Isolated Rat Aorta Research Articles

A Lipid Emulsion Reverses Toxic-Dose Bupivacaine-Induced Vasodilation during Tyrosine Phosphorylation-Evoked Contraction in Isolated Rat Aortae.

The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH2-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization.

Diethyl-4,4ʹ-dihydroxy-8,3ʹ-neolign-7,7ʹ-dien-9,9ʹ-dionate exhibits antihypertensive activity in rats through increase in intracellular cGMP level and blockade of calcium channels

We report here the antihypertensive and vasorelaxant potential of some steroidal and non-steroidal compounds identified through a library of compounds. All the novel analogues showed vasorelaxant potential in isolated rat aorta. The most potent lead neolignan1 (Diethyl-4,4ʹ-dihydroxy-8,3ʹ-neolign-7,7ʹ-dien-9,9ʹ-dionate) produced concentration dependent relaxation with [pD2 5.16±0.05; n=16 and Emax 96.97%±1.12%; n=16]. The neolignan1 relaxation is independent of endothelium and is sensitive to ODQ (1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one; a blocker of soluble guanylyl cyclase (sGC) which synthesizes cGMP (cyclic guanosine monophosphate)). ELISA analysis of treated arterial tissues showed concentration-dependent increase in cGMP level in treated tissues compared to control (2.03 and 7.16 fold of control at 10 and 30µM of neolignan1, respectively) and a synergistic increase in cGMP level by 26.66 fold compared to control when used in combination with sildenafil (10µM; a known inducer of cGMP level by selectively blocking cGMP specific phosphodiesterase 5). Our present study reports for the first time that neolignans produce relaxation in isolated rat aorta through increase in intracellular cGMP level. The ODQ resistant relaxation of neolignan1 is mediated by blockade of voltage dependent L-type calcium channel (VDCC) as observed in the experiment with CaCl2. Neolignan1 upon intravenous administration via tail vein in Spontaneously Hypertensive Rats (SHR) produced significant decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). The present study concludes that neolignan1 exhibited antihypertensive potential in rats through rise in intracellular cGMP and blockade of VDCC.

Dexmedetomidine Inhibits Phenylephrine-induced Contractions via Alpha-1 Adrenoceptor Blockade and Nitric Oxide Release in Isolated Rat Aortae.

The goal of this in vitro study was to examine the effect of the alpha-2 adrenoceptor agonist dexmedetomidine on phenylephrine (alpha-1 adrenoceptor agonist)-induced contraction in isolated rat aortae and to elucidate the associated cellular mechanisms, with a particular focus on alpha-1 adrenoceptor antagonism. Dexmedetomidine dose-response curves were generated in isolated endothelium-intact and endothelium-denuded rat aortae precontracted with phenylephrine or 5-hydroxytryptamine. Endothelium-denuded aortic rings were pretreated with either dexmedetomidine or the reversible alpha-1 adrenoceptor antagonist phentolamine, followed by post-treatment with the irreversible alpha-1 adrenoceptor blocker phenoxybenzamine. Control rings were treated with phenoxybenzamine alone. All rings were repeatedly washed with Krebs solution to remove all pretreatment drugs, including phenoxybenzamine, phentolamine and dexmedetomidine. Phenylephrine dose-response curves were then generated. The effect of rauwolscine on the dexmedetomidine-mediated change in phenylephrine-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells was examined using western blotting. The magnitude of the dexmedetomidine-mediated inhibition of phenylephrine-induced contraction was higher in endothelium-intact aortae than in endothelium-denuded aortae or endothelium-intact aortae treated with Nω-nitro-L-arginine methyl ester. However, dexmedetomidine did not significantly alter 5-hydroxytryptamine-induced contraction. In further experiments, prazosin attenuated dexmedetomidine-induced contraction. Additionally, pretreatment with either dexmedetomidine plus phenoxybenzamine or phentolamine plus phenoxybenzamine produced greater phenylephrine-induced contraction than phenoxybenzamine alone, suggesting that dexmedetomidine protects aortae from the alpha-1 adrenoceptor blockade induced by phenoxybenzamine. Rauwolscine attenuated the dexmedetomidine-mediated enhancement of phenylephrine-induced eNOS phosphorylation. Taken together, these results suggest that dexmedetomidine attenuates phenylephrine-induced contractions via alpha-1 adrenoceptor blockade and endothelial nitric oxide release in the isolated rat aorta.

Differential Contribution of Nerve-Derived Noradrenaline to High K+-Induced Contraction Depending on Type of Artery.

High K+-induced contraction of arterial smooth muscle is thought to be mediated by membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels (VDCCs). In line with this, this study found that contraction induced by 80 mM K+ was almost abolished by nifedipine (1 µM), a VDCC inhibitor, in isolated rat aorta, and was markedly suppressed in the iliac artery. However, nifedipine (1 µM) only partially suppressed high K+-induced contraction in the tail artery. The contractions remaining in the arteries were further reduced by non-selective cation channel (NSCC) inhibitors, including 2-aminoethoxydiphenyl borate (2-APB) (100 µM), SK&F96365 (10 µM), and 3,4-dihydro-6,7-dimethoxy-α-phenyl-N,N-bis[2-(2,3,4-trimethoxyphenyl)ethyl]-1-isoquinolineacetamide hydrochloride (LOE908) (10 µM). In particular, sustained tonic contraction was nearly abolished. Prazosin (0.3 µM), an α1-adrenoceptor antagonist, partially inhibited high K+-induced contraction in the tail and iliac arteries, but had no effect in the aorta. Consistently, tyramine potently induced contraction in the tail and iliac arteries, but not in the aorta. Furthermore, the inhibition by prazosin and NSCC inhibitors of the high K+-induced contraction in the presence of nifedipine was comparable. These results suggest that depending on the type of artery, high K+-induced contraction is mediated by Ca2+ influx not only through VDCCs but also through NSCCs, the activation of which is due to the activation of α1-adrenoceptors by the released noradrenaline from sympathetic nerve terminals resulting from high K+ stimulation.

The Relaxant Activity of Safranal in Isolated Rat Aortas is Mediated Predominantly via an Endothelium-Independent Mechanism: -Vasodilatory mechanism of safranal.

Objectives:Safranal is a pharmacologically active component of saffron and is responsible for the unique aroma of saffron. The hypotensive effect of safranal has been shown in previous studies. This study evaluates the mechanism for the vasodilatory effects induced by safranal on isolated rat aortas.Methods:To study the vasodilatory effects of safranal (0.2, 0.4 and 0.8 mM), we contracted isolated rat thoracic aorta rings by using 10-6-M phenylephrine (PE) or 80-mM KCl. Dimethyl sulfoxide (DMSO) was used as a control. The vasodilatory effect of safranal was also evaluated both on intact and denuded endothelium aortic rings. Furthermore, to study the role of nitric oxide and prostacyclin in the relaxation induced by safranal, we incubated the aortic rings by using L-NAME (10-6 M) or indomethacin (10-5 M), each for 20 minutes.Results:Safranal induced relaxation in endothelium-intact aortic rings precontracted by using PE or KCl in a concentration-dependent manner, with a maximum relaxation of more than 100%. The relaxant activity of safranal was not eliminated by incubating the aortic rings with L-NAME (EC50 = 0.29 vs. EC50 = 0.43) or with indomethacin (EC50 = 0.29 vs. EC50 = 0.35), where EC50 is the half maximal effective concentration. Also, the vasodilatory activity of safranal was not modified by endothelial removal.Conclusion:This study indicated that relaxant activity of safranal is mediated predominantly through an endothelium- independent mechanism.

The vasorelaxant mechanisms of methanol on isolated rat aortic rings: Involvement of ion channels and signal transduction pathways.

It is reported that methanol is generally used as an industrial solvent, antifreeze, windshield washer fluid, cooking fuel and perfume. Methanol ingestion can lead to severe metabolic disturbances, blindness, or even death. So far, few studies about its negative effects on cardiovascular system have been reported. The purpose of this study was to determine the vasoactive effect of methanol and roles of ion channels and signal transduction pathways on isolated rat aorta. The results suggested that the mechanism of methanol-induced vasorelaxation at low concentrations (<500 mM) was mediated by ATP-sensitive K+ (KATP) and L-type Ca2+ channels, but the mechanism at high concentrations (>600 mM) was related to KATP, voltage-dependent K+, big-conductance Ca2+-activated K+, L-type Ca2+ channels as well as prostacyclin, protein kinase C, β-adrenoceptors pathways. In addition, methanol induced a dose-dependent inhibition of vasoconstrictions caused by calcium chloride, potassium chloride, or norepinephrine. Further work is needed to investigate the relative contribution of each channel and pathway in methanol-induced vasoactive effect.

Dexmedetomidine-Induced Contraction Involves CPI-17 Phosphorylation in Isolated Rat Aortas.

Dexmedetomidine, a highly selective α-2 adrenoceptor agonist, produces vasoconstriction, which leads to transiently increased blood pressure. The goal of this study was to investigate specific protein kinases and the associated cellular signal pathways responsible for the increased calcium sensitization induced by dexmedetomidine in isolated rat aortas, with a particular focus on phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17). The effect of Y-27632 and chelerythrine on the dexmedetomidine-induced intracellular calcium concentration ([Ca2+]i) and tension were assessed using fura-2-loaded aortic strips. The effects of rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride on the dexmedetomidine-induced phosphorylation of CPI-17 or of the 20-kDa regulatory light chain of myosin (MLC20) were investigated in rat aortic vascular smooth muscle cells. The effects of rauwolscine, Y-27632, and chelerythrine on the membrane translocation of Rho-kinase and protein kinase C (PKC) phosphorylation induced by dexmedetomidine were assessed. Y-27632 and chelerythrine each reduced the slopes of the [Ca2+]i-tension curves of dexmedetomidine-induced contraction, and Y-27632 more strongly reduced these slopes than did chelerythrine. Rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride attenuated the dexmedetomidine-induced phosphorylation of CPI-17 and MLC20. Taken together, these results suggest that dexmedetomidine-induced contraction involves calcium sensitization, which appears to be mediated by CPI-17 phosphorylation via Rho-kinase or PKC.

Crocin-Induced Endothelium-Dependent Relaxation in Isolated Rat Aorta

Background: Crocin, an active ingredient of saffron, has been found to possess hypotensive effects. Objectives: The aim of this study was to evaluate the mechanism of vasodilatory effects induced by crocin on isolated rat aorta. Methods: To study the vasodilatory effects of crocin (0.1, 0.2, 0.4 and 0.8 M), isolated rat thoracic aorta rings were contracted by 10-6 M Phenylephrine (PE) or 80 mM of KCl. To assess the role of nitric oxide in mechanism of relaxation, induced by crocin, aortic rings were incubated by L-NG-Nitroarginine methyl ester (L-NAME: 10-6 M) for 20 minutes. Furthermore, the relaxant effect of crocin was evaluated both in intact and denuded endothelium aortic rings. Results: Crocin induced relaxation in endothelium-intact aortic rings precontracted with PE in a concentration dependent manner yet not in KCl precontracted aortic rings. The relaxant activity of crocin was abolished by incubation of aortic rings with L-NAME. In addition, the endothelium removal inhibited the relaxant activity of crocin. Conclusions: This study indicated that relaxant activity of crocin is mainly mediated through an endothelium-dependent mechanism.

Crocin-Induced Endothelium-Dependent Relaxation in Isolated Rat Aorta

Crocin-Induced Endothelium-Dependent Relaxation in Isolated Rat Aorta

Allanblackia floribunda Oliv.: An aphrodisiac plant with vasorelaxant properties

Ethnopharmacological relevanceAllanblackia floribunda Oliv. is one of the most commonly used medicinal plant in Cameroon. The stem bark of the plant is traditionally used for its aphrodisiac and antihypertensive properties. Aim of the studyTo validate the traditional uses of Allanblackia floribunda stem bark ethanol extract through the evaluation of their aphrodisiac and vasorelaxant properties. Materials and methodsThe extract's ability to increase sexual desire and the frequencies of erection (mount), intromission and prolonged latency of ejaculation were studied on adult male rats. The vasodilator effect was investigated using isolated rat aorta rings. Tests were conducted using fractions obtained by reverse phase column-chromatography (CC), after the acquisition of the HPLC fingerprint of the ethanol extract, resulted the most active in previous studies. ResultsThe CC allowed the isolation of five fractions whose aphrodisiac and vasodilator activities were tested and compared with those of the whole extract. Four compounds were identified and characterized, three of them, Fukugiside, Morelloflavone and Volkensiflavone, are secondary metabolites known to be in Allanblackia floribunda; the fourth, Spicataside, is a biflavonoid glycoside known to be present in the genus Garcinia but never found neither in Allanblackia floribunda nor in Allanblackia genus.The crude ethanolic extract (CEE) induced a relaxation on aorta rings with EC50=11±2μg/mL and Morelloflavone displayed a similar activity with EC50=42±6μg/mL; for all the other compounds only the vasodilation % at the maximum concentration assessable (90μg/mL) was determined: 30±8 (Fukugiside), 24±6 (Spicataside), 33±4 (Morelloflavone+Volkensiflavone), 47±1 (Volkensiflavone). Regarding the activity on male sexual behaviour, only CEE and Fukugiside showed activity in the 9 parameters evaluated. ConclusionsThese results may support the traditional uses of Allanblackia floribunda as aphrodisiac plant with antihypertensive properties suggesting the phytocomplex as responsible for the claimed activity.

Alteration of time-resolved autofluorescence properties of rat aorta, induced by diabetes mellitus

Changes in autofluorescence properties of isolated rat aorta, induced by diabetes mellitus, were detected using time-resolved fluorescence spectroscopy with pulsed ultraviolet (UV) laser excitation. We demonstrated that time-resolved spectroscopy was able to detect changes in aorta tissues related to diabetes and unambiguously discriminate diabetic (τ1 0.63 ± 0.05 ns, τ2 3.66 ± 0.10 ns) samples from the control (τ1 0.76 ± 0.03 ns, τ2 4.48 ± 0.15 ns) group. We also report changes in the ratio of relative amplitudes of the two lifetime component in aorta tissue during diabetes, most likely related to the pseudohypoxic state with altered NADH homeostasis.

Hypotensive, cardiodepressant, and vasorelaxant activities of black currant (Ribes nigrum 'Ben Sarek') juice.

The aim of this study was to evaluate the effects of black currant (Ribes nigrum L. 'Ben Sarek') juice on the blood pressure and frequency of cardiac contractions, as well as vasomotor responses of rat aortic rings. Arterial blood pressure was measured directly from the carotid artery in the anaesthetized rabbits. The aortic rings were pre-contracted with KCl (80 mmol·L-1), after which black currant juice was added. An intravenous injection of black currant juice (0.33-166.5 mg·kg-1) induced a significant and dose-dependent decrease of rabbit arterial blood pressure and heart rate. The black currant juice decreased arterial blood pressure of rabbit by 22.33% ± 3.76% (p < 0.05) and heart rate by 17.18% ± 2.93% (p < 0.05). Cumulative addition of the black currant juice (0.01-3 mg·mL-1) inhibited concentration-dependent KCl induced contractions of the isolated rat aorta. The black currant juice, at the concentration of 3 mg·mL-1, caused a maximum relaxation of 21.75% ± 3.15% (p < 0.05). These results demonstrate that black currant juice can induce hypotension. The hypotensive effect of the black currant may occur as the consequence of its inhibitory activity on the rate of heart contraction and vasorelaxant effects.

Whey peptide Isoleucine-Tryptophan inhibits expression and activity of matrix metalloproteinase-2 in rat aorta

Aortic stiffness is an independent risk factor for development of cardiovascular diseases. Activation of renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) activity leads to overproduction of angiotensin II (ANGII) from its precursor angiotensin I (ANGI). ANGII leads to overexpression and activation of matrix metalloproteinase-2 (MMP2), which is critically associated with pathophysiology of aortic stiffness. We previously reported that the whey peptide Isoleucine-Tryptophan (IW) acts as a potent ACE inhibitor. Herein, we critically elucidate the mechanism of action by which IW causes inhibition of expression and activity of MMP2 in aortic tissue. Effects of IW on expression and activity of MMP2 were assessed on endothelial and smooth muscle cells (ECs and SMCs) in vitro and ex vivo (isolated rat aorta). As controls we used the pharmaceutical ACE inhibitor – captopril and the ANGII type 1 receptor blocker – losartan. In vitro, both ANGII and ANGI stimulation significantly (P<0.01) increased expression of MMP2 assessed with western blot. Similarly, to captopril IW significantly (P<0.05) inhibited ANGI, but not ANGII mediated increase in expression of MMP2, while losartan also blocked effects of ANGII. Signaling pathways regulating MMP2 expression in ECs and SMCs were similarly inhibited after treatment with IW or captopril. In ECs IW significantly (P<0.05) inhibited JNK pathway, whereas in SMCs JAK2/STAT3 pathway, assessed with western blot. In vitro findings were fully consistent with results in isolated rat aorta ex vivo. Moreover, IW not only inhibited the MMP2 expression, but also its activation assessed with gelatin zymography. Our findings demonstrate that IW effectively inhibits expression and activation of MMP2 in rat aorta by decreasing local conversion of ANGI to ANGII. Thus, similar to pharmaceutical ACE inhibitor captopril the dipeptide IW may effectively inhibit ACE activity and prevent the age and hypertension associated rise of aortic stiffness.

Effects of intravenous anaesthetics on cyclopiazonic acid-induced contractions in isolated rat aorta

Effects of intravenous anaesthetics on cyclopiazonic acid-induced contractions in isolated rat aorta

Vasorelaxant Effect of 5'-Methylthioadenosine Obtained from Candida utilis Yeast Extract through the Suppression of Intracellular Ca(2+) Concentration in Isolated Rat Aorta.

Our study is the first to demonstrate the vasorelaxant effect of Candida utilis yeast extract on rat aorta (EC50 of 7.2 ± 3.2 mg/mL). Among five identified compounds, 5'-methylthioadenosine (MTA) exhibited comparable vasorelaxant effect (EC50 of 190 ± 40 μM) with adenosine, a known vasodilator, on 1 μM phenylephrine (PE)-contracted Sprague-Dawley rat aortic rings. MTA induced vasorelaxation in an endothelium-independent manner and independent of the adenosine receptors. MTA reduced a CaCl2-induced vasocontraction stimulated by 1 μM PE, whereas the effect was abolished in a 60 mM KCl-induced vasocontraction. This indicates that MTA was not involved in the suppression of extracellular Ca(2+) influx. MTA significantly (P < 0.01) attenuated the PE-induced activation of calmodulin-dependent kinase II (CaMK II) in aortic rings and inhibited the phosphorylation of L-type Ca(2+) channel (VDCC). In conclusion, the underlying mechanism(s) of MTA-induced vasorelaxation involves the inhibition of Ca(2+)/CaMK II/VDCC phosphorylation pathway, resulting in the suppression of intracellular Ca(2+) concentration in aortic rings.

Flavonoid metabolite 3‐(3‐hydroxyphenyl)propionic acid formed by human microflora decreases arterial blood pressure in rats

There are reports of positive effects of quercetin on cardiovascular pathologies, however, mainly due to its low biovailability, the mechanism remains elusive. Here, we report that one metabolite formed by human microflora (3-(3-hydroxyphenyl)propionic acid)relaxed isolated rat aorta and decreased arterial blood pressure in rats.

Atorvastatin acutely reduces the reactivity to spasmogens in rat aorta: implication of the inhibition of geranylgeranylation and MYPT-1 phosphorylation.

Statins are known to display benefits in various diseases independently from their cholesterol lowering properties. In this study, we investigated the acute effects of atorvastatin on vascular reactivity to various spasmogens in isolated rat aorta. The responses to noradrenaline (NA, 10(-8) -10(-4) m), endothelin-1 (ET-1, 10(-10) -10(-7) m), and potassium chloride (KCl, 10-100 mm) were evaluated in aortic rings pretreated with atorvastatin (10(-7) -10(-4) m, 30 min). To verify the mechanism of action, the effects of atorvastatin were studied in the presence of cholesterol precursor, mevalonate (10(-2) m, 45 min), mevalonate-derived isoprenoids, namely geranylgeranyl pyrophosphate (GGPP, 5 × 10(-6) m, 30 min) and farnesyl pyrophosphate (FPP, 5 × 10(-6) m, 30 min), and in the absence of endothelium. In parallel, aortic rings were pretreated with the specific inhibitor of Rho kinase, Y-27632 (10(-7) -10(-6) m). Atorvastatin significantly and concentration-dependently reduced the contractions to spasmogens in rat aorta. This acute inhibitory effect was also evident in endothelium-denuded rings. Pretreatment with mevalonate and GGPP, but not with FPP, reversed the inhibitory effect of atorvastatin (10(-4) m) on NA and ET-1 induced contractions. Similar to atorvastatin, pretreatment with Y-27632 inhibited the contractions to NA and KCl in a concentration-dependent manner. Western blot analysis revealed that both atorvastatin (10(-4) m) and Y-27632 (10(-6) m) pretreatment inhibited the phosphorylation of myosin phosphatase target subunit-1 (MYPT-1) triggered by NA, indicating an inhibitory influence on myosin phosphatase. In conclusion, atorvastatin displayed an acute inhibitory effect on vascular contractility evoked by various spasmogens and the inhibitory effect was possibly mediated by the inhibition of mevalonate and GGPP synthesis as well as the prevention of MYPT-1 phosphorylation induced by Rho/Rho kinase.

Effects of Acidification and Alkalinization on the Lipid Emulsion-Mediated Reversal of Toxic Dose Levobupivacaine-Induced Vasodilation in the Isolated Rat Aorta.

The goal of this in vitro study was to examine the effects of pre-acidification and pre-akalinization on the lipid emulsion-mediated reversal of toxic dose levobupivacaine-induced vasodilation in isolated rat aorta. Isolated aortic rings with and without the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) were exposed to four types of Krebs solution (pH 7.0, 7.2, 7.4, and 7.6), followed by the addition of 60 mM potassium chloride. When the toxic dose of levobupivacaine (3 × 10-4 M) produced a stable and sustained vasodilation in the isolated aortic rings that were precontracted with 60 mM potassium chloride, increasing lipid emulsion concentrations (SMOFlipid®: 0.24, 0.48, 0.95 and 1.39%) were added to generate concentration-response curves. The effects of mild pre-acidification alone and mild pre-acidification in combination with a lipid emulsion on endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells were investigated by Western blotting. Mild pre-acidification caused by the pH 7.2 Krebs solution enhanced the lipid emulsion-mediated reversal of levobupivacaine-induced vasodilation in isolated endothelium-intact aortic rings, whereas mild pre-acidification caused by the pH 7.2 Krebs solution did not significantly alter the lipid emulsion-mediated reversal of the levobupivacaine-induced vasodilation in isolated endothelium-denuded aortic rings or endothelium-intact aortic rings with L-NAME. A lipid emulsion attenuated the increased eNOS phosphorylation induced by the pH 7.2 Krebs solution. Taken together, these results suggest that mild pre-acidification enhances the lipid emulsion-mediated reversal of toxic dose levobupivacaine-induced vasodilation in the endothelium-intact aorta via the inhibition of nitric oxide.

In vitro fructose exposure overactivates NADPH oxidase and causes oxidative stress in the isolated rat aorta

Fructose acutely interferes with cardiovascular function in humans and in animals, but the mechanisms remain unclear. Thus, we tested whether fructose can affect endothelial function without the interference of its metabolic effect by exposing the rat aorta to a high fructose concentration and then evaluate the vascular responses to vasoactive agents. We observed that fructose exposure causes overactivation of NADPH oxidase, which enhances superoxide anion production and increases NO degradation. Additionally, the enhanced vasoconstrictor action of hydrogen peroxide might exacerbate contractile responses. This vasoactive imbalance might be the key role by which fructose induces vascular dysfunction.

Contribution of oxidative stress and prostanoids in endothelial dysfunction induced by chronic fluoxetine treatment

ObjectivesThe effects of chronic fluoxetine treatment were investigated on blood pressure and on vascular reactivity in the isolated rat aorta. Methods and resultsMale Wistar rats were treated with fluoxetine (10mg/kg/day) for 21days. Fluoxetine increased systolic blood pressure. Chronic, but not acute, fluoxetine treatment increased the contractile response induced by phenylephrine, serotonin (5-HT) and KCl in endothelium-intact rat aortas. l-NAME and ODQ did not alter the contraction induced by phenylephrine and 5-HT in aortic rings from fluoxetine-treated rats. Tiron, SC-560 and AH6809 reversed the increase in the contractile response to phenylephrine and 5-HT in aortas from fluoxetine-treated rats. Fluoxetine treatment increased superoxide anion generation (O2−) and the expression of cyclooxygenase (COX)-1 in the rat aorta. Reduced expression of nNOS, but not eNOS or iNOS was observed in animals treated with fluoxetine. Fluoxetine treatment increased prostaglandin (PG)F2α levels but did not affect thromboxane (TX)B2 levels in the rat aorta. Reduced hydrogen peroxide (H2O2) levels and increased catalase (CAT) activity were observed after treatment. ConclusionsThe major new finding of our study is that chronic fluoxetine treatment induces endothelial dysfunction, which alters vascular responsiveness by a mechanism that involves increased oxidative stress and the generation of a COX-derived vasoconstrictor prostanoid (PGF2α). Moreover, our results evidenced a relation between the period of treatment with fluoxetine and the magnitude in the increment of blood pressure. Finally, our findings raise the possibility that fluoxetine treatment increases the risk for vascular injury, a response that could predisposes to cardiovascular diseases.