猫大脑动脉的胆碱能性血管收缩(英文)

本文对猫脑动脉的胆碱能神经冲动传递的离体研究结果进行如下两方面的探讨:1)在乙酰胆碱亚舒张浓度下的反应;2)在阿托品敏感性神经源性血管舒张的可能性上的争议. 观察结果表明,55％的脑动脉血管条对0.1～3nmol·L~(-1)浓度的乙酰胆碱(ACh)产生了收缩反应,高于上述浓度的乙酰胆碱引起了血管内皮依赖性的舒张反应.进一步提高乙酰胆碱浓度则导致直接的血管平滑肌的收缩反应,0.1～3 nmol·L~(-1)亚舒张浓度乙酰胆碱引起的血管收缩反应以及高于此浓度乙酰胆碱所致的血管内皮依赖性舒张反应仅发生干预先已收缩而有张力的脑血管,亚舒张浓度乙酰胆碱(0.1～3nmol·L~(-1))所致的收缩反应并不依赖于血管内皮的存在,在Krebs溶液4℃条件下保存5d的同样脑血管对亚舒张浓度乙酰胆碱(0.1～3nmol·L~(-1))所致的收缩反应频率下降至13％,但血管内皮依赖性舒张反应或直接的血管平滑肌收缩反应在如此条件下保存的脑血管上依然完好. 以上结果与乙酰胆碱作为脑血管神经末梢递质导致神经源性血管舒张的假说是不相符合的。     

Analysis of the receptors mediating vascular actions of bradykinin

Summary A range of bradykinin (BK) analogues was assessed for their ability to antagonise the action of BK on rabbit jugular vein, a B₂-receptor containing tissue, and compared with their action against BK-induced increases in skin vascular permeability in the rabbit and rat. The results demonstrate that modification of the BK (nonapeptide) structure by the insertion of certain d-amino acids in positions 5, 7 and 8 in addition to elongation of the amino terminal resulted in compounds with potent antagonistic action against BK on rabbit jugular vein and rabbit skin vascular permeability. The same BK analogues did not antagonise the action of BK on rat skin vascular permeability. It is concluded that the kinin receptor mediating an increase in vascular permeability in the rabbit is the same as that mediating contraction of the rabbit jugular vein in vitro, that is the B₂-type. The kinin receptor mediating an increase in skin vascular permeability in the rat is difficult to classify but does not appear to be of the B₂ type. Send offprint requests to E. T. Whalley     

Effects of chronic in vivo administration of nitroglycerine on ACh-induced endothelium-dependent relaxation in rabbit cerebral arteries

BACKGROUND AND PURPOSE: In the setting of nitrate tolerance, endothelium-dependent relaxation is reduced in several types of peripheral vessels. However, it is unknown whether chronic in vivo administration of nitroglycerine modulates such relaxation in cerebral arteries. EXPERIMENTAL APPROACH: Isometric force and smooth muscle cell membrane potential were measured in endothelium-intact strips from rabbit middle cerebral artery (MCA) and posterior cerebral artery (PCA). KEY RESULTS: ACh (0.1-10 microM) concentration-dependently induced endothelium-dependent relaxation during the contraction induced by histamine in both MCA and PCA. Chronic (10 days) in vivo administration of nitroglycerine reduced the ACh-induced relaxation in PCA but not in MCA, in the presence of the cyclooxygenase inhibitor diclofenac (3 microM). In the presence of the NO-synthase inhibitor N (omega)-nitro-L-arginine (L-NNA, 0.1 mM) plus diclofenac, in MCA from both nitroglycerine-untreated control and -treated rabbits, ACh (0.1-10 microM) induced a smooth muscle cell hyperpolarization and relaxation, and these were blocked by the small-conductance Ca(2+)-activated K(+)-channel inhibitor apamin (0.1 microM), but not by the large- and intermediate-conductance Ca(2+)-activated K(+)-channel inhibitor charybdotoxin (0.1 microM). In contrast, in PCA, ACh (<3 microM) induced neither hyperpolarization nor relaxation under these conditions, suggesting that the endothelium-derived relaxing factor is NO in PCA, whereas endothelium-derived hyperpolarizing factor (EDHF) plays a significant role in MCA. CONCLUSIONS AND IMPLICATIONS: It is suggested that in rabbit cerebral arteries, the function of the endothelium-derived relaxing factor NO and that of EDHF may be modulated differently by chronic in vivo administration of nitroglycerine.     

Pharmacological evidence for the 5-HT7 receptor mediating smooth muscle relaxation in canine cerebral arteries.

1. We investigated in the present study whether 5-HT is able to exert direct relaxant responses in canine basilar and middle cerebral arteries via the 5-HT7 receptor. 2. In arterial rings deprived of endothelium and pre-contracted with prostaglandin F2 alpha (2 microM), 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, sumatriptan or alpha-methyl-5-HT produced further increase in tone and/or slight relaxation. Blockade of 5-HT1B 1D and 5-HT2A receptors with GR127935 (1 microM) and ketanserin (0.1 microM), respectively, antagonized the vasoconstrictor component of the response and unmasked a concentration-dependent relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and alpha-methyl-5-HT remained inactive as relaxant agonists. The rank order of agonist potency in both arteries was 5-CT > 5-HT > 5-methoxytryptamine > sumatriptan > or = alpha-methyl-5-HT. 3. In dog basilar artery, pre-incubated with GR127935 (1 microM) and ketanserin (0.1 microM) and precontracted with prostaglandin F2 alpha (2 microM), the 5-HT7 ligands, clozapine (1 microM), mesulergine (0.3 microM), methiothepin (3 nM), risperidone (3 nM), spiperone (1 microM) and LY215840 (10-100 nM), produced significant rightward shifts of the concentration-response curves for 5-HT and 5-CT. Only methiothepin and risperidone reduced significantly the maximum relaxant response (Emax), whilst the other drugs behaved as competitive antagonists with affinity values (pKB) that significantly correlated with their binding affinity (pKi) at recombinant 5-HT7 receptors. 4. These data disclosing the involvement of the 5-HT7 receptor in cerebrovascular relaxation may be strongly relevant in the light of: (1) the involvement of 5-HT in migraine; (2) the putative linkage between cephalovascular vasodilatation and migraine headache; and (3) the relatively high 5-HT7 receptor affinity of migraine prophylactic 5-HT antagonists.     

Peroxynitrite-induced relaxation in isolated canine cerebral arteries and mechanisms of action

The present study was undertaken to determine the vascular actions of peroxynitrite (ONOO(-)), the product of superoxide and nitric oxide (NO), in isolated canine cerebral arteries and to gain insight into its potential mechanisms of action. In the absence of any vasoactive agent, ONOO(-) (from 10(-7) to 10(-6) M) was able to reduce the basal tension. In prostaglandin F2alpha-precontracted canine basilar arterial rings, ONOO(-) elicited concentration-dependent relaxation at concentrations from 10(-8) to 10(-5) M. The effective concentrations producing approximately 50% maximal relaxation (EC(50)) to ONOO(-) were 4.06 x 10(-6) and 4.12 x 10(-6) M in intact and denuded rings, respectively (P > 0.05). No significant differences in relaxation responses were found in ring preparations with or without endothelium (P > 0.05). The presence of either 5 microM methylene blue (MB) or 5 microM 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one (ODQ) significantly inhibited the relaxations induced by ONOO(-). Tetraethylammonium chloride (T-2265) significantly decreased the ONOO(-)-induced relaxations in a concentration-dependent manner. However, ONOO(-) had no effect on rings precontracted by high KCL (P > 0.05). Addition of low concentrations of calyculin A (50 nM) was able to abolish the ONOO(-)-induced relaxation. Furthermore, ONOO(-) significantly inhibited calcium-induced contractions of K(+)-depolarized canine cerebral rings in a concentration-related manner. Lastly, a variety of pharmacological agents and antagonists including L-NMMA, l-arginine, indomethacin, atropine, naloxone, diphenhydramine, cimetine, glibenclamide, haloperidol, etc., did not influence the relaxant effects of ONOO(-) on the rings. Our new results suggest that ONOO(-)-triggered relaxation, on canine cerebral arteries, is mediated by elevation of cyclic guanosine monophosphate (cGMP) levels, membrane hyperpolarization via K+ channel activation, activation of myosin light chain phosphatase activity, and interference with calcium movement and cellular membrane Ca(2+) entry.     

B2 kinin receptor activation is the predominant mechanism by which trypsin mediates endothelium-dependent relaxation in bovine coronary arteries

The roles of kinin and protease-activated receptors (PAR) in endothelium-dependent relaxations to the serine protease, trypsin, were examined in rings of bovine left anterior descending coronary artery (LAD). Trypsin (0.01-30 U/ml) caused biphasic, endothelium-dependent relaxations-a high potency (0.01-0.3 U/ml), low efficacy relaxation [maximum relaxation (R (max)), 9.0 +/- 5.1%] followed by a lower potency (1-30 U/ml) but high efficacy (R (max), 90.4 +/- 5.5%) relaxation, which was abolished by aprotinin. Captopril (10 muM) caused an ~10-fold leftward shift of the second phase response such that the first phase was masked. The second phase relaxation to trypsin was inhibited in a concentration-dependent, non-surmountable manner by the B(2) antagonist, HOE-140. At 3 nM HOE-140, the second phase response to trypsin was abolished unmasking the first phase. Kallikrein (0.0003-0.3 U/ml) caused monophasic, endothelium-dependent relaxations (R (max), 33.7 +/- 14.6%), which were potentiated by captopril (R (max), 94.2 +/- 1.0%) and abolished by HOE-140. In the presence of captopril, the second phase relaxation to trypsin was only minimally inhibited by either N(G)-nitro-L: -arginine (100 muM) or 67 mM [K(+)](o) alone but markedly reduced when these two treatments were combined (R (max), 26.1 +/- 11.6% versus 98.6 +/- 2.9% in controls). The PAR1-activating peptide, SFLLRN (0.1-30 muM), but not the PAR2-activating peptide, SLIGRL, caused concentration-dependent relaxations (pEC(50), 5.9 +/- 0.0%; R (max), 43.3 +/- 8.3%). In conclusion, trypsin causes endothelium-dependent relaxations in the bovine LAD predominantly via release of endogenous BK, which in turn activates endothelial B(2) receptors. Only a minor role for PAR1-like receptors was evident in this tissue.     

Differential modulation of murine lung inflammation by bradykinin B1 and B2 selective receptor antagonists

The effect of bradykinin receptor antagonists was studied in a mouse (C57Bl/6) model of allergic lung inflammation. Bradykinin B(2) receptor antagonist HOE-140 (D-Arg-[Hyp(3),Thi(5),Dtic(7)-Oic(8)]bradykinin) or bradykinin B(1) receptor antagonist R-954 (Ac-Orn[Oic(2),alphaMePhe(5),betaD-Nal(7)Ile(8)]des-Arg(9)-bradykinin) were given i.p. to ovalbumin sensitized mice 30 min before antigen challenge. After 24 h, bronchoalveolar lavage was performed for cell analysis and the lungs were removed for evaluation of airway hyperreactivity and histopathology. Treatment with HOE-140 caused a significant increase in bronchoalveolar lavage cell number: eosinophils (182%), neutrophils (98%), lymphocytes CD(4)(+) (192%), CD(8)(+) (236%), B220 (840%), Tgammadelta(+) (194%) and NK1.1(+) (246%). Hyperreactivity and mucus secretion were not significantly affected in this group. Treatment with R-954 significantly reduced eosinophil (79%) and neutrophil (83%) but has no effect on lymphocytes number in bronchoalveolar lavage fluid. Airway hyperreactivity and mucus secretion were reduced by this treatment (84% and 35%, respectively). These results show important modulatory effect of bradykinin B(1) and B(2) receptors on allergic lung inflammation.     

Characterization of bradykinin receptors mediating catecholamine release in PC12 cells

The rat pheochromocytoma cell line PC12, which is a widely used model for analyzing stimulus-secretion coupling, was investigated for the effects of kinins on catecholamine release. Subtypes of kinin receptors were characterized using the B₁ agonist desArg⁹-bradykinin, the B₂ agonist bradykinin and the B₂ antagonists [Thi^5,8, D-Phe⁷]-bradykinin, D-Arg[Hyp³, D-Tic⁷, Oic⁸]-bradykinin (HOE 890307) and D-Arg-[Hyp³, Thi⁵, D-Tic⁷, Oic⁸]-bradykinin (HOE 140). The effectiveness of acute and chronic exposure to angiotensin I converting enzyme inhibitors as well as pretreatment of the cells with bacterial lipopolysaccharides in modulating B₁ or B₂ receptor systems was also tested.Bradykinin stimulated noradrenaline release from PC12 cells at low concentrations (EC₅₀ = 1 nM), maximally inducing a release of 43.7% of the cellular content within 15 min. In comparison with acetylcholine and K⁺-induced depolarization, bradykinin was the most effective stimulus. DesArg⁹-bradykinin was only effective at very high concentrations (> 30 M). Like in other neuronal cells, the B₂-specific partial antagonist [Thi^5,8, D-Phe⁷]-bradykinin acted as a low-affinity agonist without any antagonistic effects. The B₂ antagonists HOE 890307 and HOE 140 exerted no agonistic effects and concentration-dependently inhibited bradykinin-induced noradrenaline release, showing competitive antagonism with K_i values of 1.38 nM and 0.66 nM, respectively. Only at the highest concentration used (1 M), HOE 140 did depress the maximal response to bradykinin. HOE 890307 also abolished the effects of desArg⁹-bradykinin and [Thi^5,8, D-Phe⁷]-bradykinin. Acute or chronic inhibition of the angiotensin I converting enzyme or application of lipopolysaccharides, which all can lead to induction of the B₁ receptor subtype in vivo, did not alter the secretory response of PC12 cells to either bradykinin (0.1 and 30 nM) or desArg⁹-bradykinin (1 M).In conclusion, noradrenaline release from PC12 cells is stimulated via B₂, but not B₁, receptors. Despite the fact that the receptor system is highly susceptible to stimulation by low-affinity ligands, HOE 890307 and HOE 140 are pure antagonists, with only high concentrations of HOE 140 (> 1 M) showing a non-competitive type of inhibition. Induction of B₁ receptors which could stimulate noradrenaline release could not be demonstrated in this model. The possible role of bradykinin in modulating sympathetic neurotransmission during inhibition of angiotensin I converting enzyme is discussed.     

Pharmacological and functional characterization of bradykinin B2 receptor in human prostate

The objective of this study was to pharmacologically characterize bradykinin receptors, a component of the kallikrein-kinin system, in normal human prostate cells. In primary cultured human prostate stromal cells, bradykinin, but not [des-Arg9]bradykinin or [des-Arg10]kallidin, produced calcium mobilization or inositol phosphates accumulation with potencies (pEC50) of 8.8+/-0.2 and 8.2+/-0.2, respectively. This was consistent with abundance of bradykinin B2 mRNA over bradykinin B1 mRNA in prostate stromal cells. Although the prostate epithelial cells (prostate epithelium, BPH-1, and PC-3) expressed mRNA for bradykinin B2 receptors (albeit in lesser amounts than stromal cells), bradykinin was not functionally efficacious in the epithelial cells. Increasing concentrations of D-arginyl-L-arginyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-D-1,2,3,4-tetrahhydro-3-isoquinolinecarbonyl-L-(2alpha,3beta,7alphabeta)-octahydro-1H-indole-2-carbonyl-L-arginine (HOE-140), a bradykinin B2-selective peptide antagonist, attenuated bradykinin concentration-response curves in human prostate stromal cells with apparent estimate of affinity similar to that for the human bradykinin B2 receptor. Bradykinin (10 nM) caused proliferation of prostate stromal cells and phosphorylated extracellular signal-regulated kinases (ERK-1 and ERK-2) that were blocked by HOE-140 (1 microM). This study demonstrated that, in primary cultures of normal human prostate stromal cells, bradykinin activates bradykinin B2 receptors that may play a significant role in proliferation via activation of ERK-1/2 pathways.     

胆碱能M受体信号通路在芍药苷抗脑缺血神经保护中的作用

目的研究芍药苷(PAE)调节胆碱能M受体及其信号通路抗脑缺血的神经保护作用,为脑缺血临床防治提供理论与实验依据。方法在大脑中动脉梗死(MCAO,缺血90min,再灌24 h)诱导的大鼠局灶性脑缺血模型上,观察缺血同时给予PAE(2.5、5和10 mg.kg-1,ip,14 days)对脑梗死体积及神经症状的影响;于再灌24 h后,分别取皮层、海马和纹状体脑组织,以RT-PCR方法研究PAE对M受体、G蛋白及ATP敏感性钾通道基因表达的影响。结果 PAE可明显降低脑梗塞体积、改善神经功能缺陷;拮抗脑缺血诱导的M1、M3、M4和M5基因表达的降低及M2基因表达的增高;抑制Gi蛋白的病理性增高及Gαq/11蛋白的降低;逆转Kir6.2/Kir6.1的病理性降低。结论 M受体及其通路可能参与PAE的抗脑缺血神经保护作用。     

Comparison of cromakalim-induced relaxation of potassium precontracted rabbit,cat, and rat isolated cerebral arteries

Summary The effects of cromakalim were investigated in KCl-precontracted cat, rabbit, and rat isolated cerebral arteries with intact endothelium. Potassium induced contraction of all cerebral arteries studied, but exhibited marked vessel and species variation with no spasm to 20 or 30 mmol/l KCl in the rat basilar artery or 20 mmol/l KCl in the rabbit middle cerebral artery. On sustained tension to 20 mmol/l KCl, cromakalim induced concentration-related relaxation in the rabbit basilar artery and the cat basilar and middle cerebral arteries with Hill coefficients greater than unity. Cromakalim was more potent in the rabbit basilar artery precontracted with 20 or 30 mmol/KCl than in the rabbit middle cerebral artery or the cat basilar or middle cerebral artery. Elevation of the KCl concentration to 50 mmol/l inhibited cromakalim-induced relaxation and produced a decrease in the Hill coefficient. Preincubation of cerebral arteries with glibenclamide (100 nmol/l–1 mol/1) produced concentration-related inhibition of the cromakalim-induced relaxation in the rabbit basilar, cat basilar, and cat middle cerebral arteries precontracted with 20 mmol/l KCl. The degree of rightward shift of concentration-effect curves by glibenclamide was calculated at the EC₂₅, EC₅₀, and EC₇₅ levels. A good correlation was observed between the shifts at the EC₅₀ and EC₅₀ levels. However, the shift in concentration — effect curves for cromakalim produced at the EC₂₅ level was markedly less than the-EC₅₀ or EC₇₅ levels in the presence of 1 mol/1 glibenclamide. The pA ₂ values for glibenclamide calculated at the EC₅₀ level were 6.6 ± 0.09, 7.1 ± 0.1, and 6.5 ± 0.5 in the rabbit basilar, cat basilar, and cat middle cerebral artery, respectively. The slope of the Schild regression for the inhibitory effect of glibenclamide in the rabbit basilar artery was significantly greater than unity but did not differ from unity in cat cerebral arteries. Glibenclamide (1 mol/l) produced a similar degree of inhibition of the cromakalim-induced relaxation in the 30 mmol/l KCl precontracted rabbit middle cerebral artery and in the rabbit basilar artery exposed to 20 mmol/l KCl. In contrast, tolbutamide 10 mol/l was essentially inactive against the cromakalim-induced relaxation in all vessels studied. It is concluded that cromakalim produces concentration-dependent relaxations of rabbit and cat isolated cerebral arteries by a mechanism that is similar to that identified in peripheral vasculature and visceral smooth muscle. In this study we were unable to demonstrate effects of cromakalim on the KCl precontracted rat basilar artery, possibly due to the low sensitivity of this preparation to KCl. Send offprint requests to M. Wahl at the above address     

Analysis of the mechanism of action of bradykinin on human basilar artery in vitro

Summary Bradykinin (BK) initially produced concentration-related relaxations of human basilar artery in vitro. Concentration-effect curves constructed at 2 h intervals to BK over an 8 h period were reproducible. The rank order of potency of three kinins on the human basilar artery was found to be BK > methionyl-lysyl-BK > des-Arg⁹-BK. The B₂-receptor antagonist Thi^5,8 d-Phe⁷-BK but not the B₁-receptor antagonist des-Arg⁹-Leu⁸-BK selectively blocked BK-induced relaxations of the human basilar artery.The relaxant effects of bradykinin and acetylcholine but not papaverine were attenuated after removal of the endothelium or treating the tissues with BW755C. Indomethacin was without effect. Concentration-effect curves to angiotensin I were markedly attenuated by captopril at a concentration which had no effect on BK, angiotensin II or 5-hydroxytryptamine responses. It is concluded that BK induced relaxations of the human basilar artery are mediated via activation of a B₂ receptor and the response is dependent upon the release of a factor present in the endothelium. Angiotensin converting enzyme is present in the human basilar artery and is important for the conversion of angiotensin I to angiotensin II but apparently not for the degradation of BK. It is likely that other kininases are present and active in the tissue. Send offprint requests to E. T. Whalley at the above address     

Cocaine-like action of diphenhydramine in cat cerebral arteries

Diphenhydramine (5.3 X 10(-7) M) significantly reduced the tritium efflux evoked by 10(-7) M tyramine from cat cerebral arteries preloaded with [3H]noradrenaline but not that brought about by 50 mM KCl. These results indicate the ability of diphenhydramine to block the amine neuronal uptake.     

Effect of stretching on the sensitivity of the guinea pig ileum to bradykinin and on its modification by bradykinin potentiating peptides

The sensitivity of the guinea pig isolated ileum to bradykinin, but not to other agonists, was increased ca. 2-fold during the 3–4 h following mounting of the preparation under 1 g load. Concomitantly, a decrease was observed in the bradykinin potentiating effect of BPP9a, and of potentiator B but not potentiator C. This decrease was observed only with analogues of BPP9a or potentiator B which retained one or both of the basic amino acid residues in these peptides. Similar stretching of the rat isolated uretus did not affect bradykinin sensitivity or the potency of bradykinin potentiating peptides. Kininase activity of the ileum significantly increased during the 4 h period after mounting of the loaded preparation, but was not affected by treatment with BPP9a. It is proposed that bradykinin sensitivity is favoured by the changes in sodium and potassium transport in the cell membrane caused by stretching of the ileum, and that a similar mechanism may be partly responsible for the action of bradykinin potentiating peptides.     

Neurogenic vasoconstriction of cat cerebral and femoral arteries

1. Segments of cat posterior communicating artery and femoral artery submitted to field electrical stimulation showed frequency-dependent contractile responses which were decreased by tetrodotoxin, bretylium, and reserpine pretreatment. Phentolamine could only reduce the response of femoral artery segments. Superior cervical gangliectomy also decreased the contractions of cerebral cylinders. 2. The tritium released by electrical stimulation from both kinds of vessels preloaded with [3H]noradrenaline appeared reduced in the presence of tetrodotoxin, bretylium, and after reserpine pretreatment. It was also decreased in cerebral segments after superior cervical gangliectomy. 3. These results suggest that the electrical field stimulates the sympathetic nerve endings of these vessels.     

Chronic At1 receptor blockade alters the mechanisms mediating hypoxic dilation in middle cerebral arteries

The purpose of this study was to determine whether chronic blockade of the angiotensin II (ANG II) AT1 receptor under normal physiological conditions impairs vascular relaxation mechanisms in isolated middle cerebral arteries (MCA). Male Sprague-Dawley rats on a standard diet were given losartan (1 mg/mL) in the drinking water or normal water ad libitum for 7 days. Vessel diameters were measured by television microscopy before and during exposure to various vasodilator agonists and reductions in PO2 from 140 mm Hg to 35-45 mm Hg. Dilations to acetylcholine (1 microM), the stable prostacyclin analogue iloprost (10 pg/mL), and the Gs protein activator cholera toxin (1 ng/mL) were completely eliminated in vessels from losartan-treated animals. However, middle cerebral arteries from control and losartan-treated rats still demonstrated significant dilations in response to reduced PO2. Hypoxic dilation of middle cerebral arteries from control rats was eliminated by indomethacin (1 microM) and unaffected by the NOS inhibitor L-NAME (100 microM) whereas dilation in response to reduced PO2 in middle cerebral arteries from losartan-treated rats was eliminated by L-NAME and unaffected by indomethacin. Middle cerebral arteries from control and losartan-treated animals exhibited similar dilations in response to the NO-donor sodium nitroprusside (1 microM). These data suggest that AT1 receptor activation is important in maintaining normal vascular relaxation mechanisms in cerebral resistance arteries during normal physiological conditions, and that AT1 receptor blockade causes a shift in the mechanisms of hypoxic dilation of middle cerebral arteries from cyclooxygenase metabolites to NO.     

Influence of the endothelium on histamine-induced relaxation of rat middle cerebral arteries in vitro.

Histamine relaxed PGF2 alpha-precontracted rat isolated middle cerebral arteries (ID approximately 230 microns) concentration dependently with a pD2 of 5.31 (EC50: 5 x 10(-6) M). Cimetidine induced a concentration-dependent rightward shift of the histamine concentration-response curve of endothelium-intact arteries. The slope of the Schild plot was indistinguishable from unity, and the estimated pA2 for cimetidine was 6.14. The selective H2-receptor agonist dimaprit induced a concentration dependent relaxation of the cerebral arteries similar to that induced by histamine. This indicates that the histamine receptor mediating the relaxation in rat middle cerebral arteries belongs to the H2-receptor subtype. 2-Pyridylethylamine, a selective H1-receptor agonist, induced a small concentration-dependent contraction of the arteries with a pD2 of 4.16. Mepyramine, a selective H1-receptor antagonist had no potentiating effect on the relaxation induced by histamine, suggesting either that the contractile effect of 2-pyridylethylamine is nonselective or that H1 receptors mediating contraction are of minor importance for the overall histamine response. The selective H3-receptor agonist, (R)-alpha-methylhistamine, was without effect in a specific concentration range (10(-7)-10(-5) M) excluding participation of H3 receptors in the histamine-induced relaxation of these vessels. Indomethacin did not affect the vessel response to histamine, but removal of the endothelium and treatment of endothelium-intact arteries with 3 x 10(-6) M methylene blue induced a similar 0.5 log rightward shift of the histamine concentration-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)     

缓激肽预处理对大鼠局灶性脑缺血的影响

目的研究缓激肽预处理对大鼠局灶性脑缺血/再灌注损伤的影响。方法线栓法制备大鼠大脑中动脉缺血/再灌注模型,在缺血前由颈外动脉泵入缓激肽,对照组给予等量生理盐水,缺血2 h再灌注24 h后,观察脑梗死体积、脑含水量、血脑屏障通透性及组织病理学的变化。结果缺血前15 m in给予缓激肽组与对照组相比,梗死体积减小、水肿程度减轻、血脑屏障通透性降低、相关脑区神经元损伤程度减轻。结论预先给予缓激肽可对脑缺血损伤起保护作用,这可能是通过保护脑血管、减少梗死体积来起作用的。     

In vivo evidence for GABAergic control of serotonin release in the cat substantia nigra

Push-pull cannulae were used for estimating the release of endogenously synthesized [3H]serotonin in both substantia nigra and caudate nuclei of halothane-anaesthetized cats. The unilateral nigral application of GABA (10-5 M) reduced the local release of [3H]serotonin picrotoxin induced an opposite effect. Both treatments failed to modify [3H]serotonin release in the caudate nuclei or in the contralateral substantia nigra. These results suggest that GABAergic neurons innervating the substantia nigra may regulate nigral serotonin transmission. The possibility that such a regulation could be presynaptic (direct or through other nigral neurotransmitters) or related to a change in the activity of the nigro-raphe projection is discussed.