New perspectives of nitric oxide donors in cardiac arrest and cardiopulmonary resuscitation treatment

Nitric oxide (NO) is often used to treat heart failure accompanied with pulmonary edema. According to present knowledge, however, NO donors are contraindicated when systolic blood pressure is less than 90 mmHg. Based on recent findings and our own clinical experience, we formulated a hypothesis about the new breakthrough complex lifesaving effects of NO donors in patients with cardiac arrest and cardiopulmonary resuscitation therapy. It includes a direct hemodynamic effect of NO donors mediated through vasodilation of coronary arteries in cooperation with improvement of cardiac function and cardiac output through reversible inhibition of mitochondrial complex I and mitochondrial NO synthase, followed by reduction in reactive oxygen species and correction of myocardial stunning. Simultaneously, an increase in vascular sensitivity to sympathetic stimulation could lead to an increase in diastolic blood pressure. Confirmation of this hypothesis in clinical practice would mean a milestone in the treatment for cardiac arrest and cardiopulmonary resuscitation

Red wine polyphenols correct vascular function injured by chronic carbon tetrachloride intoxication

The aim of the study was to evaluate the effect of red wine polyphenols extract Provinols™ on the development of cardiovascular injury in the model of carbon tetrachloride (CCl4) intoxication. We followed the thoracic aorta vasoactivity and left ventricle nitric oxide (NO) synthase activity in male Wistar rats. In the preventive experiment lasting for 12 weeks the control group, the group receiving CCl4 (0.5 ml/kg) two times a week subcutaneously, the group receiving Provinols™ (30 mg/kg/day) in drinking water and the group receiving CCl4+Provinols™ was used. In the recovery experiment, the initial 12 weeks of CCl4 treatment were followed by 3 weeks of spontaneous recovery or recovery with Provinols™. CCl4-intoxication resulted in the injury of vasoactivity which was demonstrated by the inhibition of acetylcholine-induced relaxation as well as noradrenaline-induced contraction. In the preventive as well as recovery experiment administration of polyphenols refreshed endothelium-dependent relaxant response and normalized inhibited contraction to adrenergic stimuli. Provinols™ treatment significantly increased NO-synthase activity in all groups. The results revealed beneficial effects of red wine polyphenols on vascular function injured by chronic CCl4 intoxication. The correction of endothelial function seems to be attributed to the activation of NO pathway by polyphenols

Dual effect of polyphenolic compounds on cardiac Na+/K+-ATPase during development and persistence of hypertension in ratsThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

The enzyme kinetics of cardiac Na+/K+-ATPase were used for characterizing the ATP- and Na+-binding sites after administration of red wine polyphenolic compounds (Provinol) during developing and sustained hypertension. Hypertension was induced in rats (LN group) by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 40 mg·kg–1·day–1). Provinol (40 mg·kg–1·day–1) was applied during developing hypertension (LNPF4 group) and sustained hypertension (LNPF7/3 group). Provinol reduced the number of active Na+/K+-ATPase molecules in cardiac tissue, as indicated by decreased Vmax values (by 33% in LNPF4 and 26% in LNPF7/3 compared with LN). Concerning qualitative properties of the enzyme, Provinol induced different effects on the ATP- and Na+-binding sites of Na+/K+-ATPase. The ATP-binding site was impaired by Provinol, as indicated by increased Km value (by 52% in LNPF4 vs. LN), suggesting worsened utilization of substrate by the enzyme. In sustained hypertension, however, Provinol had no..., On a utilisé la cinétique enzymatique de la Na+/K+-ATPase pour caractériser les sites de liaison de l’ATP et du Na+ après l’administration de composés polyphénoliques du vin rouge (Provinol) durant l’installation de l’hypertension et l’hypertension confirmée. On a induit l’hypertension chez des rats (groupe LN) par le biais de l’inhibiteur de la monoxyde d’azote synthase, l-NAME (40 mg·kg–1·jour–1). On a administré le Provinol (40 mg·kg–1·jour–1) durant l’installation de l’hypertension (LNPF4) et durant l’hypertension confirmée (LNPF7/3). Le Provinol a réduit le nombre de molécules actives de la Na+/K+-ATPase dans le tissu cardiaque, comme l’indique la diminution des valeurs de Vmax (de 33 % chez LNPF4 et de 26 % chez LNPF7/3 comparativement à celles du groupe LN). Du point de vue qualitatif, le Provinol a induit divers effets sur les sites de liaison de l’ATP et du Na+ de la Na+/K+-ATPase. Il a altéré le site de liaison de l’ATP, comme le montre l’augmentation de la valeur de Km (de 52 % chez le groupe L..

Red wine polyphenols prevent cyclosporine-induced nephrotoxicity at the level of the intrinsic apoptotic pathway

Flavonoids, polyphenol derivatives of plant origin, possess a broad range of pharmacological properties. A number of studies have found both pro/anti-apoptotic effects for many of these compounds. For these reasons we investigated whether Provinols flavonoids obtained from red wine, have anti-apoptotic properties. The investigations have been carried out in rats treated with Cyclosporine A (CsA). In particular, four groups of rats have been treated for 21 days with either olive oil (control group), with CsA, with Provinols, or with CsA and Provinols simultaneously. Oxidative stress, systolic blood pressure, body weight, biochemical parameters and different markers of pro/anti-apoptotic pathway were measured. CsA produced an increase of systolic blood pressure, a decrease in body weight, serum creatinine levels, urinary total protein concentration and creatinine clearance. Moreover, CsA induced renal alterations and the translocation of Bax and cytochrome c from cytoplasm to mitochondria and vice versa. These changes activated the caspase cascade pathway, that leads to morphological and biochemical features of apoptosis. Provinols restored morphological and biochemical alterations and prevented nephrotoxicity. In conclusion, this study may augment our current understanding of the controversial pro-/anti-apoptotic properties of flavonoids and their molecular mechanisms

Differential modulation of oxidative and nitrosative stress pathways by red wine polyphenols, ProvinolsTM, in tissues from Zucker fatty rats (fa/fa).

Date du colloque : 2009National audienc

Microparticles from patients with metabolic syndrome induce in vivo endothelial dysfunction and vascular hypo-reactivity by increasing oxidative and nitrosative stresses in mouse aorta

National audienc

Effect of Bioactive Compound of Aronia melanocarpa

Aronia melanocarpa has attracted scientific interest due to its dense contents of different polyphenols. We aimed to analyse effects of Aronia melanocarpa (AME) extract on blood pressure (BP), lipid peroxidation, cytokine level, total NOS activity in the left ventricle (LV), and aorta of L-NAME-induced hypertensive rats. 12-week-old male WKY rats were assigned to the control group and groups treated with AME extract (57.90 mg/kg/day), L-NAME (40 mg/kg/day), or combination of L-NAME (40 mg/kg/day) and AME (57.90 mg/kg/day) in tap water for 3 weeks. NOS activity, eNOS protein expression, and conjugated diene (CD) concentration were determined in the LV and aorta. After 3 weeks of L-NAME treatment, BP was increased by 28% and concomitant treatment with AME reduced it by 21%. NOS activity of the LV and aorta in the L-NAME group was decreased by about 40%, while AME increased it almost on the control level. AME-induced eNOS upregulation may contribute to increase NOS activity. Moreover, AME decreased CD concentration in the LV and aorta and TNF-α and IL-6 production in the plasma were increased by L-NAME treatment. In conclusion, our results showed that active substances of Aronia melanocarpa may have a positive effect on blood pressure, NOS activity, and proinflammatory processes in L-NAME-induced hypertension

Paradoxical Effect of Nonalcoholic Red Wine Polyphenol Extract, Provinols™, in the Regulation of Cyclooxygenases in Vessels from Zucker Fatty Rats (fa/fa)

The aim of this work was to study the vascular effects of dietary supplementation of a nonalcoholic red wine polyphenol extract, Provinols, in Zucker fatty (ZF) obese rats. ZF or lean rats received diet supplemented or not with Provinols for 8 weeks. Vasoconstriction in response to phenylephrine (Phe) was then assessed in small mesenteric arteries (SMA) and the aorta with emphasis on the contribution of cyclooxygenases (COX). Although no difference in vasoconstriction was observed between ZF and lean rats both in SMA and the aorta, Provinols affected the contribution of COX-derived vasoconstrictor agents. The nonselective COX inhibitor, indomethacin, reduced vasoconstriction in vessels from both groups; however, lower efficacy was observed in Provinols-treated rats. This was associated with a reduction in thromboxane-A2 and 8-isoprostane release. The selective COX-2 inhibitor, NS398, reduced to the same extent vasoconstriction in aortas from ZF and Provinols-treated ZF rats. However, NS398 reduced response to Phe only in SMA from ZF rats. This was associated with a reduction in 8-isoprostane and prostaglandin-E release. Paradoxically, Provinols decreased COX-2 expression in the aorta, while it increased its expression in SMA. We provide here evidence of a subtle and paradoxical regulation of COX pathway by Provinols vessels from obese rats to maintain vascular tone within a physiological range