Clonidine induces rat aorta relaxation by nitric oxide-dependent and -independent mechanisms

To find more effective components which can trigger apoptosis in crude rattlesnake venom, and the possible mechanisms by which the venom causes apoptosis in vascular endothelial cells (VECs), we investigated the function of integrin beta4 by using the monoclonal antibody (mAb) of this integrin. We added anti-beta4 mAb 5 microg.ml(-1) to the cells treated with 2 microg.ml(-1) rattlesnake venom; apoptosis of these cells was completely inhibited 6 h after the treatment. Furthermore, the increase of P53 expression induced by the venom was markedly suppressed. The results first demonstrated that there was at least one important component target to integrin beta4 in crude rattlesnake (Crotalus atrox) venom; moreover, this component played its role in the early phase of apoptosis. The results also showed that integrin beta4 participated in signal transduction of apoptosis induced by rattlesnake venom in VEC by up-regulating the expression of p53.     

Stimulation of prostanoid IP and EP(2) receptors dilates retinal arterioles and increases retinal and choroidal blood flow in rats

We examined the effects of vasodilatory prostaglandins (prostacyclin and prostaglandin E₂) and selective agonists for prostanoid EP₂ and EP₄ receptor on the diameters of retinal blood vessels and fundus (retinal/choroidal) blood flow in rats. Male Wistar rats (8- to 10-week-old) were treated with tetrodotoxin (50 μg/kg, i.v.) to eliminate any nerve activity and prevent movement of the eye and infused with a mixture solution of norepinephrine and epinephrine (1:9) to maintain adequate systemic circulation under artificial ventilation. Fundus images were captured with a digital camera that was equipped with the special objective lens for small animals, and the diameters of retinal arterioles and venules were measured on a personal computer. Fundus blood flow was estimated using a laser Doppler flowmetry. Intravenous infusions of prostacyclin and prostaglandin E₂ dilated retinal blood vessels, increased fundus blood flow and decreased systemic blood pressure in a dose-dependent manner. The effects of vasodilatory prostaglandins on retinal arterioles were greater than those on retinal venules. Similarly, a prostanoid EP₂ receptor agonist (ONO-AE1-259-01) dilated retinal blood vessels, and increased fundus blood flow and decreased systemic blood pressure. However, a prostanoid EP₄ receptor agonist (ONO-AE1-329) failed to increase fundus blood flow, despite its comparable depressor response with those to vasodilatory prostaglandins and the prostanoid EP₂ receptor agonist. The responses to forskolin, an activator of adenylyl cyclase, were very similar to those to prostacyclin and the prostanoid EP₂ receptor agonist.

These results suggest that prostacyclin and prostaglandin E₂ act as vasodilators in retinal and choroidal circulation, and prostanoid IP and EP₂ receptors play an important role in the regulation of ocular hemodynamics in rats.     

The neuroprotective effect of a nitric oxide inhibitor in a rat model of focal cerebral ischaemia.

Recent data showed that glutamate toxicity in primary cortical cultures is mediated by nitric oxide. In order to investigate the effect of inhibition of NO synthase on focal cerebral ischaemia in rats, we studied the histological consequences of a middle cerebral artery (MCA) occlusion after post-operative treatment with NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. We found a significant reduction of cortical (-43%) and striatal (-25%) necrotic volumes induced by MCA occlusion, indicating that NO synthesis plays an important role in the neurotoxic cascade leading to neuronal damage after focal cerebral ischaemia in rats.     

Subcutaneous apomorphine increases regional cerebral blood flow in parkinsonian patients via peripheral mechanisms.

1. We have measured regional cerebral blood flow (rCBF) and motor function before and after the subcutaneous (s.c.) injection of apomorphine in parkinsonian patients deprived of their usual treatment for at least 48 h. 2. Nineteen patients, pretreated with domperidone (20 mg three times daily for 48 h), received a mean dose of 5.8 mg s.c. apomorphine. All patients switched 'on'. The mean motor score was significantly improved (-65%, P less than 0.01) but no significant change in rCBF was observed. 3. Seven other patients, not pretreated with domperidone, received a lower dose (0.3 mg) of s.c. apomorphine. No change in motor score was observed while the mean rCBF significantly increased (+12%, P less than 0.05). 4. We conclude that s.c. apomorphine increases rCBF in parkinsonian patients. This effect is independent of the central therapeutic effects of the drug. It is mediated by the stimulation of dopaminergic receptors of the cerebral vessels. These receptors are located outside the cerebral blood brain barrier and can be considered as 'peripheral' ones.     

Nifedipine reduces the increases in cerebral blood flow during hypercapnic episodes

1. Cerebral blood flow (CBF) in the rat was monitored by a venous outflow technique with an extracorporeal circulation which allowed for continuous monitoring of flow over the several hours of the study. 2. Brief challenges with carbon dioxide (CO2) increased the CBF. 3. Nifedipine (1.00 mg/kg), a dihydropyridine calcium antagonist, attenuated the response of the animal to hypercapnia, while leaving the basal flow rate unchanged. 4. This study may have significant implications as to the effect of nifedipine on CBF. 5. Since similar results have been obtained with nifedipine in anoxia, this study suggests that the responses to anoxia and hypercapnia are interrelated and that the resulting hyperemia may be governed by the same mechanisms.     

Differential effects of lumenal L-arginine and NG-nitro L-arginine on blood flow and water fluxes in rat ileum.

1. The role of endogenous mucosal nitric oxide (NO) in the local regulation of H2O absorption and blood flow in rat ileum was studied by perfusing L-arginine (L-Arg) (0.1-1.0 mM) and NG-nitro L-arginine (L-NOARG) (0.01-1.0 mM) through the lumen. D-Arginine (D-Arg) or L-Arg (1 mM), combined with L-NOARG, were used to determine if any of the measured intestinal effects of L-NOARG were exerted through NO formation. 2. Net and unidirectional H2O fluxes and effective mucosal blood flow were measured using 3H2O and [14C]-inulin in the perfusate. Mucosal NO formation was measured as the appearance of lumenal NO2-. 3. L-NOARG, beginning at a concentration of 0.1 mM, decreased net H2O absorption, but had only minor effects on unidirectional H2O fluxes or on blood flow. L-NOARG increased blood pressure, beginning at a concentration of 0.5 mM. 4. L-Arg had no significant effects on net H2O absorption or blood pressure, and only minor effects on unidirectional H2O fluxes and blood flow. 5. NO appearance in the lumen was marginally decreased by 1.0 mM L-NOARG, but not increased by L-Arg. 6. Mucosal blood flow resistance paralleled systemic blood pressure suggesting that vascular effects on the mucosa were exerted only after L-NOARG had reached the general circulation. 7. Lumenal L-Arg reversed the effects of lumenal L-NOARG on net H2O absorption and blood pressure, but D-Arg did not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional cerebral blood flow during enkephalin-induced seizures in the rat

Blood flow, determined by the radioactive microsphere technique during epileptiform seizures induced by [D-Ser2,Leu5]enkephalyl-Thr (DSLET), a specific delta-opioid receptor agonist, was examined in different areas of the brain of the rat at various time intervals. An increase in blood flow to the hippocampus and brain stem was observed 2.5 min after administration of DSLET into the left lateral ventricle. An additional increase in flow occurred in the striatum and cerebellum 2.5 min later (5 min after the injection), at which time both the neural and vascular effects of the drug were most marked. Ten minutes after the administration of the drug, cerebral blood flow in all regions except the hippocampus, returned to the respective baseline values. Since the time-course and the magnitude of functional activity and blood flow in the hippocampus showed a good correlation, it is suggested that this region of the brain may play an essential role in triggering and maintaining the seizure phenomena induced by enkephalin.     

牛磺酸对急性局部脑缺血大鼠脑血流和脑梗死体积的影响

目的 :研究牛磺酸对脑缺血再灌注模型大鼠的局部脑血流和脑梗死体积的影响。方法 :用大脑中动脉栓塞 (MCAO)法制作大鼠急性局部脑缺血再灌注模型 ,分别用 10 ,4 0和 80mg·kg- 1牛磺酸经腹腔注射给药 ,检测缺血 1h和灌注 30min内脑血流 ,再灌注 2 4h后进行神经功能缺损评分并计算脑梗死体积的大小。结果 :MCAO引起大脑中动脉供血区脑血流显著下降 ,牛磺酸可减少脑血流量下降的幅度 ;缺血 1h再灌注 2 4h后 ,模型组脑梗死体积为 (33±s 9) % ,而牛磺酸治疗组脑梗死体积明显缩小 ,各组分别为 (17± 5 ) % ,(12± 5 ) %和 (11± 3) % ;牛磺酸治疗组神经缺损评分比模型组小。结论 :牛磺酸可以增加缺血局部的脑血流量 ,缩小脑梗死体积 ,对急性脑缺血具有脑保护作用。     

Transdermally administered nitric oxide by application of acidified nitrite increases blood flow in rat epigastric island skin flaps

Surgical flaps are commonly used in the reconstruction of tissue defects after tumour surgery and trauma. Flap failure continues to be a clinical problem and the underlying causes are not fully understood. In the present study a system that generates nitric oxide (NO) in a non-enzymatic fashion was created through the acidification with vitamin C of a cream containing increasing concentrations (0.125%, 0.25%, 0.5%, 1.25% and 2.5%) of nitrite (NO(2)(-)). The cream was applied for 30 min to a modified epigastric island skin flap in the rat. Blood flow in the supplying artery was measured by transit-time ultrasound flowmetry throughout the experiment and superficial skin blood flow was measured by laser Doppler perfusion imaging before and after treatment. Mean arterial blood pressure was also monitored. NO and the gas nitrogen dioxide (NO(2)), which is formed when NO reacts with atmospheric oxygen, were measured above the cream using chemiluminescence. In flaps treated with the NO generating cream, a concentration-dependent increase in blood flow in the supplying artery and flap skin of up to 130% was observed. Cream base alone or cream base acidified with vitamin C had no effect on blood flow. Also, concentration-dependent formation of both NO and NO(2) was seen. NO increases both supplying artery blood flow and superficial cutaneous blood flow in an epigastric island skin flap model in the rat indicating that NO is of importance in flap physiology and possibly also for flap survival.     

The L-arginine inhibition of rat middle cerebral artery contractile responses is mediated by inducible nitric oxide synthase

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Acute cerebral focal ischaemia alters the adrenergic and NANC responses in the bisected rat vas deferens

1.Disturbances of the autonomic nervous system are common in right hemisphere stroke patients, including a marked decline in male sexual functions. There is a lack of information on the influence of stroke on male secondary sex organs such as the vas deferens. 2. This study investigates the effect of right brain focal ischaemia on the adrenergic and purinergic responses in isolated epididymal and prostatic portions of rat vas deferens. 3. In both epididymal and prostatic portions the concentration-response curves to noradrenaline are flattened resulting in a reduction (up to 67 - 76%) of the maximum contractile response in the tissue from ischaemic rats compared to the controls. In the prostatic portion from ischaemic rats the concentration-response curve to alpha,beta-methylene ATP was also depressed. 4. The first purinergic and the second delayed adrenergic phase to single pulse was not modified by brain ischaemia. In contrast both phasic and tonic components of the electrically induced contractions by trains of stimuli at high frequencies (2 - 30 Hz) were significantly depressed in the epididymal and prostatic portions from ischaemic rats. 5. These results demonstrate an autonomic imbalance at the level of male sexual secondary organs which may contribute to sexual impairment after stroke.     

Changes in cerebral blood flow during a migraine attack.

Regional cerebral blood flow studies during a typical prodromal phase of a migraine attack in a young woman showed a global decrease of cerebral blood flow in the carotid artery territory. These studies were repeated during the subsequent headache phase of the same attack and hemispheric blood flow increased considerably. Ergotamine tartrate was then administered intramuscularly which brought definite relief of symptoms but no change in cerebral blood flow. Carotid angiography performed immediately afterwards showed retrograde filling of the proximal portion of the basilar artery, which suggested that the brain stem was the site of hyper-perfusion. These findings illustrate certain features underlying both the pathophysiology of migraine itself and its response to ergotamine preparations.     

三七皂苷Rg1对大鼠脑血流量和小鼠微循环的影响及作用机制

目的观察三七皂苷Rg1对脑血流量及微循环的影响,探讨其防治心脑血管疾病,改善预后的作用机制。方法将动物随机分组,分别评价三七皂苷Rg1对大鼠脑血流量,对小鼠脑缺血和小鼠耳廓微循环的影响。结果50 mg.kg-1的三七皂苷Rg1可明显增加大鼠脑血流量,显著延长小鼠断头后喘气时间,且明显增加小鼠耳廓细动脉、细静脉管径及增多耳廓毛细血管数量。结论三七皂苷Rg1可能通过改善动物微循环而增加脑血流量,发挥改善脑缺血的作用。     

Anti-ischaemic efficacy of a nitric oxide synthase inhibitor and a N-methyl-D-aspartate receptor antagonist in models of transient and permanent focal cerebral ischaemia.

1. We have recently developed a new model of transient focal ischaemia in the rat utilising topical application of endothelin-1 to the left middle cerebral artery (MCA). In order to validate this approach the present study assessed the neuroprotective efficacy of the NMDA receptor antagonist dizocilpine (MK-801) in the endothelin-1 model. The anti-ischaemic efficacy of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was subsequently evaluated, and contrasted with its efficacy against permanent focal ischaemia, to determine the utility of the endothelin-1 model for identification of novel pharmacoprotective agents. 2. MK-801 (0.12 mg kg-1 bolus, 108 micrograms kg-1 h-1 infusion i.v., either 1 or 2.5 h pre-transient MCA occlusion (MCAO)) induced hypotension that persisted for approximately 1.5 h so that mean arterial blood pressure (MABP) at the time of MCAO was significantly lower in the 1 h group compared with control (MABP: 86 +/- 11, 68 +/- 6 and 84 +/- 4 mmHg (mean +/- s.d.) for saline, 1 h MK-801 and 2.5 h MK-801 groups respectively). The 2.5 h pretreatment schedule resulted in significant reduction (71%) in the volume of hemispheric damage (assessed 4 h post onset of ischaemia) while the 1 h pretreatment schedule did not (volumes of hemispheric damage: 59 +/- 38, 51 +/- 51 and 17 +/- 28 mm3 for saline, 1 h and 2.5 h MK-801 groups). 3. Thus the considerable neuroprotective effect of MK-801 in the endothelin-1 model of transient focal cerebral ischaemia was highly sensitive to drug-induced hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat.

1. In vivo microdialysis has been used to investigate the concentration of various amino acids and lactate in the extracellular fluid of the rat cortex following focal ischaemia, the probe being placed in the core of the infarct area. 2. An ischaemic infarct was produced in the cortex by use of a photochemical dye (Rose Bengal) and light irradiation. There was a marked increase in lactate concentration (300%) over the next 4 h. Substantial increases were also seen in the concentration of the excitatory (glutamate and aspartate), inhibitory (GABA and taurine) and other amino acids (serine, alanine, asparagine). 3. Administration of chlormethiazole (200 mg kg-1, i.p.) 5 min after the onset of ischaemia reduced the ischaemia-induced neurodegeneration by approximately 30%, measured histologically 24 h later. 4. Chlormethiazole (200 mg kg-1, i.p.) administration also reduced the rise in the concentration of lactate and all the amino acids by between 30-60% during the first 4 h after the onset of ischaemia. 5. Analysis of the time course of the amino acid changes suggested that chlormethiazole is not neuroprotective because of the inhibition of excitatory amino acid release but rather that the attenuated rise in the concentration of all the amino acids is reflective of neuroprotection and therefore decreased cell death. 6. This conclusion was supported by the observation that the enhanced efflux of glutamate from slices of cerebral cortex which had been induced by incubation of the slices in an hypoxic medium was unaltered by the presence of a high concentration of chlormethiazole (1 mM) in the medium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Delayed administration of ethyl eicosapentate improves local cerebral blood flow and metabolism without affecting infarct volumes in the rat focal ischemic model.

The objective of this study was to assess whether delayed administration of ethyl eicosapentate has a favorable effect on cerebral blood flow and metabolism in rats suffering from cerebral infarction. Adult male Sprague-Dawley rats weighing 250-300 g were used. Left middle cerebral artery occlusion was induced for 2 h. After 24-h reperfusion, rats were treated with ethyl eicosapentate (100 mg kg(-1); ethyl eicosapentate treated) or saline (saline treated) by gavage, once a day for 4 weeks. After 4 weeks, local cerebral blood flow and local cerebral glucose utilization were measured autoradiographically, and infarction size was measured. In the ischemic side, the local cerebral blood flow and local cerebral glucose utilization values in the parietal cortex and the lateral caudoputamen, which constituted the ischemic core, were equivalent to zero in both groups. The peri-infarcted areas, i.e., the frontal cortex and medial caudoputamen, were significantly higher in the ethyl eicosapentate treated group than the saline treated group. In the non-ischemic side, ethyl eicosapentate treated group had a tendency to improve local cerebral blood flow and local cerebral glucose utilization values in a medial caudoputamen. These results suggest that ethyl eicosapentate treatment may be beneficial for maintaining cerebral circulation and metabolism except for infarction area after cerebral infarction.     

Polydeoxyribonucleotides and nitric oxide release from guinea-pig hearts during ischaemia and reperfusion.

1. Two polydeoxyribonucleotides, produced by the controlled hydrolysis of DNA of mammalian lung (defibrotide and its lower molecular weight fraction, P.O. 085 DV), were studied for their ability to modify the release of nitrite and the coronary flow in perfusates collected from isolated, normally perfused hearts of guinea-pigs and from hearts subjected to regional ischaemia and reperfusion. 2. In guinea-pig normally perfused hearts, both defibrotide (DFT) and its fraction, P.O. 085 DV, increase the amount of nitrite appearing in perfusates in a concentration-dependent fashion. At the highest concentration studied (10(-6) M), P.O. 085 DV was more effective than DFT. A concomitant increase in the coronary flow was observed. 3. The increase in nitrite in perfusates and the increase in coronary flow induced by both DFT and P.O. 085 DV were significantly reduced by NG-monomethyl-L-arginine (L-NMMA, 10(-4) M), an inhibitor of nitric oxide synthase (NOS). 4. The endothelium-dependent vasodilator, acetylcholine (ACh), enhances the formation of nitrite and the coronary flow. Both the increase in coronary flow and in the formation of nitrite were significantly reduced by L-NMMA (10(-4) M). 5. In guinea-pig hearts subjected to ischaemia and reperfusion, the effect of both compounds in increasing the amount of nitrite in perfusates was more evident and more pronounced with P.O. 085 DV. 6. Reperfusion-induced arrhythmias were significantly reduced by both compounds to the extent of complete protection afforded by compound P.O. 085 DV. 7. The cardioprotective and antiarrhythmic effects of DFT and P.O. 085 DV are discussed.     

Uncoupling of cerebral blood flow and glucose utilization by dihydroergocristine in the conscious rat

Summary Dose-dependent effects of the dihydrogenated ergot alkaloid dihydroergocristine on physiological variables, local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were evaluated in the conscious rat after intravenous injection. Heart rate was reduced with 2.5 mg/kg and 20 mg/kg dihydroergocristine. LCBF and LCGU were determined autoradiographically by employing the ¹⁴C-iodoantipyrine or ¹⁴C-2-deoxyglucose technique, respectively. At a dose of 0.5 mg/kg, dihydroergocristine neither changed LCGU nor LCBF, while at 2.5 mg/kg a slight decrease in LCGU was measured, which was more pronounced at 20 mg/kg. LCBF was significantly increased in several structures at 2.5 mg/kg, but it was markedly reduced at 20 mg/kg. The divergent effects on LCBF and LCGU at a dose of 2.5 mg/kg suggest a potential capacity of dihydroergocristine to uncouple the close interrelation of cerebral blood flow and cerebral energy metabolism.Send offprint requests to T. Beck at the above address     

Celiprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release

Celiprolol is a selective beta(1)-adrenoceptor antagonist with antihypertensive actions, which causes renal vasodilation by increasing tissue nitric oxide (NO) levels. The authors tested whether celiprolol increases coronary blood flow (CBF) by increasing cardiac NO release in the ischemic heart in vivo. In open-chest dogs, coronary perfusion pressure of the left anterior descending coronary artery was reduced so that CBF decreased to 60% of control levels, and thereafter, coronary perfusion pressure was maintained constant. Ten minutes after the reduction of coronary perfusion pressure, we infused celiprolol into the left anterior descending coronary artery and measured fractional shortening and lactate extraction ratio as indices of regional myocardial contractility and metabolism. CBF significantly increased from 51.5 mL/100 g/min +/- 1.9 to 67.0 mL/100 g/min +/- 5.1 20 minutes after celiprolol infusion without changes in coronary perfusion pressure, while fractional shortening and lactate extraction ratio increased. Celiprolol also increased cardiac NO release. The L omega-nitroarginine methyl ester, the inhibitor of NO synthase, attenuated the increases in CBF, fractional shortening, lactate extraction ratio, and cardiac NO release due to celiprolol. ICI 118551, a beta(2)-adrenoceptor antagonist, did not blunt the effects of celiprolol and a nonselective beta-adrenoceptor antagonist, propranolol, increased neither CBF nor cardiac NO release, indicating that the effect of celiprolol is independent of beta-adrenoceptor blockade. It was concluded that celiprolol mediates coronary vasodilation and improves myocardial ischemia through NO-dependent mechanisms.     

DMPP-evoked increases in postganglionic sympathetic nerve activity and blood pressure occurs by two mechanisms in the rat

1 Intravenous administration of the ganglionic nicotinic receptor agonist DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) into urethane-anaesthetized rats evoked dose-dependent increases in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). 2 The ganglionic nicotinic receptor antagonists pentolinium and hexamethonium either alone or combined did not inhibit the increase in RSNA and MAP evoked by 50 to 200 μg kg^?1 doses of DMPP. The increase in renal sympathetic nerve activity evoked by DMPP occurred as a brief burst in firing. 3 The increase in MAP, but not RSNA, evoked by DMPP in the presence of pentolinium was inhibited by the selective α₁-adrenergic receptor antagonist prazosin. 4 The non-selective α-adrenoceptor and NPY receptor antagonist benextramine also inhibited the increase in MAP without inhibiting the increase in RSNA. Surprisingly, the combination of benextramine and pentolinium, or benextramine and hexamethonium, completely blocked the DMPP-evoked increase in RSNA and thus the increase in MAP. 5 The uptake₁ antagonist desipramine combined with pentolinium did not affect the DMPP-evoked increases in MAP or RSNA when compared to the responses evoked in the presence of pentolinium alone. 6 Adding the selective M₁ muscarinic receptor antagonist telenzepine to pentolinium and prazosin did not inhibit the increase in RSNA evoked by a 100 μg kg^?1 dose of DMPP. 7 While the DMPP-evoked increase in MAP in the presence of ganglionic nicotinic receptor antagonists is primarily dependent upon activation of α₁-adrenoceptors, the increase in RSNA occurs via activation of ganglionic nicotinic receptors and activation of a mechanism susceptible to blockade by benextramine.