All experiments were performed on pithed and vagotomized rats treated with rauwolscine 1 mumol/kg. In normotensive Wistar rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 35 mmHg. Two H3 receptor agonists, R-(-)-alpha-methylhistamine and imetit, inhibited the electrically induced increase in diastolic blood pressure in a dose-dependent manner. The maximal effect (about 25%) was obtained for R-(-)-alpha-methylhistamine at about 10 mumol/kg and for imetit at about 1 mumol/kg. Two H3 receptor antagonists, thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 mumol/kg. R-(-)-alpha-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 mumol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had only a very low affinity for H3 binding sites (labelled by 3H-N alpha-methylhistamine; pKi 4.46). In pithed Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s) stimulation increased diastolic blood pressure by 28 and 37 mmHg, respectively. Imetit inhibited the neurogenic vasopressor response to about the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 mumol/kg to about the same degree in rats of either strain. The present study confirms the occurrence of presynaptic H3 receptors on sympathetic nerve fibres involved in the inhibition of the neurogenic vasopressor response. Moreover, it demonstrates that these H3 receptors are probably activated by endogenous histamine and appear to be operative in hypertension.
Treatment with psychotropic or antiallergic drugs which block histamine H1-receptors is known to be connected with weight gain. Also in experimental animals food intake is changed after manipulation ...of the histaminergic system, food intake may be decreased by various treatments with increase histaminergic activity and increased if histaminergic activity is reduced. Recent studies are reviewed illustrating the potential role of brain histaminergic system in the fascinating and complicated regulation of feeding.
The purpose of this study was to characterize the transport properties of trimetrexate in WI-L2 human lymphoblastoid cells and determine the mode of resistance that had developed in a subline, ...WI-L2/TMQ, that was grown in increasing concentrations of trimetrexate. WI-L2/TMQ cells were 62-fold resistant to trimetrexate and 68- and 96-fold cross-resistant to the other lipophilic antifolates metoprine and piritrexim (BW 301U). No cross-resistance was observed with vincristine or doxorubicin, and sensitivity was not increased with 5 micrograms/ml of verapamil, indicating that it was not a typical multidrug resistance phenotype. WI-L2/TMQ exhibited a 2-fold increase in dihydrofolate reductase; however, this did not contribute significantly to the observed resistance, since these cells retained full sensitivity to methotrexate. Nor were there any kinetic alterations in dihydrofolate reductase toward trimetrexate or differences in the levels of thymidylate synthase. The major difference between the sensitive and resistant cell line was a 50% decrease in the influx rate of WI-L2/TMQ cells which produced a corresponding decrease in cellular trimetrexate at the steady state. No difference in efflux rates was detected nor were there any differences in intracellular water or metabolism of trimetrexate. Additional characterization of trimetrexate transport in WI-L2 showed that influx was nonsaturable up to 5 mM extracellular trimetrexate, relatively insensitive to sodium azide, and exhibited a Q10 of 2.7. Influx was, however, inhibited in a dose-dependent manner by concentrations of p-chloromercuribenzylsulfonate above 10 microM. Efflux studies revealed a large nonexchangeable fraction of trimetrexate that was well above the dihydrofolate reductase binding capacity and varied depending on the initial level of cell-associated drug. The intracellular exchangeable trimetrexate concentration at the steady state was always several-fold higher than the extracellular concentration. Retention of trimetrexate appeared to be coupled to some component of energy metabolism, since the presence of sodium azide stimulated this process by 2- to 3-fold. The data suggest that trimetrexate enters cells by passive diffusion but then is distributed and concentrated within the cell through more complex mechanisms which may involve energy coupling, compartmentation, or binding to macromolecules or organelles, although some type of carrier-mediated process cannot be ruled out.
Effects of pharmacological manipulations which mimic or enhance histaminergic neuronal transmission were determined on the activity of 5-hydroxytryptaminergic neurons projecting to the hypothalamus ...of male rats. Intracerebroventricular administration of histamine decreased 5-hydroxytryptamine (5-HT) and increased 5-hydroxyindoleacetic acid (5-HIAA) concentrations in several hypothalamic nuclei; these effects were blocked by the histamine H1 receptor antagonist mepyramine but not the histamine H2 receptor antagonist zolantidine. Blockade of the 5-HT reuptake system by fluoxetine did not prevent histamine-induced decreases in 5-HT concentrations suggesting that histamine is not transported into nerve terminals via the 5-HT reuptake system to subsequently displace 5-HT stores. These data suggest that exogenous histamine increases 5-hydroxytryptaminergic neuronal activity through an action at histamine H1 receptors. In contrast, neither the histamine H3 receptor antagonist thioperamide, the histamine-N-methyltransferase inhibitor metoprine, nor combined thioperamide-metoprine treatment affected concentrations of 5-HT or 5-HIAA suggesting these agents, which purportedly enhance endogenous histaminergic transmission, do not affect 5-hydroxytryptaminergic neuronal activity. These results reveal that procedures commonly employed to study central actions of histamine differentially affect 5-hydroxytryptaminergic neuronal activity in the rat hypothalamus.
The effect of metoprine, an inhibitor of histamine (HA) catabolism, on fluid balance was studied in Wistar (W) and Long-Evans (LE) rats. AVP deficient Brattleboro (BB) rats were used to evaluate ...which phenomena were AVP-related. W and LE rats were quite different: LE rats were “dry” rats, they drank less, had higher plasma AVP, smaller urine volume and excreted more AVP, and responded less to salt loading and water deprivation. Furthermore, LE and W rats responded differently to metoprine. When water was provided as drinking fluid, metoprine increased water intake and urine flow in W rats, but these changes were not significant in LE rats. In contrast, when the rats drank saline, urine output and saline consumption were similarly decreased in LE and W rats. Although no metoprine-induced changes in plasma AVP were observed, urinary excretion of AVP per 24 h was reduced in metoprine treated rats. Inhibition of HA catabolism by metoprine caused only minor changes in fluid balance of AVP deficient BB rats. The results show that significant differences in fluid balance can exist between rat strains and that increased availability of HA after IP given metoprine strongly affects body fluids in normal rats, especially those of the W strain. The results provide further support to the involvement of HA in the regulation of fluid balance, but to obtain a more complete picture, other factors, such as atrial natriuretic peptide, should be studied.
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