Pravastatin restores DDAH activity and endothelium-dependent relaxation of rat aorta after exposure to glycated protein

This study was designed to investigate whether glycated bovine serum albumin (AGE-BSA) inhibits dimethylarginine dimethylaminohydrolase (DDAH) activity to contribute to its adverse effect on endothelium-dependent relaxation in rat aorta, and whether pravastatin reverses the inhibition of DDAH activity and endothelial dysfunction induced by AGE-BSA. Endothelium-dependent relaxation of aortic rings was measured by isometric tension recording, and DDAH activity, and the contents of nitrite/nitrate as well as malondialdehyde (MDA) in aortic tissue were determined after exposure of Sprague-Dawley rat aorta to AGE-BSA (1.70 mmol/L) for 60 minutes in the presence or absence of pravastatin. In comparison with control, both endothelium-dependent relaxation and DDAH activity (0.032 +/- 0.002 versus 0.095 +/- 0.003 U/g protein, n = 5, P < 0.01) were significantly inhibited in isolated rat aorta after exposure to AGE-BSA, which was accompanied by decreases of nitrite/nitrate contents and elevations of MDA levels in aorta. Treatment with pravastatin (1 mmol/L) not only prevented the inhibition of endothelial function but also reversed the decrease of DDAH activity induced by AGE-BSA and normalized the alterations in nitrite/nitrate and MDA contents. Similar effects were observed when rat aorta exposed to AGE-BSA in the presence of antioxidant pyrrolidine dithiocharbamate (PDTC, 30 micromol/L) or protein kinase C inhibitor chelerythrine (1 micromol/L). These results suggested that decreased DDAH activity may be involved in endothelial dysfunction of rat aorta induced by AGE-BSA, and that pravastatin restores DDAH activity and endothelium-dependent relaxation after aorta exposure to AGE-BSA, which may be secondary to its antioxidative effects.     

Captopril restores endothelium-dependent relaxation induced by advanced oxidation protein products in rat aorta

To explore whether advanced oxidation protein products (AOPP) can cause endothelial dysfunction in vitro, and whether captopril exerts beneficial effect on impaired endothelium-dependent relaxation induced by exogenous advanced oxidation protein products and to investigate the potential mechanisms. Both the Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside-induced endothelium-independent relaxation of aortic rings were measured by recording isometric tension after the rings were exposed to AOPP-BSA in the absence or presence of captopril to assess the injury effect of AOPP-BSA and the protective effect of captopril on the aortic endothelium, respectively. Co-incubation of aortic rings with AOPP-BSA (3 mmol/L) for 90 minutes resulted in a significant inhibition of EDR to ACh, but had no effects on endothelium-independent relaxation to SNP. After incubation of the rings in the co-presence of captopril (3 to 30 micromol/L) or enalaprilat (30 micromol/L) with AOPP-BSA (3 mmol/L) for 90 minutes, captopril significantly and enalaprilat only partly attenuated the inhibition of EDR induced by AOPP-BSA. This protective effect of captopril (30 micromol/L) was abolished by N-nitro-L-arginine methyl ester (10 micromol/L), an inhibitor of nitric oxide synthase. Furthermore, the superoxide anion scavenger superoxide dismutase (SOD, 200 U/mL), and the nitric oxide precursor L-arginine (3 mmol/L) also ameliorated the impaired EDR caused by AOPP-BSA. But D-arginine had no effect on the impaired EDR caused by AOPP-BSA. AOPP-BSA can trigger endothelial dysfunction and captopril can protect the endothelium against functional damage induced by AOPP-BSA in rat aorta, increase nitric oxide bioavailability. The mechanisms of endothelial dysfunction induced by AOPP-BSA may include the decrease of NO and the generation of oxygen-free radicals.     

Phorbol esters impair endothelium-dependent and independent relaxation in rat aortic rings

• 1.1. This study examined the ability of various nitro-vasodilators, 8-bromo cyclic guanosine 3′:5′ monophosphate (8-BrcGMP) and forskolin to relax rings of rat thoracic aorta pre-contracted with either noradrenaline (0.1 μM) or the protein kinase C activators, phorbol 12,13-dibutyrate (PDB, 0.1 μM) or phorbol 12-myristate 13-acetate (PMA, 0.5 μM).
• 2.2. In noradrenaline pre-contracted rings, acetylcholine (10 nM−10 μM), sodium nitroprusside (1 nM−0.5 μM), the calcium ionophore A23187 (10 nM−10 μM) and 8-BrcGMP (10 mM) totally reversed the smooth muscle contraction. In PDB-contracted aortic rings acetylcholine, sodium nitroprusside and 8-BrcGMP-induced relaxation was reduced compared to that in noradrenaline-contracted aortic rings, but A23187 and forskolin-induced relaxations were unaffected. Both acetylcholine and A23187-induced relaxations in PDB-contracted rings were abolished in the presence of the nitric oxide synthesis inhibitor Nω-nitro-l-arginine (NOLA, 100 μM).
• 3.3. Acetylcholine and sodium nitroprusside were even less potent in their ability to relax PMA-contracted aortic rings compared with noradrenaline and PDB-contracted rings. A23187-induced relaxation was also inhibited in PMA-contracted rings.
• 4.4. These results show that protein kinase C activation reduces the ability of agents which liberate nitric oxide to induce smooth muscle relaxation, and also inhibits the biochemical pathways which are subsequently activated by nitric oxide and lead to vascular smooth muscle relaxation.

     

Cyclic nucleotide interactions involved in endothelium-dependent dilatation in rat aortic rings

The role of cyclic nucleotides in the dilation of rat aortic rings induced by isoprenaline was studied by measuring changes in isometric tension and in cyclic nucleotide levels in rings preconstricted with phenylephrine or U46619. Isoprenaline produced significantly greater relaxation in endothelium-containing than in endothelium-denuded rings. Relaxation of endothelium-containing rings to isoprenaline was markedly inhibited by pretreating the rings with methylene blue (30 microM) or haemoglobin (10 microM). Basal cyclic-AMP levels were not affected by the presence of endothelium in the rings, but basal cyclic-GMP levels were 5-6-fold higher in endothelium-containing rings. Isoprenaline (1 microM) elevated levels of cyclic-AMP to an extent which was not affected by the presence of endothelium. In contrast, isoprenaline had no effect on cyclic-GMP levels in rings with or without endothelium. Pretreatment of de-endothelialized rings with sodium nitroprusside or 8-bromo-cyclic-GMP, in concentrations that by themselves caused minor alterations in vascular tone, markedly amplified the relaxant responses to isoprenaline and mimicked the relaxant responses of endothelium-containing rings to isoprenaline. These data indicate that isoprenaline does not stimulate release of endothelium-derived relaxing factor, but suggest a major synergistic interaction between cyclic-GMP-mediated and cyclic-AMP-mediated relaxation in rat aorta.     

Excess l-arginine restores endothelium-dependent relaxation impaired by monocrotaline pyrrole

The pyrrolizidine alkaloid plant toxin monocrotaline pyrrole (MCTP) causes pulmonary hypertension in experimental animals. The present study aimed to examine the effects of MCTP on the endothelium-dependent relaxation. We constructed an in vitro disease model of pulmonary hypertension by overlaying MCTP-treated bovine pulmonary artery endothelial cells (CPAEs) onto pulmonary artery smooth muscle cell-embedded collagen gel lattice. Acetylcholine (Ach) induced a relaxation of the control CPAEs-overlaid gels that were pre-contracted with noradrenaline, and the relaxation was inhibited by L-NAME, an inhibitor of NO synthase (NOS). In contrast, when MCTP-treated CPAEs were overlaid, the pre-contracted gels did not show a relaxation in response to Ach in the presence of 0.5 mM l-arginine. Expression of endothelial NOS protein, Ach-induced Ca2+ transients and cellular uptake of l-[3H]arginine were significantly smaller in MCTP-treated CPAEs than in control cells, indicating that these changes were responsible for the impaired NO production in MCTP-treated CPAEs. Since cellular uptake of l-[3H]arginine linearly increased according to its extracellular concentration, we hypothesized that the excess concentration of extracellular l-arginine might restore NO production in MCTP-treated CPAEs. As expected, in the presence of 10 mM l-arginine, Ach showed a relaxation of the MCTP-treated CPAEs-overlaid gels. These results indicate that the impaired NO production in damaged endothelial cells can be reversed by supplying excess l-arginine.     

Impairment of endothelium-dependent relaxation of rat aortas by homocysteine thiolactone and attenuation by captopril

To explore the effects of angiotensin-converting enzyme (ACE) inhibitors on endothelial dysfunction induced by homocysteine thiolactone (HTL). Both endothelium-dependent relaxation and nondependent relaxation of thoracic aortic rings in rats induced by acetylcholine (Ach) or sodium nitroprusside (SNP) and biochemical parameters including malondialdehyde (MDA) and nitric oxide (NO) were measured in rat isolated aorta. Exposure of aortic rings to HTL (3 to 30 mM) for 90 minutes made a significant inhibition of endothelium-dependent relaxation induced by Ach, decreased contents of NO, and increased MDA concentration in aortic tissue. After incubation of aortic rings with captopril (0.003 to 0.03 mM) attenuated the inhibition of endothelium-dependent relaxation (EDR) and significantly resisted the decrease of NO content and elevation of MDA concentration caused by HTL (30 mmol/L) in aortic tissues, a similarly protective effect was observed when the aortic rings were incubated with both N-acetylcysteine (0.05 mM). Treatment with enalaprilat (0.003 to 0.01 mM) made no significant difference with the HTL (30 mM) group regarding EDR, but enalaprilat (0.03 mM) and losartan (0.03 mM) could partly restore the EDR in response to HTL (30 mM). Captopril was more effective than enalaprilat and losartan in attenuation of the inhibition of on acetylcholine-stimulated aortic relaxation by HTL in the same concentration. Moreover, superoxide dismutase (SOD, 200 U/mL), which is a scavenger of superoxide anions, apocynin (0.03 mM), which is an inhibitor of NADPH oxidase, and l-Arginine (3 mmol/L), a precursor of nitric oxide (NO), could reduce HTL (30 mM)-induced inhibition of EDR. After pretreatment with not only the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester (L-NAME, 0.01 mM) but also the free sulfhydryl group blocking agent p-hydroxymercurybenzoate (PHMB, 0.05 mM) could abolish the protection of captopril and N-acetylcysteine, respectively. These results suggest that mechanisms of endothelial dysfunction induced by HTL may include the decrease of NO and the generation of oxygen free radicals and that captopril can restore the inhibition of EDR induced by HTL in isolated rat aorta, which may be related to scavenging oxygen free radicals and may be sulfhydryl-dependent.     

Increased nitroglycerin-induced relaxation by genistein in rat aortic rings.

The effect of genistein, a tyrosine kinase inhibitor, on nitroglycerin-induced relaxation was examined in rat aortic rings contracted by phenylephrine. In rat aortic rings, genistein (10(-5) M and 3x10(-5) M), a tyrosine kinase inhibitor, but not daidzein, an analogue of genistein, increased relaxation induced by nitroglycerin in a concentration-dependent manner. Iberiotoxin, an inhibitor of Ca2+ -activated K+ channels, inhibited the relaxation induced by nitroglycerin, but it did not affect the effect of genistein. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, did not affect the relaxation induced by nitroglycerin. Theophylline, an inhibitor of cyclic AMP-dependent phosphodiesterase, increased the relaxation induced by nitroglycerin, and genistein (10(-5) M) failed to affect the relaxation induced by nitroglycerin in the presence of theophylline. Genistein also inhibited the activity of cyclic AMP-dependent phosphodiesterase. In addition, 6-[4-(4'-pyridyl)amino phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, an inhibitor of cyclic GMP-inhibitable cyclic AMP phosphodiesterase, inhibited the relaxation induced by nitroglycerin. These results suggest that, in the rat aortic rings, genistein inhibits cyclic AMP-dependent phosphodiesterase activities, resulting in the increase of the relaxation induced by nitroglycerin.     

Peroxynitrite-induced relaxation in isolated rat aortic rings and mechanisms of action

The present study was designed to evaluate the effects of peroxynitrite (ONOO-), the product of superoxide and nitric oxide, on isolated segments of rat aorta. In the absence of any vasoactive agent, ONOO- (from 10(-8) to 10(-4) M) failed to alter the basal tension. In phenylephrine (PE; 5 x 10(-7) M)-precontracted rat aortic rings (RAR), ONOO- elicited concentration-dependent relaxation at concentrations of from 10(-8) to 10(-4) M. The effective concentrations producing approximately 50% of maximal relaxation (ED50) to ONOO- were 1.84 x 10(-5) M and 1.96 x 10(-5) M in intact and denuded RAR, respectively (P > 0.05). No significant differences in the relaxation responses were found between RAR 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-. Sildenafil (10(-7) M), on the other hand, significantly potentiated the ONOO--induced relaxations. Tetraethylammonium chloride (T-2265) significantly decreased the ONOO--induced relaxations in a concentration-dependent manner. However, ONOO- had no effect on RAR precontracted by high KCL (40 mM, n = 6, P > 0.05). Addition of calyculin A also significantly decreased the ONOO--induced relaxation in a dose-dependent manner. Furthermore, ONOO- significantly inhibited calcium-induced contractions of K+-depolarized aortic rings in a concentration-related manner. Lastly, a variety of other pharmacological agents and antagonists including L-NMMA, L-arginine, indomethacin, atropine, naloxone, diphenhydramine, cimetine, glibenclamide, haloperidol, superoxide dismutase (SOD), and catalase did not influence the relaxant effects of ONOO- on RAR. Our new results suggest that ONOO--triggered relaxation on rat aortic rings is mediated by elevation of cGMP levels, membrane hyperpolarization via K+-channel activation, activation of myosin phosphatase activity, and interference with calcium movement and cellular membrane Ca2+ entry.     

Ambient particulate matter induces relaxation of rat aortic rings in vitro

Epidemiological studies have shown an association between ambient levels of particulate matter (PM) and increased mortality from cardiovascular diseases. However, the underlying mechanisms are still not clear. We hypothesised that PM, when translocated after inhalation, could affect vascular smooth muscle function. Therefore, total suspended particulate matter (TSP) was sampled and investigated for its ability to affect aortic muscle contraction. Both TSP and TSP supernatant (TSP-sup) induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted aortic rings. Relaxation induced by 100 microg/ml TSP was 51.5 +/- 3.1% of total contraction. At 60 and 100 microg/ml, relaxation induced by TSP was significantly higher compared to TSP-sup. Ultrafine TiO2, used as a model to investigate the role of ultrafine particles, did not show an effect. Soluble iron, present in TSP suspensions, seems not to be involved, as chelating with deferoxamine did not affect TSP-induced relaxation. However, TSP effects were inhibited by Trolox, suggesting a role of oxidants. Nudation of aortic rings showed that effects of TSP were only partly endothelium-dependent, while preincubation with L-NAME increased TSP-induced relaxation. From these data, we conclude that both the particle core and soluble components of TSP can affect the smooth muscle function, leading to changes in the vascular contractile response.     

链佐星所致糖尿病大鼠主动脉内皮依赖舒张反应损伤的特征(英文)

目的:研究早期糖尿病大鼠内皮依赖舒张反应(EDR)损伤的机制。方法:离体主动脉环张力实验。结果:乙酰胆碱(ACh),组胺(His),缓激肽,环匹阿尼酸(CPA)在糖尿病组EDR均比对照组明显减弱。而卡西霉素诱导的EDR未见损伤。L-NAME(0.3mmol·L~(-1))预处理取消所有EDR,并使两组间效应均一化。ACh或CPA诱导最大EDR时,卡西霉素(1μmol·L~(-1))进一步扩张糖尿病而非正常组血管环。硝普钠扩血管及CPA或His缩血管效应均无组间差异。结论:在4周链佐星糖尿病大鼠主动脉,受体而不是非受体介导的EDR普遍损伤,其机制与内皮细胞电容性钙内流信号通路受损从而使NO合成减少有关。     

Endothelium-dependent and -independent relaxation induced by pinocembrin in rat aortic rings

The aim of present study was to evaluate the vasorelaxant effects of the flavonone pinocembrin and its possible mechanisms in isolated rat aortic rings. Pinocembrin (5 approximately 100 microM) induced relaxation in aortic rings pre-contracted with norepinephrine (NE, 1 microM) or KCl (60 mM), with pEC(50) value 4.37+/-0.02 and 4.52+/-0.04. Pretreatment with pinocembrin (30 or 50 microM) also inhibited contractile responses to NE and KCl. The vasorelaxant effect of pinocembrin relied on intact endothelium partially, and incubation with n(omega)-nitro-l-arginine methyl ester (l-NAME, 100 microM) or methylene blue (10 microM) significantly inhibited the effect, however indomethacin (5 microM) had no influence on the action. In endothelium-denuded rings, the vasorelaxant effect of pinocembrin was reduced by glibenclamide (10 microM), tetraethylammonium (5 mM) and 4-aminopyridine (100 microM). Pinocembrin also reduced NE-induced transient contraction in Ca(2+)-free solution and inhibited contraction induced by increasing external calcium in Ca(2+)-free medium plus 60 mM KCl. Our results suggest that pinocembrin induces relaxation in rat aortic rings through an endothelium-dependent pathway, involving NO-cGMP, and also through an endothelium-independent pathway, opening K(+) channels and blockade of Ca(2+) channels.     

The potentiation of nitroglycerin-induced relaxation by PKG inhibition in rat aortic rings

• 1.1. In rat aortic rings precontracted by phenylephrine, H7 (10⁻⁵M) and staurosporine (10⁻⁷M), which inhibit PKA, PKG and PKC, and H-89 (10⁻⁶M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10⁻⁵M).
• 2.2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10⁻⁷M), which inhibits PKC, H-89 (10⁻⁷M), which inhibits PKA, and staurosporine (2 × 10⁻⁹M), which inhibits PKC.
• 3.3. Iberiotoxin (3 × 10⁻⁸M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglyc. erin-induced relaxations.
• 4.4. The potentiating effect of zaprinast (10⁻⁵M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10⁻⁵M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin.
• 5.5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.

     

（—）Epicatechin induces and modulates endotheliumdependent relaxation in isolated rat mesenteric artery rings

AIM:The present study was aimed to examine the role of endothelial nitric oxide in the relaxant response to green tea (-)epicatechin and its modulation of endothelium-mediated relaxation in the isolated rat mesenteric artery rings.METHODS:Changes in the isometric tension were measured with Grass force-displacement transducers.RESULTS:The (-)epicatechin-induced relaxation was largely dependent on the presence of intact endothelium and was reversed by N^G-nitro-L-arginine methyl ester 10μmol/L or methylene blue 10μmol/L,the inhibitors of nitric oxidemediated relaxation.L-Arginine at 1mmol/L antagonized the effect of L-NAME or methylene blue.Pretreatment of endothelium-intact rings with (-)epicatechin 10μmol/L enhanced the relaxation induced by endothelium-dependent vasodilator,acetylcholine,while this concentration did not influence the endothelium-independent relaxation induced by sodium nitroprusside in the endothelium-denuded artery rings.CONCLUSION:The results indicate that the endothelium-dependent vasodilation by (-)epicatechin is mainly mediated through nitric oxide and low concentration of (-)epicatechin augments endothelium-dependent vasorelaxation in the rat mesenteric arteries.     

Endophytic fungal metabolite fumigaclavine C causes relaxation of isolated rat aortic rings

Two indole alkaloids were isolated from the culture of Aspergillus fumigatus (strain No. CY018), an endophytic fungus harboring inside the elder leaf of Cynodon dactylon. These two chemicals were identified as fumigaclavine C and fumitremorgin C. In screening the bioactivity of these two indole alkaloids, their vasorelaxant effects on isolated rat thoracic aortic rings were observed. The results showed that fumigaclavine C exhibited potent concentration-dependent vasorelaxant actions in isolated rat aortic rings pre-contracted by high K+ or phenylephrine (with EC50 values of 5.62 micromol/L and 1.58 micromol/L, respectively) whereas fumitremorgin C displayed a weaker vasorelaxation. A detailed investigation was therefore performed with fumigaclavine C. The vasorelaxing action of fumigaclavine C is independent of the presence of endothelium, suggesting its effect of vasorelaxation was not related to endothelial mediators. Blockage of L-type voltage-dependent calcium channels, activation of ATP-sensitive potassium channels and inhibition of Ca2+ release from intracellular Ca2+ stores may be involved in fumigaclavine C induced relaxation of rat isolated aortic rings. These results demonstrate that fumigaclavine C from the endophytic fungus has a potential capacity in vascular protection and thus may have therapeutic use in protection against cardiovascular disease.     

L-citrulline mediated relaxation in the control and lipopolysaccharide-treated rat aortic rings.

The present study was undertaken to investigate relaxant effect of L-citrulline in phenylephrine precontracted endothelium intact thoracic aortic rings obtained from control or lipopolysaccharide (1 mg/kg)-treated rats. L-citrulline produced 40+/-3% (n=36) and 60+/-5% (n=24) relaxations in control and lipopolysaccharide-treated rings, respectively. Nitric oxide (NO) release and cyclic guanosine-3',5'-monophosphate levels from the rings were also increased following treatment with L-citrulline. Inhibition of guanylate cyclase, L-citrulline recycling to L-arginine or denudation of the endothelium, significantly reduced L-citrulline-induced relaxations both in control and lipopolysaccharide-treated rings. Treatment of rings with protein synthesis inhibitors prevented relaxations to L-citrulline. Inhibitor of Ca2+-activated K+ channels, tetrabutylammonium or precontraction of the rings with KCl (80 mM), significantly attenuated L-citrulline mediated relaxations in control and lipopolysaccharide-treated rings. Thus, L-citrulline seems to exert significant relaxation by supplementing the release of NO due to its recycling to L-arginine, which gets further augmented after lipopolysaccharide treatment.     

链佐星所致糖尿病大鼠主动脉内皮依据舒张反应损伤的特征

AIM: To study whether impaired endothelium-dependent relaxation (EDR) in early diabetic mellitus in response to different receptor-mediated and nonreceptor-mediated vasodilators ran parallel and its possible mechanism. METHODS: Isometric tension recording in aortic rings from streptozotocin (Str)-induced diabetic and age-matched nondiabetic rats. RESULTS: EDR induced by receptor agonist acetylcholine (ACh), histamine (His) or bradykinin (BK) were all significantly reduced in diabetic rings compared with control rings, whereas nonreceptor agonist calcimycin-induced EDR was well reserved in diabetic rings [IC50 control: (0.13 +/- 0.07) mumol.L-1 diabetic: (0.14 +/- 0.06) mumol.L-1, P > 0.05, n = 7]. Cyclopiazonic acid (CPA) which also is a nonreceptor mediated endothelium-dependent vasorelaxant and cells' capacitative Ca2+ entry stimulant, failed to trigger EDR in diabetic rings. Pretreatment with N omega-nitro-L-arginine methylester (L-NAME, 0.3 mmol.L-1) not only abolished all of the EDR elicited by above mentioned vasodilators in either of diabetic or control rings, but also leveled responses triggered by each of the agonists between diabetic and control rings. Upon the maximal EDR induced by ACh (1 mol.L-1) or CPA (3 mumol.L-1) in phenylephrine (1 mumol.L-1) precontracted rings, calcimycin (1 mumol.L-1) further relaxed diabetic rings, but contracted control preparations. When endothelium was denuded, relaxation evoked by sodium nitroprusside and contractions triggered by CPA or His were all identical between diabetic and control rings. CONCLUSION: Receptor agonists but not nonreceptor agonists-induced EDR are commonly impaired in 4-wk Str-induced diabetic rat aorta, and this defective effect is attributable to the low formation of EDRF/NO which is related to impaired capacitative Ca2+ entry pathway in endothelium.     

黄芪甲苷对正常大鼠离体血管功能的影响

目的观察黄芪甲苷对血管功能的影响并探讨其作用机制。方法采用大鼠离体主动脉环灌流模型,观察黄芪甲苷对血管环收缩和舒张功能的影响。结果黄芪甲苷能够浓度依赖性舒张血管。一氧化氮合酶抑制剂、鸟苷酸环化酶及环加氧酶抑制剂可抑制黄芪甲苷诱导的血管舒张作用。黄芪甲苷能够抑制苯肾上腺、KC l和CaC l2引起的血管收缩。结论黄芪甲苷具有内皮依赖性的舒张血管作用,此作用主要通过NO-cGMP途径发挥作用。黄芪甲苷抑制血管收缩主要通过拮抗外钙内流实现。     

Cocaine-induced relaxation of isolated rat aortic rings and mechanisms of action: possible relation to cocaine-induced aortic dissection and hypotension

Cocaine HCl is well known for its toxic effects on the cardiovascular system, but little is known about its effects on different regional blood vessels. We designed experiments to determine if cocaine HCl could influence the tension of isolated aortic rings, i.e., induce contraction or relaxation. Surprisingly, cocaine HCl (1 x 10(-5) to 6 x 10(-3) M) relaxed isolated aortic rings precontracted by phenylephrine in a concentration-dependent manner. No significant differences were found between intact or denuded isolated aortic rings (P>0.05). The maximal % relaxations of intact vs. denuded isolated aortic rings were 108.9+/-24.3% vs. 99.5+/-8.3% (P>0.05). Cocaine HCl, 2 x 10(-3) M, was found to inhibit contractions by phenylephrine; EC50s were increased (P<0.01) and Emax's were decreased (51.3+/-16.4% vs. 89.8+/-10.6%, P<0.01). A variety of amine antagonists could not inhibit the relaxant effects of cocaine HCl (P>0.05). The cyclooxygenase-1 inhibitor, indomethacin, also failed to inhibit relaxations induced by cocaine HCl (P>0.05). Neither L-arginine, NG-monomethyl-L-arginine (L-NMMA), nor methylene blue could inhibit the relaxations induced by cocaine HCl (P>0.05), suggesting cocaine HCl does not relax isolated aortic rings by inducing the synthesis or release of nitric oxide (NO) or prostanoids from either endothelial or vascular muscle cells. Inhibitors of cAMP, cGMP and protein kinase G (PKG) also failed to inhibit cocaine-induced relaxations. Cocaine HCl (1 x 10(-5) to 6 x 10(-3) M) could also relax isolated aortic rings precontracted by phenylephrine in high K+ depolarizing buffer. Surprisingly, calyculin A, an inhibitor of myosin light chain (MLC) phosphatase, inhibited cocaine-induced relaxations in a concentration-dependent manner, suggesting the probable importance of cocaine-induced MLC phosphatase activation in rat aortic smooth muscle cells. It was also found that cocaine HCl could dose-dependently inhibit Ca2+-induced contractions of isolated aortic rings in high K+-Ca2+-free buffer, suggesting that cocaine HCl may inhibit Ca2+ influx and/or intracellular release.