Abstract-The effects of short-term oral administration of red wine polyphenolic compounds on hemodynamic parameters and on vascular reactivity were investigated in rats. Endothelial function and vascular smooth muscle contractility were studied in association with the induction of gene expression in the vascular wall. Rats were treated daily for 7 days by intragastric administration of either 5% glucose or red wine polyphenolic compounds (20 mg/kg). Administration of these compounds produced a progressive decrease in systolic blood pressure, which became significantly different on day 4. Aortas from rats treated with red wine polyphenolic compounds displayed increased endothelium-dependent relaxation to acetylcholine that was related to increased endothelial NO activity and involved a mechanism sensitive to superoxide anion scavengers. However, no increase in whole-body oxidative stress has been observed in rats treated with red wine polyphenolic compounds, as shown by plasma glutathione assay. Also, in the aorta, red wine polyphenolic compounds increased the expression of cyclooxygenase-2 and increased the release of endothelial thromboxane A 2 , which compensated for the extraendothelial NO-induced hyporeactivity in response to norepinephrine, resulting from enhanced inducible NO synthase expression. The present study provides evidence that short-term oral administration of red wine polyphenolic compounds produces a decrease in blood pressure in normotensive rats. This hemodynamic effect was associated with an enhanced endothelium-dependent relaxation and an induction of gene expression (of inducible NO synthase and cyclooxygenase-2) within the arterial wall, which together maintain unchanged agonist-induced contractility. These effects of red wine polyphenolic compounds may be a potential mechanism for preventing cardiovascular diseases.

1 The effects of short-term oral administration of red wine polyphenolic compounds (RWPC, 20 mg kg À1 day À1 for 7 days) on haemodynamics, ex vivo cardiac responsiveness and ischaemiareperfusion injury were investigated in rats. The involvement of nitric oxide (NO) was evaluated using the NO synthase inhibitor, N G -nitro-L-arginine methyl ester (L-NAME, 2 mg kg À1 day À1 for 7 days), at a dose which did not affect blood pressure. 2 Ex vivo reactivity of hearts from RWPC-treated rats showed lower basal developed pressure, greater heart rate and decreased inotropic responses to either b-adrenoceptor or muscarinic receptor stimulation with isoprenaline or carbachol, respectively. 3 RWPC treatment did not modify cardiac expression of endothelial NO synthase or Cu/Zn superoxide dismutase. However, it increased nitrite in the coronary effluent. 4 In ischaemia-reperfusion, RWPC treatment reduced infarct size and oxidative stress, as shown by the myocardial content of the end products of lipid peroxidation, malondialdehyde and 4-hydroxynonenal, without affecting post-ischaemic contractile dysfunction. All the observed effects of RWPC were prevented by L-NAME treatment. 5 Altogether, these data show that short-term treatment with RWPC decreases blood pressure and cardiac responsiveness, and protects against post-ischaemic infarction via decreased oxidative stress. All the above effects of RWPC are sensitive to NO synthase inhibition that implies an involvement of NO-dependent pathway. This study suggests a basis for the beneficial effects of plant-derived polyphenols against cardiovascular disease.

The effects of short-term oral administration of red wine polyphenolic compounds (RWPCs) on blood pressure and vascular reactivity were investigated in rats. The consequence of RWPCs treatment on agonist-induced contractility of rat aorta with respect to Ca2+ handling was assessed, by examining both intracellular Ca2+ store and extracellular Ca2+ influx components of the response. Rats were treated daily for 7 days by intragastric administration of either 5% glucose, or RWPCs (20 mg/kg) [from two different sources, i.e. Provinols (SFD, Vallont Pont d'Arc, France) and RWPC1 (INRA, Montpellier, France)]. Administration of these compounds produced a decrease in systolic blood pressure. The consequence of RWPCs treatment on vascular smooth muscle was investigated in rat aorta without endothelium exposed to noradrenaline. In Ca(2+)-free medium, RWPC1 but not Provinols treatment induced an increase in noradrenaline-induced contraction. After depletion of intracellular Ca2+ stores by noradrenaline in Ca(2+)-free medium, addition of CaCl2 in the continuous presence of agonist induced an increase in contraction, which was not significantly different between control, Provinols- and RWPC-treated rats. The presence of an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin, significantly reduced noradrenaline-induced contraction in Ca(2+)-free medium in RWPCs-treated aorta, as compared to that of control. Interestingly, the inhibitory effect of thapsigargin on the response linked to the release of Ca2+ from internal stores in RWPCs-treated vessels was completely prevented in the presence of NO-synthase inhibitor, L-nitro arginine methyl ester, the inhibitor of guanylyl cyclase, oxadiazolo-quinoxaline or the protein kinase G inhibitor, 8-Bromoguanosine-3'-5-cyclic mono-phosphorothioate, Rp isomer. These results suggest that short-term administration of RWPCs in rats induced subtle alteration of thapsigargin-sensitive component of agonist-induced contraction in rat aorta linked to Ca2+ release from intracellular store. Calcium release from intracellular stores sensitive to thapsigargin was implicated in this mechanism. The prevention of the inhibitory effect of thapsigargin by the inhibitors of NO/cyclic guanosine monophosphate pathway after RWPCs treatment highlights the role of NO in this phenomenon.

The use of arterial TEVM, brings new insights into the mechanisms by which polyphenols regulate vascular contraction in the human artery.

Diebolt, M., L. Germain, F. A. Auger, and R. Andriantsitohaina. Mechanism of potentiation by polyphenols of contraction in human vein-engineered media.

The effects of Cognac polyphenolic compounds (CPC) on aorta and isolated heart, the consequences of oral administration on haemodynamic parameters, vascular reactivity and cardiac recovery after ischaemia were investigated. CPC induced an endothelium-dependent vasorelaxation on rat-isolated aorta. This effect was prevented by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine-methyl ester, but not by the cyclo-oxygenase inhibitor, indomethacin, suggesting the implication of NO pathway. On isolated rat hearts, CPC induced positive inotropic, chronotropic, and lusitropic effect at 10(-4)-10(-2) g/L while at 10(-1) g/L, it had negative lusitropic effect and other parameters returned to baseline values. Oral administration of 40 mg/kg of CPC for 2 weeks did not modify systolic blood pressure and heart rate of rats throughout the treatment. CPC treatment did not affect ex vivo response of isolated thoracic aorta either to the contractile agent noradrenaline or to the endothelial-relaxant agent, acetylcholine. Isolated hearts from treated rats were submitted to 30-min global ischaemia followed by 120 min of reperfusion. Post-ischaemic recovery of functional cardiac parameters was not modified by treatment with CPC. Infarct size measured after the reperfusion in heart from CPC-treated rats was significantly decreased in comparison with hearts from control group. We conclude that in vitro, CPC had NO-dependent vasorelaxant effects and stimulated cardiac function. Oral treatment with CPC appeared to have no impact in vivo on blood pressure, heart rate of the rats or on cardiac contractility ex vivo; however, it could decrease the infarct size after an ischaemia-reperfusion.

The present study was aimed to evaluate the mechanisms involved in the vasorelaxant effects of red wine polyphenol compounds (RWPC) in small mesenteric rat arteries. RWPC produce relaxation in small mesenteric arteries. This relaxant effect was abolished by endothelial denudation, NO-synthase blockade with L-NAME and partial depolarization with KCl or L-NAME plus KCl. Incubation with the reactive oxygen species scavenger, superoxide dismutase (SOD) plus catalase, or inhibition of NAD(P)H-dependent oxidoreductases with diphenyleneiodonium also inhibited RWPC induced vascular relaxation. Application of RWPC elicited a transient increase in intracellular calcium concentration ([Ca2+]i) in bovine aortic endothelial cells (BAEC), which was attenuated by a mixture of SOD and catalase. Incubation of BAEC with RWPC increased the SOD inhibitable production of O2-. These results suggest the involvement of O2- in the [Ca2+]i increase evoked by RWPC, leading to the activation of enzymes involved in the release of endothelial relaxant factors and subsequent vasodilatation of resistance arteries.

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