Fatma Akar

Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl−cotransporter in rat aorta

Little is known about the function and regulation of the Na+-K+-2Cl-cotransporter NKCC1 in vascular smooth muscle. The activity of NKCC1 was measured as the bumetanide-sensitive efflux of86Rb+from intact smooth muscle of the rat aorta. Hypertonic shrinkage (440 mosmol/kgH2O) rapidly doubled cotransporter activity, consistent with its volume-regulatory function. NKCC1 was also acutely activated by the vasoconstrictors ANG II (52%), phenylephrine (50%), endothelin (53%), and 30 mM KCl (54%). Both nitric oxide and nitroprusside inhibited basal NKCC1 activity (39 and 34%, respectively), and nitroprusside completely reversed the stimulation by phenylephrine. The phosphorylation of NKCC1 was increased by hypertonic shrinkage, phenylephrine, and KCl and was reduced by nitroprusside. The inhibition of NKCC1 significantly reduced the contraction of rat aorta induced by phenylephrine (63% at 10 nM, 26% at 30 nM) but not by KCl. We conclude that the Na+-K+-2Cl-cotransporter in vascular smooth muscle is reciprocally regulated by vasoconstrictors and nitrovasodilators and contributes to smooth muscle contraction, indicating that alterations in NKCC1 could influence vascular smooth muscle tone in vivo.

High-fructose corn syrup causes vascular dysfunction associated with metabolic disturbance in rats: Protective effect of resveratrol

High-fructose corn syrup (HFCS) is used in many prepared foods and soft drinks. However, limited data is available on the consequences of HFCS consumption on metabolic and cardiovascular functions. This study was, therefore, designed to assess whether HFCS drinking influences the endothelial and vascular function in association with metabolic disturbances in rats. Additionally, resveratrol was tested at challenge with HFCS. We investigated the effects of HFCS (10% and 20%) and resveratrol (50mg/l) beverages on several metabolic parameters as well as endothelial relaxation, vascular contractions, expressions of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), gp91(phox) and p22(phox) proteins and superoxide generation in the aortas. Consumption of HFCS (20%) increased serum triglyceride, VLDL and insulin levels as well as blood pressure. Impaired relaxation to acetylcholine and intensified contractions to phenylephrine and angiotensin II were associated with decreased eNOS and SIRT1 whereas increased gp91(phox) and p22(phox) proteins, along with provoked superoxide production in the aortas from HFCS-treated rats. Resveratrol supplementation efficiently restored HFCS-induced deteriorations. Thus, intake of HFCS leads to vascular dysfunction by decreasing vasoprotective factors and provoking oxidative stress in association with metabolic disturbances. Resveratrol has a protective potential against the harmful consequences of HFCS consumption.

Nitric-oxide production by human umbilical vessels in severe pre-eclampsia.

Objective: Pre-eclampsia is characterized by an increased vascular tone which might be related to an abnormal endothelial cell function. As representatives of the fetal circulation, we compared the nitric oxide (NO)-releasing capacity of human umbilical vessels from normal and pre-eclamptic pregnancies. Methods: Normal and pre-eclamptic umbilical vessels were mounted in parallel in an organ chamber with three perfusion lines superfusing the same detector tissue (rubbed rat aortic ring). In this cascade system the capacity of the umbilical vessels to release NO was measured under basal conditions and after stimulation with histamine, bradykinin or calcium ionophore A 23187. Results: Relaxations dependent on basal NO release were found to be significantly higher in pre-eclamptic vessels (especially in veins) than in normal vessels. Conversely, stimulaled NO release in response to histamine or bradykinin was significantly decreased in pre-eclamptic umbilical arteries, but not in veins, compared with normal vessels. However, there was no significant difference in the release of NO in response to A 23187 between normal and pre-eclamptic vessels. Conclusions: The NO-releasing and NO-producing capacity in the vessels from fetal circulation is not diminished in pre-eclampsia. However, in pre-eclamptic umbilical arteries the NO release in response to certain stimuli (histamine or bradykinin) is diminished, probably as a result of alterations in the receptor function.

Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats

Dietary intake of fructose and sucrose can cause development of metabolic and cardiovascular disorders. The consequences of high-fructose corn syrup (HFCS), a commonly consumed form of fructose and glucose, have poorly been examined. Therefore, in this study, we investigated whether HFCS intake (10% and 20% beverages for 12 weeks) impacts vascular reactivity to insulin and endothelin-1 in conjunction with insulin receptor substrate-1(IRS-1), endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) mRNA/proteins levels in aorta of rats. At challenge, we tested the effectiveness of resveratrol (28-30 mg/kg body weight/day) on outcomes of HFCS feeding. HFCS (20%) diet feeding increased plasma triglyceride, VLDL, cholesterol, insulin and glucose levels, but not body weights of rats. Impaired nitric oxide-mediated relaxation to insulin (10⁻⁹ to 3×10⁻⁶ M), and enhanced contraction to endothelin-1 (10⁻¹¹ to 10⁻⁸ M) were associated with decreased expression of IRS-1 and eNOS mRNA and protein, but increased expression of iNOS, in aortas of rats fed with HFCS. Resveratrol supplementation restored many features of HFCS-induced disturbances, probably by regulating eNOS and iNOS production. In conclusion, dietary HFCS causes vascular insulin resistance and endothelial dysfunction through attenuating IRS-1 and eNOS expressions as well as increasing iNOS in rats. Resveratrol has capability to recover HFCS-induced disturbances.

Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury.

We investigated the influences of the K+ channel opening drugs cromakalim and diazoxide and their blocker, glibenclamide, in indomethacin-induced gastric injury in rats. Cromakalim (0.1 and 0.3 mg/kg) and diazoxide (10 and 30 mg/kg) produced dose-dependent gastroprotection at doses that were also effective on the cardiovascular system. Glibenclamide reversed their gastroprotective effects and aggravated indomethacin-induced gastric damage by its own. Cromakalim (10(-9)-10(-5) M) and diazoxide (10(-9)-10(-4) M) relaxed noradrenaline pre-contracted gastric arteries (94.59+/-1.58% and 93.86+/-2.99%, respectively). Their relaxant effects were inhibited by glibenclamide (10(-5) M) but not by indomethacin (10(-5) M) and LG-nitro-L-arginine (10(-4) M). Cromakalim (0.1 and 0.3 mg/kg) did not change gastric mucosal blood flow but increased the gastric mucosal vascular conductance in anaesthetized rats as measured by the hydrogen gas clearance technique. Indomethacin increased myeloperoxidase activity in the gastric mucosa, an effect which was reversed by cromakalim and diazoxide. Glibenclamide abolished their effects on myeloperoxidase activity and, alone, increased this parameter. Additionally, indomethacin caused infiltration of neutrophils which was reduced by cromakalim and diazoxide in a glibenclamide sensitive manner. The effects of cromakalim and diazoxide on mucosal myeloperoxidase activity, neutrophil infiltration and gastric injury correlated with each other. The effects of diazoxide (30 mg/kg) and glibenclamide (10 mg/kg) on blood glucose level were not correlated with their effects on gastric injury. Taken together, K+ channel opening drugs show misoprostol-like protective effects in indomethacin-induced gastric injury which seems to be related to modulation of neutrophil function.

The effect of long-term resveratrol treatment on relaxation to estrogen in aortae from male and female rats: role of nitric oxide and superoxide.

Resveratrol, which is found in several foods, has vasorelaxing and estrogen-like activities. The aim of the present study was to determine whether the relaxation to estrogen is differently modified between male and female genders after long-term resveratrol treatment. To test this, we compared endothelium-dependent and -independent relaxations to estrogen in the aortae of control and resveratrol-treated male and female rats. Nitric oxide and superoxide levels were also evaluated to explain the mechanism of action of resveratrol. Concentration-response curves to estrogen (10(-10)-10(-4) M) were obtained in aortic rings with and without endothelium from control or long-term resveratrol-treated (50 mg/l in drinking water for 21 days) male and female rats. Estrogen produced mainly endothelium-dependent relaxation in aortic rings of rats, with a higher potency in females than males. Resveratrol treatment increased both endothelium-dependent and -independent relaxations to estrogen especially in aortae from males. The relaxations to estrogen in the aortae of resveratrol-treated rats were inhibited, almost to the same extent as those of control, by pretreatment with ICI 182,780 (10(-6) M), an estrogen receptor antagonist. In both genders, resveratrol treatment increased basal nitric oxide and nitrite/nitrate productions and decreased both basal and NAD(P)H-induced superoxide productions in the aortae. In addition, plasma estrogen levels were found decreased in long-term resveratrol-treated animals of both genders. The improvement in the relaxations to estrogen observed in resveratrol-treated animals could be related to elevated nitric oxide and/or decreased superoxide productions and possibly mediated by classical estrogen receptors. The modulating effect of resveratrol on estrogen responsiveness may differ between male and female.

The comparison of vascular reactivities of arterial and venous grafts to vasodilators: Management of graft spasm

Graft spasm in the perioperative or postoperative period increases the risk of morbidity and mortality after coronary revascularization and hence necessitates urgent treatment. We have studied the effects of various vasodilators against noradrenaline- and endothelin-1-induced spasms in saphenous vein, internal mammary artery and gastroepiploic artery. In internal mammary and gastroepiploic arteries, the nitrovasodilators, sodium nitroprusside and glyceryl trinitrate, effectively reversed the spasms induced either with noradrenaline (for sodium nitroprusside; internal mammary artery: 101.07% +/- 1.63%; gastroepiploic artery: 94.10% +/- 2.07%) or endothelin-1 (for sodium nitroprusside; internal mammary artery: 97.67% +/- 4.94%; gastroepiploic artery: 90.69% +/- 2.61%). However, in saphenous vein contracted with endothelin-1, the responsiveness to nitrovasodilators was significantly blunted (for sodium nitroprusside: 52.33% +/- 5.19%) than that of rings contracted with noradrenaline (for sodium nitroprusside: 95.04% +/- 1.94%). Both arterial and venous grafts exhibited moderate beta-receptor function in response to isoproterenol. Isoproterenol was less effective in inhibiting the contractions of endothelin-1 in saphenous vein and gastroepiploic artery but not in internal mammary artery. On the other hand, nifedipine and papaverine were fully effective in reversing all the spasms in three of the graft materials. From these results, it can be deduced that saphenous vein is refractory against cyclic guanidine monophosphate (cGMP)-dependent and beta-receptor mediated relaxations when endothelin-1 was used as the spasmogenic agent. Internal mammary artery is the most responsive graft material to the vasodilators regardless of the nature of spasmogenic stimulus. Gastroepiploic artery exhibits functional similarity with internal mammary artery, with the exception of beta-receptor responsiveness.

Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol

Background/Aims: There is limited knowledge on the gender differences in the effects of dietary fructose. In the current study, we investigated whether long-term fructose intake impacts metabolic parameters and vascular reactivity differently between male and female rats. Moreover, we tested whether resveratrol has a gender-specific effectiveness on the alterations. Methods: Male and female rats were divided into four groups as control; resveratrol; fructose and resveratrol plus fructose. Fructose was given to the rats as 10% solution in drinking water for 24 weeks. All rats were fed with the standard diet with or without resveratrol. Results: High-fructose diet increased plasma insulin, triglyceride and VLDL levels as well as omental weights in both genders. Long-term dietary fructose causes marked increase in body weight of males, but not females. Dietary fructose impaired endothelial relaxation to acetylcholine and intensified contraction to phenylephrine in the aortas of male and female rats, but differently it also reduced insulin-induced vasodilation in aortas of female rats. These changes were associated with decreased expression levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, but increased in inducible NOS (iNOS), in aortas of male and female rats. Dietary fructose suppressed expression levels of sirtuin 1 (SIRT1) and insulin receptor substrate-2 (IRS-2) mRNA in aortas from female rats. Resveratrol supplementation efficiently restored fructose-induced metabolic and vascular dysfunction in both genders probably by regulating eNOS and iNOS production. Moreover, the augmentations in SIRT1 and IRS-2 mRNA in females and IRS-1 mRNA in males may possibly contribute to the beneficial effects of resveratrol as well. Conclusion: Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol.

Possible prostacyclin-mediated vascular effect of angiotensin II in the isolated perfused rat lung.

Angiotensin I (A I) and angiotensin II (A II) when injected through the pulmonary artery caused an increase in perfusion pressure (PP) of the isolated perfused rat lung and a contraction when the venous outflow was superfused over rat ascending colon (RC). Nicotine (N) when added to the perfusion medium caused a significant increase in PP to A II without altering that to A I. Further addition of ZK 36374, a stable analog of prostacyclin (PGI2), to the medium prevented the potentiating effect of N on the A II pressor response. Neither N nor ZK 36374 altered the superfused RC responses to A I and A II-injected venous effluent. Lysine acetylsalicylate (ASA), however, caused a potentiation in the pressor response to A I. The response of venous effluent superfused RC to A I was also found to be potentiated by ASA. ASA failed to alter the responses to A II. These results were taken as evidence that A II is a potent activator for the biosynthesis of PGI2 in the pulmonary vascular bed. Moreover, PGI2 does not affect angiotensin converting enzyme activity in the lung circulation while other stable metabolites of arachidonic acid can inhibit the conversion of A I to A II.

Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol

The effects of high-fructose diet on adipose tissue insulin signaling and inflammatory process have been poorly documented. In this study, we examined the influences of long-term fructose intake and resveratrol supplementation on the expression of genes involved in insulin signaling and the levels of inflammatory cytokines and sex hormones in the white adipose tissues of male and female rats. Consumption of high-fructose diet for 24 weeks increased the expression of genes involved in insulin signaling including IR, IRS-1, IRS-2, Akt, PI3K, eNOS, mTOR, and PPARγ, despite induction of proinflammatory markers, iNOS, TNFα, IL-1β, IL-18, MDA, and ALT, as well as anti-inflammatory factors, IL-10 and Nrf2 in adipose tissues from males and females. Total and free testosterone concentrations of adipose tissues were impaired in males but increased in females, although there were no changes in their blood levels. Resveratrol supplementation markedly restored the levels of MDA, IL6, IL-10, and IL-18, as well as iNOS, Nrf2, and PI3K mRNA, in adipose tissues of both genders. Dietary fructose activates both insulin signaling and inflammatory pathway in the adipose tissues of male and female rats proposing no correlation between the tissue insulin signaling and inflammation. Resveratrol has partly modulatory effects on fructose-induced changes.