Assessment of renal dopaminergic system activity during cyclosporine A administration in the rat.

1. Administration of cyclosporine A (CsA; 50 mg kg-1 day-1, s.c.) for 14 days produced an increase in both systolic (SBP) and diastolic (DBP) blood pressure by 60 and 25 mmHg, respectively. The urinary excretion of dopamine, DOPAC and HVA was reduced from day 5-6 of CsA administration onwards (dopamine from 19 to 46%, DOPAC from 16 to 48%; HVA from 18 to 42%). In vehicle-treated rats, the urinary excretion of dopamine and DOPAC increased (from 7 to 60%) from day 5 onwards; by contrast, the urinary excretion of HVA was reduced (from 27 to 60%) during the second week. 2. No significant difference was observed between the Vmax and Km values of renal aromatic L-amino acid decarboxylase (AAAD) in rats treated with CsA for 7 and 14 days or with vehicle. 3. Km and Vmax of monoamine oxidase types A and B did not differ significantly between rats treated with CsA for 7 and 14 days or with vehicle. 4. Maximal catechol-O-methyltransferase activity (Vmax) in homogenates of renal tissues obtained from rats treated with CsA for 7 or 14 days was significantly higher than that in vehicle-treated rats; Km (22.3 +/- 1.5 microM) values for COMT did not differ between the three groups of rats. 5. The accumulation of newly-formed dopamine and DOPAC in cortical tissues of rats treated with CsA for 14 days was three to four times higher than in controls. The outflow of both dopamine and DOPAC declined progressively with time and reflected the amine and amine metabolite tissue contents. No significant difference was observed between the DOPAC/dopamine ratios in the perifusate of renal tissues obtained from CsA- and vehicle-treated rats. In addition, no significant differences were observed in k values or in the slope of decline of both DA and DOPAC between experiments performed with CsA and vehicle-treated animals. 6. The Vmax for the saturable component of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in renal tubules from rats treated with CsA was twice that of vehicle-treated animals. Km in CsA- and vehicle-treated rats did not differ. 7. The decrease in the urinary excretion of sodium and an increase in blood pressure during CsA treatment was accompanied by a reduction in daily urinary excretion of dopamine. This appears to result from a reduction in the amount of L-DOPA made available to the kidney and does not involve changes in tubular AAAD, the availability of dopamine to leave the renal cells and dopamine metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of Panax ginseng on age-related changes in the spontaneous motor activity and dopaminergic nervous system in the rat.

Effects of Panax ginseng on the spontaneous motor activity and central dopaminergic systems in old rats were investigated and compared with those in young rats. Oral intake of a 1.8% water extract of Panax ginseng for four weeks produced an increase in spontaneous motor activity during the dark period in old rats, while it caused a decrease in the activity in young rats. After the intake of ginseng extract for five weeks, it caused a significantly low dopamine utilization in the daytime in the striatum of old rats, while it produced a high dopamine utilization in the structure of young rats. Concentrations of striatal dopamine D-2 receptors in old rats were significantly lower than that in young rats, although subchronic Panax ginseng did not affect the striatal D-1 and D-2 receptors of old rats. These results suggest that subchronic intake of ginseng extract inhibits the activity of nigro-striatal dopamine neurons in the daytime and activates spontaneous motor activity during the dark period in old rats, while it produces opposite effects in young rats.     

DOCA-Salt高血压大鼠模型的建立

目的建立一种可靠的DOCA-Salt高血压大鼠模型。方法大鼠行左侧肾脏切除术后,每周皮下注射DOCA油剂(30mg·kg-1)一次,饲饮水含有10g·L-1NaCl和2g.L-1KCl,共4wk。每周监测血压和24h尿量;检测大鼠UNaV、UClV、UKV和UCaV及尿液pH值;检测血清中SGPT、CREA、SUGA、TRIG、CHOL水平,血浆中INS、ALD和ADH水平;观察肾脏的形态学变化及测定肾小管上皮细胞Na+,K+-ATPase活性。结果模型组大鼠的尾动脉压和清醒状态血压均升高;大鼠24h尿量、UNaV、UClV增加,而UKV、UCaV和尿液pH值没有变化;血清中SGPT、CREA、SUGA、TRIG、CHOL和血浆中INS、ALD和ADH水平均没有改变;大鼠右肾重量明显增加,形态学改变表现为肾小球硬化、肾小管肥厚等;肾小管上皮细胞Na+,K+-ATPase活性降低。结论皮下注射DOCA和饲饮盐水诱导的大鼠高血压模型具有操作简单、成功率高、易复制、可靠等特点,可用于盐敏感性高血压的研究及抗高血压药物的筛选。     

Physostigmine and modulators of nitric oxide system on the mean arterial pressure of the spontaneously hypertensive rat

• 1.1. A slow intravenous infusion of L-arginine (3 mg kg⁻¹) lasting one hr produced significant hypotension in urethane-anaesthetized spontaneously hypertensive rats (SHRs).
• 2.2. A slow intravenous infusion of N^G-nitro-l-arginine methyl ester (l-NAME) (3 mg kg⁻¹ h⁻¹) did not produce any significant change in the mean arterial pressure during infusion. After stopping infusion of l-NAME, a slowly developing increase of the mean arterial pressure was observed during the following 40 min.
• 3.3. The pressor response to physostigmine (20, 40 and 80 μg kg⁻¹, IV), injected during a slow intravenous infusion of either l-arginine or l-NAME, was not changed.
• 4.4. l-arginine and l-NAME depressed the pressor responses to physostigmine, if physostigmine was injected after the end of a 1-hr infusion.
• 5.5. Acute pretreatment with increasing doses of physostigmine markedly affected the blood pressure response to L-arginine (i.e., L-arginine-caused hypotension was more pronounced), but only slightly that to l-NAME.
• 6.6. In conclusion, l-arginine, as a donor of NO, produced hypotension by itself and also decreased, but not significantly, the central cholinergically-mediated hypertension (CCMH) produced by physostigmine. It is quite possible that the peripheral NO released by l-arginine antagonized the increased adrenergic activity in the CCMH. This does happen in normotensive rats, but to a lesser degree than in SHRs, as shown in the current experiments.
• 7.7. Also, our results show that inhibition of endogenous NO biosynthesis using l-NAME does not necessarily lead to pressor response in vivo, at least in SHRs. It is concluded that l-arginine-nitric oxide pathways operate in SHRs, as well as in normotensive Wistar rats, but their role in modulating cholinergically-mediated regulation of the mean arterial pressure is less pronounced in SHRs than in normotensive animals.

     

Comparative effects of dopaminergic agonists on cardiovascular, renal, and renin-angiotensin systems in hypertensive patients.

The role of dopaminergic receptors on renal function has been extensively studied. Recently dopaminergic receptor has been classified in two subtypes D1 and D2, which seem to have different modulatory function. However, the role of dopaminergic receptors on cardiovascular function and more specifically the potential role of dopaminergic agonists as antihypertensive agents has not yet been clarified. Nine outpatients with mild and moderate hypertension were studied in the Cardiology Service of Vargas Hospital with a D1 agonist, piribedil, at 50-100 mg/day, orally, for 8 weeks, and with a D2 agonist, bromocriptine, at 2.5 - 5 mg/day, orally, for an another 8 weeks by using a placebo comparative crossover design. Piribedil reduced blood pressure with a modest increase in heart rate, plasma renin activity, and of plasma aldosterone, and an important increment of renal function. Bromocriptine reduced blood pressure with a decrease in heart rate and plasma aldosterone without altering renal function. There was no orthostatic hypotension with either agent. The authors conclude that activation of dopaminergic D1 receptor induces a vasodilatory and antihypertensive effect with a reflex increase in sympathetic tone, whereas activation of dopaminergic D2 receptor induces a decrease in sympathetic tone, probably due to a decrease in norepinephrine release at adrenergic endings. The potential effect of these compounds as antihypertensive agents is of great interest because blood pressure reduction can be induced by a new mechanism, i.e. activation of dopaminergic receptors which results in a decrease of the renin angiotensin system or a vasodilatory action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased postsynaptic dopaminergic and cholinergic functions in the ventrolateral striatum of spontaneously hypertensive rat

Dopamine and acetylcholine receptor functions in spontaneously hypertensive rats (SHR) and in control progenitor Wistar-Kyoto (WKY) rats were assessed, using dopamine D1-like/D2-like receptor-mediated and acetylcholine receptor-mediated jaw movements as readout parameters. Spontaneous behaviours such as locomotor activity, vacuous chewing, grooming, sniffing and rearing occurred significantly more in SHR than in WKY rats. In the anaesthetised rats, a mixture of SKF 38393 (5 micrograms), a dopamine D1-like receptor agonist, and quinpirole (10 micrograms), a dopamine D2-like receptor agonist, readily produced repetitive jaw movements in WKY rats, but not SHR, when bilaterally injected into the ventrolateral striatum; such injections into the nucleus accumbens shell were ineffective in each strain. Bilateral injections of carbachol (2.5 micrograms each side), an acetylcholine receptor agonist, into the ventrolateral striatum elicited repetitive jaw movements in both SHR and WKY rats, but to a far less degree in SHR. The present study demonstrates that spontaneous behaviours are enhanced in SHR, and that postsynaptic dopamine D1-like/D2-like receptors and acetylcholine receptors in the ventrolateral striatum of SHR are hyposensitive when compared to those of WKY rats.     

Cardiovascular actions of nitric oxide synthase inhibition in the portal hypertensive rat

相似文献   

Brain and vascular monoamine oxidase activity in the deoxycorticosterone-salt hypertensive rat.

1 The role of monoamine oxidase (MAO) in the maintenance of deoxycorticosterone-sodium chloride (DOCA-salt) hypertension was investigated by assaying the MAO activity both in central as well as peripheral blood vessels and in brain tissue. 2 The results suggest that the activity of MAO in the DOCA-salt hypertensive rat is similar to the activity present in the normotensive rat.     

Cardiovascular activity of SK&F 64139 in the hypertensive rat

SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) produces a dose-related antihypertensive effect in rats treated with desoxycorticosterone acetate and administered saline in their drinking water (DOCA-salt rats), lowering both systolic and diastolic blood pressure by 40 mm Hg after an oral dose of 25 mg/kg in a conscious animal. This antihypertensive effect can also be observed after intravenous infusion in an anesthetized DOCA rat. The fall in blood pressure is accompanied by bradycardia, which can be blocked by the combination of propranolol plus vagotomy, and a decrease in peripheral vascular resistance. In contrast to the results in the DOCA rat, only minimal effects on blood pressure were produced in normotensive rats. Although SK&F 64139 is a potent inhibitor of phenylethanolamine N-methyltransferase (PNMT), the time course of blood pressure reduction is not consistent with PNMT inhibition as a mechanism for its antihypertensive action. SK&F 64139 decreases the turnover rate of cardiac norepinephrine in DOCA-salt rats, suggesting that its antihypertensive effect may results from a centrally mediated inhibition of sympathetic outflow to the periphery.     

Effect of sertindole on raised mesolimbic dopaminergic activity in the rat

The effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra-accumbens injection of amphetamine (20 μg). The administration of sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13-day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine-induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra-accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. © 1994 Wiley-Liss, Inc.     

Effects of chronic inhibition of nitric oxide synthase in the genetically hypertensive rat

1. The effects of graded inhibition of nitric oxide synthase (NOS) on blood pressure in the genetically hypertensive (GH) rat strain and NOS activity in regions of the brain (cerebellum, striatum, hippocampus, frontal cortex and medulla oblongata) as a measure of body NOS inhibition were studied. 2. Male GH and normotensive (N) rats (n = 7-10 per group) were given N(G)-nitro-L-arginine methyl ester (L-NAME; 2, 5, 10 or 20 mg/kg per day in drinking water) from age 7 weeks. Age- and weight-matched controls received water only. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method from age 6 weeks. By age 10 weeks, rats were killed and NOS activity was measured. 3. Some GH rats that received over 5 mg/kg per day L-NAME developed stroke-like symptoms and were killed before the end of the treatment period. 4. No difference in NOS activity was found between untreated N and GH strains but, in those that received treatment, a graded inhibition was observed with increasing L-NAME dose levels. The frontal cortex in the GH strain given 20 mg/kg per day L-NAME had NOS inhibition of 90% where the N strain had 73% inhibition. Similar results were seen in the other areas of the brain. 5. Left ventricular mass, weight related, was significantly greater in the GH compared with N and was further elevated by treatment with L-NAME. 6. The SBP at 10 weeks was significantly elevated in GH rats by NOS inhibition with L-NAME in a dose-dependent manner; 25% for 2 mg/kg per day, 31% for 20 mg/kg per day (P < 0.001). There was a non-significant increase in BP in the N-treated groups (average change of 7.5%). 7. Nitric oxide synthase inhibition causing increased SBP in GH rats suggests an abnormality in the nitric oxide-L-arginine pathway in this strain.     

Effect of nitric oxide on apoptotic activity in the rat gastrointestinal tract.

The effect of nitric oxide (NO) on apoptosis in the gastrointestinal mucosa was investigated. Experiments involved long-term exposure of rat gastric mucosal cells in vitro to exogenous NO delivered from the NO, donor S-nitroso-N-acetyl-penicillamine, and the effect of intravenous administration of lipopolysaccharide in vivo, in the presence and absence of the selective inhibitor of inducible NO synthase N-(3-(aminomethyl)benzyl) acetamidine (1400 W). S-nitroso-N-acetyl-penicillamine produced a dose-related inhibition of caspase 3-like activity and DNA fragmentation in isolated gastric mucosal cells. Caspase 3-like activity and DNA fragmentation in gastric, ileal and colonic mucosa were increased both 5 and 24 h after injection of lipopolysaccharide (3 mg/kg, i.v.) to rats in vivo. Administration of 1400 W (5 mg/kg, i.v.) immediately after lipopolysaccharide enhanced caspase 3-like activity and DNA fragmentation above that found with lipopolysaccharide alone. In conclusion, data obtained both in vitro and in vivo suggest that NO exerts an anti-apoptotic effect on rat gastrointestinal mucosal cells.     

Estrous cycle-dependent changes in basal and ethanol-induced activity of cortical dopaminergic neurons in the rat.

The influence of the estrous cycle on dopamine levels in the rat medial prefrontal cortex under basal and ethanol-stimulated conditions was evaluated by microdialysis. The basal dopamine concentration in the dialysate varied markedly during the estrous cycle, being highest in estrus and lowest in proestrus. Furthermore, a challenge intraperitoneal administration of ethanol (0.5 g/kg) induced a significant increase in dopaminergic output (+50%) during estrus but had no effect in diestrus or proestrus. Ovariectomy or pretreatment with either finasteride (a 5alpha-reductase inhibitor) or clomiphene (an estrogen receptor antagonist) prevented this ethanol-induced increase in dopamine concentration. The effect of ethanol was restored in ovariectomized rats by pretreatment with estrogen but not by that with progesterone. Our results thus show that the basal levels of dopamine in the prefrontal cortex are dependent on the phase of the estrous cycle. Furthermore, this dependence appears to be attributable to the effects of ovarian steroid hormones and results in a differential sensitivity of the dopaminergic neurons to ethanol. The hormone-induced changes in the activity of these neurons might contribute to the differences in drug sensitivity and mood state apparent among phases of the estrous cycle and between the sexes.     

A study of the renal actions of amlodipine in the normotensive and spontaneously hypertensive rat.

1. In order to quantify the time- and voltage-dependent block of sodium channels by quinidine, we voltage clamped guinea-pig papillary muscles and measured the maximum upstroke velocity (Vmax) of the cardiac action potential. 2. Quinidine reduces Vmax presumably by blocking cardiac sodium channels. In therapeutic concentrations, quinidine causes a small amount of tonic block. Upon depolarization of the cardiac cell membrane, a use-dependent block develops. 3. A slow component of use-dependent block has time- and voltage-dependence similar to that of slow inactivation, develops for the duration of the depolarization or until a steady state is reached. 4. In addition, closely associated with the action potential upstroke, a fraction of the channels blocks very quickly. This represents block of activated or open channels. 5. Near the normal resting potential, channels recover from block with a time constant of 3 to 8 s. At more negative membrane potentials recovery from block occurs slightly faster, while at more positive potentials recovery from block proceeds somewhat more slowly. 6. In terms of the modulated receptor hypothesis, quinidine has a low affinity for the rested state, avidly blocks open sodium channels, but does not bind significantly to inactivated channels. In addition, quinidine blocks channels as they exhibit slow inactivation.     

Pterins inhibit nitric oxide synthase activity in rat alveolar macrophages.

1. The synthesis of nitrite and citrulline from L-arginine by immune-stimulated rat alveolar macrophages and the modulation of this synthesis were studied. 2,4-Diamino-6-hydroxypyrimidine (DAHP), 6R-5,6,7,8-tetrahydro-L-biopterin (BH4) and L-sepiapterin were potent inhibitors of the recombinant interferon-gamma induced production of nitrogen oxides in intact cultured cells with I50 values for BH4 and L-sepiapterin of approximately 10 microM. They were equally effective in inhibiting the induced production of citrulline. This inhibitory effect was concentration-dependent for all three modulators investigated. 2. The inhibitory effects were not dependent on incubation times of either 24 or 48 h, on the immune-stimulus used (lipopolysaccharide, interferon-gamma), or whether these stimuli were added during or after the induction period. 3. Pterin-6-carboxylic acid (PCA), which cannot be converted into BH4, and methotrexate (MTX), which inhibits dihydrofolatereductase but not de novo biosynthesis of BH4, did not change the production of nitrite. 4. The data indicate that DAHP, an inhibitor of the de novo biosynthesis of the co-factor BH4, blocks the nitric oxide synthase activity in intact cells. Since the pterins BH4 and L-sepiapterin blocked the L-arginine dependent production of nitrite and citrulline, the activity of nitric oxide synthase in phagocytic cells may be regulated by metabolic endproducts of the de novo biosynthesis of BH4.     

Acute effect of nicotine on the striatal dopaminergic system in the rat

The acute effects of nicotine (1.5 mg kg-1 day-1) on the striatal dopaminergic system have been examined in the rat. Twenty-four hours after nicotine treatment, spontaneous locomotor activity in response to apomorphine or (+)-amphetamine and the binding of [3H]spiperone to striatal particulates were determined. Pretreatment of nicotine did not alter the characteristics of [3H]spiperone binding to striatal dopamine receptors. The nicotine treatment did not affect the apomorphine-induced locomotor activity, however, the (+)-amphetamine-stimulated locomotor activity was attenuated. These results suggest that nicotine acutely alters the presynaptic dopaminergic activity without significantly affecting the postsynaptic dopaminergic function.