Maria Sotomayor - Academia.edu (original) (raw)

Papers by Maria Sotomayor

British Journal of Nutrition, 2004

Traditionally hand-pressed argan oil, obtained from Argania spinosa seeds, is eaten raw in south-... more Traditionally hand-pressed argan oil, obtained from Argania spinosa seeds, is eaten raw in south-west Morocco; its rich composition of tocopherols, MUFA and PUFA make a study of its actions on risk factors for CVD, such as hypertension, interesting. The effects of 7 weeks of treatment with argan oil (10ml/kg) on the blood pressure and endothelial function of spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto rats were investigated. Systolic blood pressure and heart rate were measured every week by the tail-cuff method and endothelial function was assessed by carbachol (10−8 to 10−4m)-induced relaxations of aortic rings and small mesenteric arteries pre-contracted with phenylephrine. Argan-oil administration reduced the mean blood pressure of SHR after the fifth week of treatment (P<0·05) and increased (P<0·01) the endothelial responses of arteries from SHR. The NO synthase inhibitor, l-N-ω-nitroarginine (3×10−5m) revealed a greater participation of NO in the r...

Journal of Ethnopharmacology, 2003

The potential health benefits of various dietary oils in relation to cardiovascular disease and c... more The potential health benefits of various dietary oils in relation to cardiovascular disease and cancer are recently receiving considerable attention. The main proposal of this study is to investigate the effect of dietary argan oil, obtained from seeds of Argania spinosa L. (Sapotaceae) endemic from Morocco, on serum lipids composition. Hyperlipidemia was induced by high calorie and cholesterol (HCC) diet administration in 16 rats (Meriones shawi, a rodent of the Gerbillideae family). Eight rats were treated with argan oil (1 ml/100 g weight) daily by oral route during 7 weeks (treated group). Control animals were also fed with HCC diet for 7 weeks. After 7-week treatment with argan oil, blood lipoproteins were significantly reduced. Total cholesterol decreased with 36.67% (P < 0.01), low density lipoprotein (LDL)-cholesterol in 67.70% (P < 0.001), triglycerides in 30.67% (P < 0.05) and body weight in 12.7% (P < 0.05). High density lipoprotein (HDL)-cholesterol concentration remained unaltered. These results indicate the beneficial effect of argan oil in the treatment of the hyperlipidemia and hypercholesterolemia. This effect will be related with the polyunsaturated fatty acids and other constituents of studied oil.

Effects of chronic treatment with argan oil (argania spinosa l.) on blood pressure and endothelia... more Effects of chronic treatment with argan oil (argania spinosa l.) on blood pressure and endothelial function in hypertensive rats.

Background: The effect of dietary pomace olive oil, which has the same concentration of oleic aci... more Background: The effect of dietary pomace olive oil, which has the same concentration of oleic acid but a higher proportion of oleanolic acid (OA) than olive oil, was examined on animal models of hypertension for the first time. Methods: During 12 weeks, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were fed with either a control 2% corn oil diet (BD), or high-fat diets containing 15% of refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in OA (up to 800 ppm) (POMO). Then, vascular reactivity and endothelial nitric oxide (NO) synthase (eNOS) expression were studied in aortic rings. Plasma nitrite ϩ nitrate levels were also determined. Results: Diets had no effects on blood pressure (BP). In contrast to the BD and OL dietary groups, POM intake improved relaxation evoked by acetylcholine in SHR aorta. The POMO intake increased vasodilatation to acetylcholine and attenuated phenylephrine-induced contractions in both strains of rats associated with a major NO participation revealed by inhibition of NOS. The enhanced relaxation shown in POM and POMO SHR aorta was attributed to an increased eNOS protein expression. Plasma nitrite levels were also increased in these groups. Although olive and pomace oils used in diets contained similar fatty acid composition, beneficial effects on endothelial function were absent in the OL group. Therefore, these effects must be associated with some minor components from pomace olive oil such as OA. Conclusions: Chronic intake of diets rich in pomace olive oil improves endothelial dysfunction in SHR aorta by mechanisms associated with enhanced eNOS expression. Important evidence is provided regarding the effects of pomace olive oil and OA on endothelial function in hypertensive animals.

L-carnitine and propionyl-L-carnitine are supplements to therapy in cardiovascular pathologies. T... more L-carnitine and propionyl-L-carnitine are supplements to therapy in cardiovascular pathologies. Their effect on endothelial dysfunction in hypertension was studied after treatment with either 200 mg/kg of L-carnitine or propionyl-L-carnitine during 8 weeks of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Endothelial function was assessed in aortic rings by carbachol-induced relaxation (CCh 10 À 8 to 10 À 4 M) and factors involved were characterized in the presence of the inhibitors: L-NAME, indomethacin, the TXA 2 / PGH 2 Tp receptor antagonist ICI-192,605 and the thromboxane synthetase inhibitor-Tp receptor antagonist, Ro-68,070. The effect on phenylephrine-induced contractions was also observed. To identify the nature of vasoactive COX-derived products, enzyme-immunoassay of incubation media was assessed. Involvement of reactive oxygen species was evaluated by incubating with superoxide dismutase and catalase. Nitric oxide production was evaluated by serum concentration of NO 2 + NO 3 .Treatment with both compounds improved endothelial function of rings from SHR without blood pressure change. Propionyl-L-carnitine increased NO participation in WKY and SHR. L-carnitine reduced endothelium-dependent responses to CCh in WKY due to an increase of TXA 2 production. In both SHR and WKY, L-carnitine enhanced concentration of PGI 2 and increased participation of NO. Results in the presence of SOD plus catalase show that it might be related to antioxidant properties of L-carnitine and propionyl-L-carnitine. Comparison between the effect of both compounds shows that both may reduce reactive

Medicina Clínica, 2009

El envejecimiento es un factor de riesgo para la aparició n de numerosas enfermedades cardiovascu... more El envejecimiento es un factor de riesgo para la aparició n de numerosas enfermedades cardiovasculares en las que subyace una circunstancia comú n: el deterioro progresivo de la funció n endotelial. En este trabajo, se resumen los mecanismos implicados en esta disfunció n, y se centra especialmente en las sustancias vasoactivas liberadas por el endotelio. La menor contribució n del ó xido nítrico, el aumento de prostanoides vasoconstrictores y las alteraciones en la acció n del factor hiperpolarizante derivado de endotelio y del pé ptido vasoconstrictor endotelina son manifestaciones del dañ o que el envejecimiento causa en el endotelio. El aumento del estré s oxidativo y la mayor producció n de especies reactivas de oxígeno, junto con el fenotipo proinflamatorio de la pared vascular, contribuyen a explicar estos efectos. Asimismo, se revisan las investigaciones que ponen de manifiesto el papel de desempeñ an la senescencia de las cé lulas endoteliales y de sus progenitoras.

British Journal of Nutrition, 2009

Pomace olive oil (POM), an olive oil subproduct traditionally used in Spain, is a good source of ... more Pomace olive oil (POM), an olive oil subproduct traditionally used in Spain, is a good source of minor components from the unsaponifiable fraction such as triterpenoids, mainly in the form of oleanolic acid, which induces vascular protection and vasodilatation. Our aim was to evaluate the effects of long-term intake of diets enriched in POM with high concentration in oleanolic acid on endothelial dysfunction associated to hypertension in small mesenteric arteries (SMA) from spontaneously hypertensive rats (SHR). During 12 weeks, rats (six rats per group) were fed either a control 2 % maize oil diet (BD), or high-fat diets containing 15 % refined olive oil (OL), pomace olive oil (POM), or pomace olive oil supplemented in oleanolic acid (POMO; up to 800 parts per million). Endothelial and vascular functions were assessed by relaxing or contracting responses to acetylcholine (ACh) or phenylephrine, respectively. The involvement of endothelium-derived relaxing factors in these responses...

Pharmacology, 2005

The acute effect of simvastatin on aortic rings from spontaneously hypertensive rats (SHRs) was i... more The acute effect of simvastatin on aortic rings from spontaneously hypertensive rats (SHRs) was identified. Simvastatin-evoked relaxations of both depolarized and phenylephrine-precontracted arteries were independent of the presence of endothelium. This effect was inhibited by diltiazem and mevalonate, but not by the Rho-kinase inhibitor, Y-27632. Simvastatin prevented contraction induced by phenylephrine, calcium ionophore A-23187 and CaCl2 in Ca2+-free medium. Y-27632 decreased the effect of simvastatin. On the contrary, contraction induced by noradrenaline in Ca2+-free medium was not affected. These results suggest that simvastatin elicited an effect on vascular smooth muscle cells from SHRs that may involve blockade of extracellular calcium entry and decrease vascular contraction by affecting Rho-kinase.

Pharmacology, 2008

Statins have been identified as a potentially interesting treatment against sepsis. Here, we stud... more Statins have been identified as a potentially interesting treatment against sepsis. Here, we study the vascular reactivity of aortae from rats treated with lipopolysaccharide (LPS), 4 mg . kg(-1), following chronic administration of simvastatin (SV) 10 mg . kg(-1). The rats were treated with either vehicle or SV for 4 weeks before administration of LPS. After 18 h, the systolic blood pressure (SBP) was measured using a tail cuff and vascular and endothelial responses of aortic rings to several agonists were studied in an organ bath. LPS injection decreased the SBP by 38 mm Hg and vascular response to phenylephrine (Phe) by 60%. Plasma nitrates and nitrites (NO(x)) were 3-fold higher after LPS. This attenuated response to Phe was prevented by incubation with either the inducible-nitric-oxide-synthase (iNOS)-selective inhibitor 1400W or the endothelial nitric oxide synthase (eNOS)/iNOS nonselective blocker L-NAME. The presence of endothelium did not alter these findings. Administering LPS to SV-treated rats also decreased the SBP and increased the NO(x) concentration. The impaired response to Phe was restored by blocking NO synthesis in endothelium-denuded but not in intact aortic rings. The response to acetylcholine demonstrated an enhanced reduction in arteries from the SV + LPS group compared with the LPS group. The inhibition of iNOS prevented acetylcholine-induced relaxation in rings from LPS-treated rats but not in those from the SV + LPS group. These results suggest that statins may reduce iNOS-mediated NO production in endothelial but not in vascular smooth-muscle cells.

Obesity, 2009

Rimonabant (RM) is a cannabinoid CB1 receptor antagonist useful in the treatment of obesity assoc... more Rimonabant (RM) is a cannabinoid CB1 receptor antagonist useful in the treatment of obesity associated cardiovascular risk factors. Since cannabinoids are vasoactive compounds, the aim of this study is to evaluate the effect of chronic treatment with RM on systolic blood pressure (SBP), and endothelial and vascular reactivity. Obese Zucker rats (OZRs) and their lean counterparts were orally treated during 20 weeks with either RM (10 mg/kg/day). Endothelial and vascular function was assessed in aorta and small mesenteric arteries (SMAs) by concentration response curves to acetylcholine (ACh) and phenylephrine (Phe), respectively. Participation of nitric oxide (NO) was evaluated by incubation with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) and cyclooxygenase (COX)-derived products involvement was analyzed by incubation with indomethacin (INDO). Plasma lipid profile, insulin and adiponectin were also analyzed. Sympathetic activity was evaluated by urinary excretion of noradrenaline. As expected, RM decreased body weight gain and enhanced adiponectin concentration. Insulin resistance and sympathetic activity were also decreased. The increase in SBP observed in OZRs was reduced by treatment with RM. Aortae and SMAs from OZRs exhibited lower contractile response to Phe, being this effect prevented by RM administration. Although ACh-induced response and NO participation remained unaltered with obesity, enhanced COX-derived constrictor products were found in OZRs. RM treatment neither altered endothelium-dependent relaxation nor L-NAME-sensitive component of the response. Nevertheless, it was able to regulate COX-derived vasoactive products participation. Those effects may contribute to explain some of the cardiovascular protective actions elicited by this drug.

Journal of Vascular Research, 2007

The effect of treatment with either 200 mg x kg(-1) of L-carnitine (LC) or propionyl-L-carnitine ... more The effect of treatment with either 200 mg x kg(-1) of L-carnitine (LC) or propionyl-L-carnitine (PLC) was studied on endothelial dysfunction of small mesenteric arteries (SMA) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured and endothelial and vascular functions were assessed by the effect of carbachol (CCh) and phenylephrine (Phe). O2- produced by SMA and eNOS expression were evaluated by chemiluminescence and Western blot, respectively. Although SBP was not affected, endothelial relaxation increased in both LC- and PLC-treated SHR. Nevertheless, the CCh-induced contraction remained sensitive to indomethacin in these rats. On the contrary, NO participation was increased in all the groups except for LC-treated WKY. Furthermore, high concentrations of Phe produced NO-dependent relaxation of SMA from PLC-treated rats. Both compounds decreased basal and NADPH-stimulated O2- in SHR toward values observed in WKY. Only PLC increased eNOS protein expression in SHR. Neither LC nor PLC affected endothelium-derived hyperpolarizing factor-induced relaxation. LC and its propionate improved endothelial responses of SMA from SHR by decreasing O2- production and thus increasing NO availability. PLC also increased NO synthesis by enhancing eNOS expression.

The Journal of Nutritional Biochemistry, 2013

Rice bran enzymatic extract (RBEE) used in this study has shown beneficial activities against dys... more Rice bran enzymatic extract (RBEE) used in this study has shown beneficial activities against dyslipidemia, hyperinsulinemia and hypertension. Our aim was to investigate the effects of a diet supplemented with RBEE in vascular impairment developed in obese Zucker rats and to evaluate the main mechanisms mediating this action. Obese Zucker rats were fed a 1% and 5% RBEE-supplemented diet (O1% and O5%). Obese and their lean littermates fed a standard diet were used as controls (OC and LC, respectively). Vascular function was evaluated in aortic rings in organ baths. The role of nitric oxide (NO) was investigated by using NO synthase (NOS) inhibitors. Aortic expression of endothelial NOS (eNOS), inducible NOS (iNOS), tumor necrosis factor (TNF)-α and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and superoxide production in arterial wall were determined. Endothelial dysfunction and vascular hyperreactivity to phenylephrine in obese rats were ameliorated by RBEE treatment, particularly with 1% RBEE. Up-regulation of eNOS protein expression in RBEE-treated aortas should contribute to this activity. RBEE attenuated vascular inflammation by reducing aortic iNOS and TNF-α expression. Aortas from RBEE-treated groups showed a significant decrease of superoxide production and down-regulation of NADPH oxidase subunits. RBEE treatment restored endothelial function and vascular contractility in obese Zucker rats through a reduction of vascular inflammation and oxidative stress. These results show the nutraceutical potential of RBEE to prevent obesity-related vascular complications.

Journal of Ethnopharmacology, 2008

Cedrelopsis grevei Baill. (Ptaeroxylaceae) trunk bark extract is empirically used in Madagascar a... more Cedrelopsis grevei Baill. (Ptaeroxylaceae) trunk bark extract is empirically used in Madagascar against several pathologies, from persistent catarrh to hypertension. The effect C. grevei extract on age-related changes in systolic blood pressure (SBP) and endothelial function was investigated. Rats (90-100 week-old) received treatment either with C. grevei extract (80 mg kg −1) or vehicle for 8 weeks. SBP was evaluated by tail-cuff and vascular reactivity and endothelial vasodilatation of both aortae and small mesenteric arteries (SMA) were assessed by acetylcholine (ACh) in the presence or in the absence of either reactive oxygen species (ROS) scavengers superoxide dismutase (SOD) plus catalase or the nitric oxide synthase inhibitor, N G-l-arginine methyl ester (l-NAME). Plasma nitric oxide (NO) was evaluated by nitrite assay and expressions of eNOS, Cu/Zn-, Mnand EC-SOD were determined by Western Blot. C. grevei administration prevented the increase of SBP and improved endothelium-dependent relaxations in aortae and SMA from aged rat via increased NO and decreased participation of ROS. Furthermore, C. grevei treatment enhanced plasma nitrite content but did not modify eNOS, Cu/Zn-, Mn-or EC-SOD expressions in the two arteries studied. These results suggest that C. grevei prevents both increased blood pressure and age-related endothelial dysfunction supporting the empirical use of C. grevei trunk bark extract against mild hypertension often associated with aging.

Journal of Cardiovascular Pharmacology, 2010

To investigate the effect of chronic cannabinoid 1 antagonism on vascular prostanoid production, ... more To investigate the effect of chronic cannabinoid 1 antagonism on vascular prostanoid production, obese Zucker rats were treated with rimonabant (10 mg/kg per day) during 20 weeks and then vascular and endothelial reactivity were assessed in aortic rings by analyzing response to phenylephrine and acetylcholine. The presence of cyclo-oxygenase-1 and cyclo-oxygenase-2 selective inhibitors (SC-560 and NS-398, respectively) and the enzyme immunoassay revealed lower PGI2 production by aortic rings from obese rats with rimonabant able to restore such response toward levels found in the lean animals. The treatment also reduced TXB2 but did not alter its participation on acetylcholine-induced relaxation as the TP receptor antagonist ICI-192,605 revealed. Those effects were associated with an enhancement of cyclo-oxygenase-2 expression without affecting p38MAPK phosphorylation. Obese rats also exhibited higher nitric oxide plasma concentrations and greater inducible nitric oxide synthase participation on vascular phenylephrine-induced response without changes in inducible nitric oxide synthase protein expression. Although rimonabant reduced such alteration, the values were still higher than those found in lean rats. Finally, rimonabant was also able to reduce tumor necrosis factor-α produced by adipose tissue of obese Zucker rats. These results highlight a crosstalk among cannabinoids and cyclo-oxygenase-derived products in the vasculature of obese animals.

Free Radical Research, 2007

To clarify the mechanism underlying the antioxidant properties of l-carnitine (LC) and propionyl-... more To clarify the mechanism underlying the antioxidant properties of l-carnitine (LC) and propionyl-l-carnitine (PLC) on spontaneously hypertensive (SHR) and normotensive WKY, animals were treated with either PLC or LC (200 mg kg(- 1)). Aorta was dissected and contraction to (R)-( - )-phenylephrine (Phe) and relaxation to carbachol (CCh) were assessed in the presence or not of the NO synthase (NOS) inhibitor, l-NAME. [image omitted] production was evaluated by lucigenin-enhanced chemiluminescence and its participation on relaxation was observed after incubation with superoxide dismutase (SOD) plus catalase. Protein expressions of eNOS, Cu/Zn-SOD and Mn-SOD were studied by western blot. Both LC and PLC treatments improved endothelial function of SHR through increasing NO participation and decreasing [image omitted] probably involving higher Cu/Zn-SOD expression. PLC treatment augmented eNOS expression in SHR. Surprisingly, LC increased [image omitted] produced by aorta from WKY and thus diminished NO and damaged endothelial function. Conversely, PLC did not affect CCh-induced relaxation in WKY. These results demonstrate that LC and PLC prevent endothelial dysfunction in SHR through an antioxidant effect.

European Journal of Pharmacology, 2011

The effect of adrenomedullin (AM), a peptide that has demonstrated vasodilatory activity, was stu... more The effect of adrenomedullin (AM), a peptide that has demonstrated vasodilatory activity, was studied in the colon and small mesenteric arteries of rats in a chronic model of inflammatory bowel disease. AM (50 ng/kg/day) was administered i.p. daily, starting 24 h after trinitrobenzensulfonic acid (TNBS, 30 mg) instillation. After 14 days, rats were sacrificed, colons were macroscopically analyzed and biochemical parameters (myeloperoxidase activity, cytokines, cyclooxygenase-2 (COX-2) as well as inducible nitric oxide synthase (iNOS) expression) were determined. Vascular function of small mesenteric arteries was assessed by addition of phenylephrine (10 −8 to 10 −4 mol/L) and participation of COX and NOS pathways was also evaluated by using different inhibitors: indomethacin, NS-398, L-NNA, and 1400w. Chronic AM treatment significantly reduced colonic macroscopic damage and inflammation markers. TNBS instillation induced COX-2 and iNOS expressions in colon and small mesenteric arteries; AM treatment decreased COX-2 expression only in microvessels from rats with colitis. An attenuation of phenylephrine-induced contraction was detected in small mesenteric arteries from both TNBS and AM-treated rats. COX and NOS inhibitors altered the contractile ability of phenylephrine in small mesenteric arteries from TNBS rats, suggesting the involvement of COX-2 and iNOS derived factors in the deleterious effect of TNBS on vascular reactivity; AM administration was able to reduce such alteration. Finally, treatment with the peptide significantly reduced colonic nitric oxide (NO) levels, without affecting plasma concentration. In conclusion, AM showed beneficial effects in the restoration of vascular function through the regulation of vasoactive products derived from COX-2 and iNOS.

British Journal of Pharmacology, 2009

The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on agere... more The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on agerelated endothelial dysfunction were investigated in the aorta of male Wistar rats. 2 Adult (12-14 weeks) and old (60-80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg À1). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL-cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status. 3 SV improved endothelium-dependent relaxation to acetylcholine and A-23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO-synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation. 4 Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A 2 from COX-2 isoform. The effect of the latter was sensitive to the T p receptor antagonist, ICI-192,605. 5 The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA 2 from cyclo-oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age-related endothelial dysfunction.

British Journal of Pharmacology, 2003

The present study was aimed to characterize the eects of ageing on vascular contraction by noradr... more The present study was aimed to characterize the eects of ageing on vascular contraction by noradrenaline in rat isolated arteries. The existence of vascular bed heterogeneity was investigated in endothelium-denuded conductance (aorta) and resistance (small mesenteric artery, SMA) arteries, with respect to Ca 2+ handling, Ca 2+ sensitization or Ca 2+-independent mechanisms. 2 In both arteries, contractions to noradrenaline were not dierent between adult and aged rats. 3 In Ca 2+-free medium, noradrenaline elicited a transient increase in tension that was reduced by the Ca 2+ mobilizing agents, ryanodine and thapsigargin, in arteries from adult rats. A loss of the thapsigargin-but not the ryanodine-sensitive component of noradrenaline-induced contraction was observed in the two arteries from aged rats. 4 After depletion of Ca 2+ stores with noradrenaline, addition of exogenous CaCl 2 produced a sustained contraction that was decreased to the same extent by the protein kinase C inhibitor, GF 109203X and the tyrosine kinase inhibitor, tyrphostin A-23, in arteries from adult and aged rats. The Rho-associated protein kinase inhibitor, Y-27632, caused identical relaxation of noradrenaline pre-contracted arteries from both age groups. 5 Basal intracellular calcium ([Ca 2+ ] i) was higher in SMA from aged than from adult rats. In addition, the noradrenaline [Ca 2+ ] i-force relationship was signi®cantly shifted to the right in the SMA from aged rats. 6 Altogether, these data indicate that responsiveness to noradrenaline is preserved both in conductance and resistance arteries with ageing. The latter results from the association of increased basal [Ca 2+ ] i , changes in Ca 2+ handling at the level of thapsigargin-sensitive sarcoplasmic reticulum Ca 2+-ATPases and decreased myo®lament sensitivity to Ca 2+ .

British Journal of Pharmacology, 2000

Vascular eects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvas... more Vascular eects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, were studied in conductance (aorta) and resistance vessels (branch II or III of superior mesenteric artery, SMA) of the rat (12 ± 14 weeks old). 2 Simvastatin produced relaxation of both aorta and SMA, with and without functional endothelium. These responses were inhibited by the product of HMG-CoA reductase, mevalonate (1 mmol l 71). 3 In vessels with functional endothelium, the NO-synthase inhibitor, L-N G-nitroarginine (L-NOARG, 30 mmol l 71), inhibited simvastatin-induced relaxation. In the presence of L-NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L-NOARG. 4 The cyclo-oxygenase inhibitor, indomethacin (10 mmol l 71), abolished endothelium-dependent component of the response to simvastatin in both arteries. The combination of L-NOARG plus indomethacin did not produce further inhibition. The T p receptor antagonist, GR 32191B (3 mmol l 71), did not aect relaxation in aorta but it reduced response to low concentrations of simvastatin in SMA. However, the inhibitory eect of L-NOARG was less marked in the presence of GR 32191B in aorta but not in SMA. 5 The endothelium-dependent relaxation to simvastatin was inhibited by the superoxide dismutase (SOD, 100 u ml 71) or by the tyrosine kinase inhibitor, genistein (30 mmol l 71) in the two arteries. 6 The present study shows that simvastatin produces relaxation of conductance and small arteries through mevalonate-sensitive pathway. The endothelium-dependent relaxation to simvastatin involves both NO and vasodilator eicosanoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eicosanoids acting on the T p receptor after blockage of NO synthase only.