Mechanisms of histamine ameliorating memory impairment induced by pentylenetetrazole-kindling epilepsy in rats / 浙江大学学报·医学版

To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms.A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed.Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine.Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.

Antiarrhythmic effect of TJ0711 / 药学学报

To study the antiarrhythmic effect of the newly developed alpha/beta-blocker TJ0711, a variety of animal models of arrhythmia were induced by CaCl2, ouabain and ischemia/reperfusion. Glass microelectrode technique was used to observe action potentials of right ventricular papillary muscle of guinea pig. The onset time of arrhythmia induced by CaCl2 was significantly prolonged by TJ0711 at 0.75, 1.5 and 3 mg x kg(-1) doses. TJ0711 (1.5 and 3 mg x kg(-1)) can significantly shorten the ventricular tachycardia (VT) and ventricular fibrillation (VF) duration, the incidence of VF and mortality were significantly reduced. On ischemia-reperfusion-induced arrhythmic model, TJ0711 (0.25, 0.5, 1 and 2 mg x kg(-1)) can significantly reduce the ventricular premature contraction (PVC), VT, VF incidence, mortality, arrhythmia score with a dose-dependent manner. At the same time, rats serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities decreased significantly by TJ0711 (1 and 2 mg x kg(-1)). Ouabain could cause arrhythmia in guinea pigs, when TJ0711 (0.375, 0.75, 1.5 and 3 mg x kg(-1)) was given, the doses of ouabain inducing a variety of arrhythmia PVC, VT, VF, cardiac arrest (CA) were significantly increased with a dose-dependent manner. In the TJ0711 0.1-30 micromol x L(-1) concentration range, guinea pig right ventricular papillary muscle action potential RP (rest potential), APA (action potential amplitude) and V(max) (maximum velocity of depolarization) were not significantly affected. APD20, APD50 and APD90 had a shortening trend but no statistical difference with the increase of TJ0711 concentration. TJ0711 has antiarrhythmic effect on the sympathetic nerve excitement and myocardial cell high calcium animal arrhythmia model. Myocardial action potential zero phase conduction velocity and resting membrane potential were not inhibited by TJ0711. APD20, APD50 and APD90 were shortened by TJ0711 at high concentration. Its antiarrhythmic action mechanism may be besides the action of blocking beta1 receptor, may also have a strong selective blocking action on alpha1 receptor and reducing intracellular calcium concentration.

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

Pharmacodynamic study of racemic TJ0711 on renal hypertensive rats after long-term administration / 药学学报

The study is to observe the effect of racemic TJ0711 on blood pressure and heart rate as well as protection of cardiovascular system of renal hypertensive rats after long-term administration. The renal hypertensive models were established by the two-kidney, one-clip (2K1C) method in Wistar rats. Four weeks later, assigned the rats whose SBP had increased at least 4 kPa randomly into 5 groups: racemic TJ0711 10, 20 and 40 mg x kg(-1) groups, carvedilol control group, model group and sham group (n=10), ig administration once daily. The changes of BP (blood press) and HR (heart rate) before and after administration were measured by tail-cuff method weekly. Plasma samples of all animals were taken in 6-8 weeks, and plasma MDA as well as renin, angiotensin II (Ang II) and endothelin-1 (ET-1) levels were measured. Left ventricle was cut off after 9 weeks, and left ventricular weight index (LVWI) and hydroxyproline were measured. The significant decrease of the BP of TJ0711 40 mg x kg(-1) group was observed after TJ0711 ig administration for 4 weeks, and this effect remained till the end of the study. In 8th week, the systolic blood pressure values were: TJ0711 40 mg x kg(-1) group 18.93 +/- 1.82 kPa (vs 21.30 +/- 2.30 kPa, P < 0.05); 20 mg x kg(-1) group 20.68 +/- 3.29 kPa (vs 22.19 +/- 2.88 kPa). The plasma MDA level of all treated groups was significantly lower than that of model group, so were the plasma renin, Ang II and ET-1 levels (P < 0.05). LVWI and hydroxyproline content of myocardial tissue decreased to some extent, but was not significant as compared with that of model group. The study showed that TJ0711 repeated dosing could reduce BP level beginning from drug administration; besides block adrenal alpha and beta receptors to play an antihypertensive role. The sustained antihypertensive effect also related to reduce plasma vasoconstrictor substances and oxidation product MDA. These effects benefited cardiovascular protection.

Reversing effect of histamine on neurotoxicity induced by beta-amyloid1-42 / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effects of histamine on the neurotoxicity induced by beta-amyloid(1-42)(Abeta42) in rat phaeochromocytoma (PC12) cells.</p><p><b>METHODS</b>The in vitro model of Alzheimer's disease was constructed with A beta42-treated PC12 cells. Cell morphology and MTT assay were used to evaluate the cell toxicity and histamine effects. The different histamine antagonists were applied to investigate the involvement of receptor subtypes.</p><p><b>RESULT</b>The neurotoxicity was induced by A beta42 in a concentration-dependent manner, which was reversed by histamine at concentration of 10(-7), 10(-6) mol/L. The effect was reversed by H(2) antagonist zolantidine and H(3)antagonist clobenpropit, but not by H(1) antagonist diphenhydramine.</p><p><b>CONCLUSION</b>Histamine reduces neurotoxicity induced by beta-amyloid(1-42), which may be mediated by H(2) and H(3)receptors.</p>

Central histaminergic involvement during stress in rats.

Effects of some drugs modulating central histaminergic (HA) transmission were evaluated on restraint stress (RS)-induced gastric ulcerogenesis, plasma corticosterone and immune responses in rats. RS for (i) 6 hr or (ii) 24 hr at room temperature, and (iii) 3 hr at 4 degrees C (CRS) all induced gastric mucosal erosions and elevated plasma corticosterone levels, the effects with the latter two RS procedures being most consistent. Pretreatment of rats with neuronal HA depletor, alpha-FMH (100 mg/kg, ip) attenuated both ulcer severity and corticosterone response, during both 24 hr RS and CRS. Similar effects were also seen with the mast cell degranulator, C-48/80 (10 micrograms/kg, i.c.v.) treatment. Further, the H1-blocker, pheniramine (25 mg/kg, ip) but not the centrally acting H2-blocker, zolantidine (5 mg/kg, ip) produced clearcut attenuations in both stress markers, during the experimental stressors. In rats immunized in SRBC, 24 hr RS (and not CRS) significantly prevented the humoral immune responses to the antigen. alpha-FMH, C 48/80 and pheniramine but not zolantidine, reversed this response during 24 hr RS. The results indicate a central HA ergic involvement in the visceral, endocrinal and immune responses during RS and suggest the probable role of both neuronal as well as extraneuronal (mast cell) HA and activation of H1-receptors in the mediation of these effects.

Influence of beta-adrenoceptor antagonists on spontaneous rate and on force of contraction of isolated rabbit atria.

The influence of beta-adrenoceptor antagonists on the spontaneous rate and on force of contraction of the myocardium was studied independently on spontaneously beating right and electrically driven isolated left atria of rabbit. On spontaneous rate, practolol had sympathomimetic effect only, N-isopropylmethoxamine (IMA), had both sympathomimetic as well as depressant effects, whereas alprenolol, procinolol, bunolol and H 35/25 had depressant effects only in higher concentrations. The order of potency was procinolol greater than bunolol greater than alprenolol greater than H 35/25 greater than and IMA. On the contractions of isolated left atria, all beta-adrenoceptor antagonists produced concentration-dependent depressant effect. In relation to procinolol, these agents were 5-125 times less potent for depressing the contractions of left atria by 15% and the order of beta-potency was procinolol greater than alprenolol greater than bunolol = H 35/25 greater than IMA greater than and practolol. The present results indicate that the depressant effects of beta-adrenoceptor antagonists on spontaneous rate of right atria and on contraction of isolated left atria are not related to each other.