The effects of peptide and nonpeptide antagonists of angiotensin II receptors on the level of brain biogenic monoamines in rats with angiotensin II-induced increase of water intake

The effects of peptide and nonpeptide angiotensin II (Ang II)-receptor antagonists (losartan, EXP-3174, saralasin and sarmesin) on the levels of the biogenic monoamines dopamine, noradrenaline and serotonin in the frontal cortex, striatum, hypothalamus and hippocampus of rats with Ang II-induced water intake were investigated. Ang II administered i.c.v. at a dose inducing drinking behavior in rats significantly changed the levels of biogenic monoamines. The latter were also significantly affected by the Ang II-receptor antagonists, as in most cases the drugs antagonized the effect of Ang II. Most pronounced were the effects of Ang II and Ang II-receptor antagonists on the dopamine levels. These levels were reduced to zero after Ang II in all brain structures studied. The drugs tested increased the dopamine levels, restoring their values to the values in vehicle-injected rats. Ang II-receptor antagonists exerted mosaic effects on noradrenaline and 5-HT (serotonin) levels depending on both--the type of biogenic monoamine and the brain structure. There was no relationship between the inhibition of Ang II-induced water intake and the changes in the levels of brain biogenic monoamines under the effect of the Ang II-receptor antagonists. These antagonists may play a role in the modulation of brain monoaminergic neurotransmitter systems.     

The effects of peptide and nonpeptide antagonists of angiotensin II receptors on the noradrenaline uptake of different brain structures in rats with angiotensin II-induced increase of water intake

Angiotensin II (ANG II) significantly increased noradrenaline (NA) uptake by cortical, hypothalamic and hippocampal synaptosomes thus activating noradrenergic neurotransmission. ANG II did not affect NA uptake by striatal synaptosomes. The interaction between AT1 receptors and noradrenergic neurons and the involvement of brain noradrenergic neurotransmitter system in ANG II-induced drinking in rats is suggested by the increase of NA uptake in hypothalamus and frontal cortex which are rich in AT1 receptors and are of importance for drinking behavior. The ANG II-receptor antagonists losartan, EXP 3174, sarmesin and saralasin decreased NA uptake in all brain regions studied as compared to the uptake in the same brain regions of ANG II-injected animals thus antagonising the effect of ANG II. There is no relationship between the inhibition of ANG II-induced water intake and the changes of NA uptake under the effect of the ANG II-receptor antagonists.     

Effects of prenatal methylmercury exposure on brain monoamine oxidase activity and neurobehaviour of rats

Monoamine oxidase (MAO) regulates levels of dopamine, serotonin, and noradrenaline in the nervous tissue and is required for proper neuronal development. The purpose of this study was to determine if oral exposure of adult female rats to methylmercury (MeHg) at 0.5 or 1 mg/kg/day before and during pregnancy would affect MAO activity in various brain regions of the offspring. Offspring neurobehaviour performance was also assessed. The brain MAO activity of female offspring was reduced at both MeHg doses with significantly lower values noted in the brainstem region. No significant MeHg dose effects on MAO activity were observed in the male offspring. Neurobehavioural evaluations indicated that MeHg exposure altered auditory startle in the female offspring. Rat whole embryos (gestational day 13.5) cultured with 750 microg/L MeHg in vitro significantly decreased total MAO activity by 15%. In conclusion, this study demonstrated that exposure to MeHg in rats before and/or during gestation resulted in a reduction of MAO activity in the developing embryo and brainstem of the female offspring with accompanying changes in auditory startle response. Evaluation of MAO activity may serve as an indicator for neurotoxicity following developmental exposure to MeHg and should be further investigated.     

Candesartan cilexetil: pharmacological properties and protective effects against organ damage of a novel nonpeptide angiotensin II-receptor antagonist

The nonpeptide angiotensin II (AII) subtype-1 (AT1) receptor antagonist candesartan cilexetil is completely converted to its active form, candesartan, during gastrointestinal absorption. In in vitro studies, candesartan has been found to act as an insurmountable antagonist at the AT1 receptor that dose-dependently reduces the maximal contractions induced by AII and, at high concentrations, virtually eliminates the AT1-receptor-mediated effects of AII. Receptor binding studies suggest that insurmountable antagonism may be due to tight binding to the AT1 receptor and slow dissociation from it. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension. Candesartan cilexetil exerts a long-lasting antihypertensive action in spontaneously hypertensive rats in the low dose range of 0.1-10 mg/kg. The long-lasting antihypertensive effect of candesartan cilexetil is confirmed by the trough/peak ratio in hypertensive patients. It has been demonstrated that administration of AII receptor antagonists is followed by a rise in AII levels, and the increased AII levels result in competition with the antagonist for binding to the receptor. Insurmountable antagonists would seem to be more advantageous since they would block more efficiently in the presence of increasing AII levels than surmountable antagonists. A growing number of studies indicate that candesartan cilexetil provides end-organ protection in addition to lowering blood pressure. The utility of AT1 antagonists may extend beyond treatment of hypertension, chronic heart failure and renal diseases, as suggested by the potential usefulness of ACE inhibitors in the treatment or prevention of many other cardiovascular diseases.     

Effect of centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats

In vitro studies of effects of some nootropic drugs (centrophenoxine, piracetam and aniracetam) on monoamine oxidase (MAO) activity in the rat striatum and hypothalamus, using tyramine, serotonin and beta-phenylethylamine as substrates, were carried out. At all concentrations used (5.10(-5)-1.10(-3) M) centrophenoxine inhibited total MAO, MAO A and MAO B in both brain structures. Piracetam activated striatal and hypothalamic total MAO, hypothalamic MAO A and MAO B but exerted a pronounced inhibitory effect on MAO A and MAO B activity in the striatum. Aniracetam inhibited total MAO and MAO A in both brain structures but activated striatal and hypothalamic MAO B. The different effects of centrophenoxine, piracetam and aniracetam on MAO activity in the brain structures support the view for the independent mode of action of nootropic drugs in spite of their similar molecular and metabolic activity.     

解郁方对抑郁模型小鼠脑内单胺类神经递质及单胺氧化酶含量的影响

目的研究解郁方抗抑郁作用的机理。方法采用酶联免疫检测试剂盒测定小鼠脑组织中单胺类神经递质含量;分光光度计法检测小鼠脑组织中单胺氧化酶(monoamine oxidase,MAO)活性,来研究解郁方抗抑郁作用的机制。结果解郁方Ⅰ和Ⅱ(12.00、6.00 g·kg-1)组均可显著升高小鼠脑内去甲肾上腺素、5-羟色胺、多巴胺(分别为P<0.01,P<0.05),解郁方Ⅰ和Ⅱ组可显著降低MAO活性(分别为P<0.01,P<0.05)。结论解郁方可能是通过抑制MAO活性,使突触间隙的单胺类神经递质含量升高,而起到抗抑郁作用。     

Effect of lignocaine on monoamine oxidase activity of brain and liver

In vivo administration of a single dose (100-150 mg/kg, i.p.) of lignocaine produces no change in MAO activity, while long-term treatment (50 mg/kg/day for 15 and 30 consecutive days, i.p.) produces a slight but appreciable inhibition of MAO activity with tyramine or serotonin but not with benzylamine as substrate in both rat brain and liver mitochondria. Lignocaine (2-20 mM) inhibits (in vitro) both brain and liver mitochondrial MAO activity, using tyramine, serotonin and benzylamine as substrates, in a concentration-dependent manner. Furthermore, lignocaine produces a marked in vitro inhibition of serotonin and tyramine oxidation in MAO-A and not in MAO-B preparation of rat brain. Ackermann-Potter plots of MAO indicate that lignocaine-induced inhibition of MAO activity is reversible in nature. Lineweaver-Burk plots show that lignocaine (2-10 mM) produces a significant increase in Km and decrease in Vmax of MAO for tyramine and serotonin in both brain and liver. Similarly Km and Vmax values are changed using benzylamine as substrate in the presence of relatively higher concentrations of lignocaine (5-20 mM). These results suggest that lignocaine-induced inhibition of mitochondrial membrane-bound MAO activity of both neuronal and non-neuronal tissues is associated with its conformational change.     

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.     

Effect of chronic administration of morphine on monoamine oxidase activity in discrete regions of the brain of rats

The effect of chronic administration of morphine on the activity of monoamine oxidase in specific regions of the brain of rats has been investigated. It was found that, shortly after the last administration of morphine, brain monoamine oxidase (EC 1.4.3.4) was drastically reduced in rats which had been chronically treated with morphine and which had exhibited a hyperactivity syndrome manifested by compulsive gnawing and spasmodic jumping. The lowest values were seen at approximately 30 min and they returned to nearly normal levels by 6 hr after the last injection. In contrast, no significant changes were observed in the activity of this enzyme in animals that did not exhibit this syndrome after morphine administration.     

Effect of Rhazya stricta Decne on monoamine oxidase and cholinesterase activity and brain biogenic amine levels in rats

The effect of treatment with the medicinal plant Rhayva stricta Decne, on monoamine oxidase (MAO) and cholinesterase activity, and on the concentration of brain biogenic amines was studied in rats. R. stricta extract, at doses of 0.2 and 0.5 g kg(-1), significantly (P < 0.05-0.01) increased the hepatic and cerebral activity of MAO by 36-127%. The higher doses used (2.0 and 8.0 g kg(-1)) produced smaller (10-26%) and statistically insignificant increases in MAO activity in liver and brain. Cholinesterase activity in blood, liver and brain was not significantly influenced by treatment with R. stricta. The concentrations of the measured biogenic amines (noradrenaline, adrenaline, 5-hydroxytryptamine and dopamine) were significantly lowered in rats treated with R. stricta. The observed increase in MAO activity may be responsible for the lowered biogenic amines levels and may, in part, be responsible for the pharmacological effects of R. stricta extract in rats.     

In vitro effects of acetylcholinesterase reactivators on monoamine oxidase activity

Administration of acetylcholinesterase (AChE) reactivators (oximes) is usually used in order to counteract the poisoning effects of nerve agents. The possibility was suggested that oximes may show some therapeutic and/or adverse effects through their action in central nervous system. There are no sufficient data about interaction of oximes with monoaminergic neurotransmitter's systems in the brain. Oxime-type AChE reactivators pralidoxime, obidoxime, trimedoxime, methoxime and HI-6 were tested for their potential to affect the activity of monoamine oxidase of type A (MAO-A) and type B (MAO-B) in crude mitochondrial fraction of pig brains. The compounds were found to inhibit fully MAO-A with half maximal inhibitory concentration (IC₅₀) of 0.375 mmol/l (pralidoxime), 1.53 mmol/l (HI-6), 2.31 mmol/l (methoxime), 2.42 mmol/l (obidoxime) and 4.98 mmol/l (trimedoxime). Activity of MAO-B was fully inhibited by HI-6 and pralidoxime only with IC₅₀ 4.81 mmol/l and 11.01 mmol/l, respectively. Methoxime, obidoxime and trimedoxime displayed non-monotonic concentration dependent effect on MAO-B activity. Because oximes concentrations effective for MAO inhibition could not be achieved in vivo at the cerebral level, we suppose that oximes investigated do not interfere with brain MAO at therapeutically relevant concentrations.     

The effects of hashish components and their mode of action on monoamine oxidase from the brain

Cannabinoids apparently interfere with the metabolism of biogenic amines in the brain, indicating that the biogenic amine system is involved in the psychomimetic effect of hashish. The effect of Δ¹-tetrahydrocannabinol (Δ¹-THC), cannabidiol (CBD) and hashish extract on monoamine oxidase (MAO) from porcine brain mitochondria was therefore studied, using several substrates including amines of biological importance, such as serotonin, dopamine and tryptamine. While Δ¹-THC and hashish extract inhibited MAO activity. to an extent varying according to the substrate, CBD was innocuous or only slightly inhibitory—in correspondence with the psychomimetic potency. Phospholipids associated with MAO were essential for the inhibition of the oxidase activity by Δ¹-THC. In enzyme preparations from which the phospholipids were extracted, the sensitivity to Δ¹-THC essentially disappeared. Sensitivity could be regained specifically upon addition of phosphatidylcholine. It is suggested that the phospholipids of the MAO complex function as the site of interaction with the Cannabinoids, leading to the observed changes in MAO activity. The differential effect of the Cannabinoids support the conclusion that MAO plays a central role in mediating the psychomimetic effect of hashish.