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J C Stoclet

Publications and source records attributed to J C Stoclet.

At least 19 recordsLinked to original sources
PubMed2001

A human tissue-engineered vascular media: a new model for pharmacological studies of contractile responses.

Our method for producing tissue-engineered blood vessels based exclusively on the use of human cells, i.e., without artificial scaffolding, has previously been described (1). In this report, a tissue-engineered vascular media (TEVM) was specifically produced for pharmacological studies from cultured human vascular smooth muscle cells (VSMC). The VSMC displayed a differentiated phenotype as demonstrated by the re-expression of VSMC-specific markers and actual tissue contraction in response to physiological stimuli. Because of their physiological shape and mechanical strength, rings of human TEVM could be mounted on force transducers in organ baths to perform standard pharmacological experiments. Concentration-response curves to vasoconstrictor agonists (histamine, bradykinin, ATP, and UTP) were established, with or without selective antagonists, allowing pharmacological characterization of receptors (H1, B2, and P2Y1, and pyrimidinoceptors). Sustained agonist-induced contractions were associated with transient increases in cytosolic Ca2+ concentration, suggesting sensitization of the contractile machinery to Ca2+. ATP caused both Ca2+ entry and Ca2+ release from a ryanodine- and caffeine-sensitive store. Increased cyclic AMP or cyclic GMP levels caused relaxation. This human TEVM displays many of functional characters of the normal vessel from which the cells were originally isolated, including contractile/relaxation responses, cyclic nucleotide sensitivity, and Ca2+ handling mechanisms comparable to those of the normal vessel from which the cells were originally isolated. These results demonstrate the potential of this human model as a versatile new tool for pharmacological research.

Adenosine Triphosphate↗
PubMed2000

Vascular bed heterogeneity in age-related endothelial dysfunction with respect to NO and eicosanoids.

1. Endothelial dysfunction has been described with ageing but the mechanisms responsible have not been clearly elucidated and might be different from one vessel to the other. This study assesses the relative contribution of endothelial nitric oxide (NO) and cyclo-oxygenase (COX) metabolites in relaxation to acetylcholine with ageing in the aorta and the small mesenteric artery of the rat. 2. In the aorta and branch II or III of superior mesenteric artery (SMA), endothelium-dependent relaxation to acetylcholine was not different between 12 - 14 (adult) and 32-week-old rats whereas it was reduced at 70 - 100 (old) weeks of age. 3. Despite an increased endothelial NO-synthase protein expression, the NO-synthase inhibitor, N(G)-nitro-L-arginine-sensitive component of relaxation decreased with ageing. 4. In old rats, exposure to the COX inhibitor, indomethacin, but not the selective COX-2 inhibitor, NS-398, potentiated response to acetylcholine. The thromboxane A(2)/prostaglandin H(2) receptor antagonist, GR 32191B enhanced relaxation to acetylcholine in aorta but it had no effect in SMA. Furthermore, acetylcholine increased thromboxane B(2) production (enzymeimmunoassay) in aorta but not in SMA. Finally, Western blot analysis showed enhanced expression of COX-1 and 2 in the two arteries with ageing. 5. These results suggest that the decrease in acetylcholine-induced relaxation with ageing involves reduced NO-mediated dilatation and increased generation of vasoconstrictor prostanoids most likely from COX-1. They also point out vascular bed heterogeneity related to the nature of prostanoids involved between the aorta (i.e., thromboxane A(2)) and the SMA (unidentified) arteries even though increased expression of COX occurs in both vessels.

Acetylcholine↗
PubMed2000

Involvement of protein kinase C, tyrosine kinases, and Rho kinase in Ca(2+) handling of human small arteries.

The mechanisms of Ca(2+) handling and sensitization were investigated in human small omental arteries exposed to norepinephrine (NE) and to the thromboxane A(2) analog U-46619. Contractions elicited by NE and U-46619 were associated with an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), an increase in Ca(2+)-independent signaling pathways, or an enhancement of the sensitivity of the myofilaments to Ca(2+). The two latter pathways were abolished by protein kinase C (PKC), tyrosine kinase (TK), and Rho-associated protein kinase (ROK) inhibitors. In Ca(2+)-free medium, both NE and U-46619 elicited an increase in tension that was greatly reduced by PKC inhibitors and abolished by caffeine or ryanodine. After depletion of Ca(2+) stores with NE and U-46619 in Ca(2+)-free medium, addition of CaCl(2) in the continuous presence of the agonists produced increases in [Ca(2+)](i) and contractions that were inhibited by nitrendipine and TK inhibitors but not affected by PKC inhibitors. NE and U-46619 induced tyrosine phosphorylation of a 42- or a 58-kDa protein, respectively. These results indicate that the mechanisms leading to contraction elicited by NE and U-46619 in human small omental arteries are composed of Ca(2+) release from ryanodine-sensitive stores, Ca(2+) influx through nitrendipine-sensitive channels, and Ca(2+) sensitization and/or Ca(2+)-independent pathways. They also show that the TK pathway is involved in the tonic contraction associated with Ca(2+) entry, whereas TK, PKC, and ROK mechanisms regulate Ca(2+)-independent signaling pathways or Ca(2+) sensitization.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Adventitia-derived nitric oxide in rat aortas exposed to endotoxin: cell origin and functional consequences.

The role of adventitial cells in bacterial lipopolysaccharide (LPS)-induced vascular nitric oxide (NO) overproduction has been largely ignored. In rat aortas exposed to LPS in vitro or in vivo, it was found that adventitia contained the major part of NO synthase (NOS)-2 protein (Western blot and immunohistochemistry) and generated the largest amount of NO (electron paramagnetic resonance spin trapping). NOS-2 immunoreactive cells were mainly resident macrophages at an early stage (5 h, in vitro or in vivo) and fibroblasts at a later stage (20 h, in vitro). Adventitial NOS-2 activity largely accounted for 1) the relaxing effect of L-arginine in rings exposed to LPS in vivo, 2) generation of an "NO store" revealed by N-acetylcysteine-induced relaxation, and 3) formation of protein-bound dinitrosyl iron complexes in the medial layer of aortic rings exposed to LPS in vitro. In conclusion, the adventitia is a powerful source of NO triggered by LPS in the rat aorta. This novel source of NO has an important impact on smooth muscle function and might be implicated in various inflammatory diseases.

Animals↗
PubMed2000

Age-related endothelial dysfunction with respect to nitric oxide, endothelium-derived hyperpolarizing factor and cyclooxygenase products.

Vascular aging is associated with both structural and functional changes that can take place at the level of the endothelium, vascular smooth muscle cells and the extracellular matrix of blood vessels. With regard to the endothelium, reduced vasodilatation in response to agonists occurs in large conduit arteries as well as in resistance arteries with aging. Reviews concerning the different hypotheses that may account for this endothelial dysfunction have pointed out alterations in the equilibrium between endothelium-derived relaxing and constricting factors. Thus, a decreased vasorelaxation due to nitric oxide and, in some arteries, endothelium-derived hyperpolarizing factor as well as an increased vasoconstriction mediated by cyclooxygenase products such as thromboxane A2 are likely to occur in age-induced impairment of endothelial vasodilatation. Furthermore, enhanced oxidative stress plays a critical role in the deleterious effect of aging on the endothelium by means of nitric oxide breakdown due to reactive oxygen species. The relative contribution of the above phenomenon in age-related endothelial dysfunction is highly dependent on the species and type of vascular bed.

Acetylcholine↗
PubMed2000

Inducible NO synthase activity in blood vessels and heart: new insight into cell origin and consequences.

Induction of the inducible form of nitric oxide synthase (iNOS) in the vascular and cardiac tissue by several inflammatory stimuli may result in the production of large amounts of nitric oxide (NO) for a sustained period. Recent data obtained in the rat aorta in which iNOS was induced by lipopolysaccharide (LPS) have demonstrated that adventitial cells represent the main site of NO production. Adventitial-derived NO can exert an immediate down-regulatory effect on smooth muscle contraction (via activation of the cyclic GMP pathway) but may also initiate longer lasting effects through the formation of NO stores within the medial layer. One candidate for such NO stores are dinitrosyl non-heme iron complexes. Low molecular weight thiols interact with preformed NO stores and promote vasorelaxation by a cyclic GMP-independent mechanism involving the activation of potassium channels. In the heart, the induction of iNOS is involved in delayed protection against ischemia-reperfusion-induced functional damages. Recent data obtained with monophosphoryl lipid A, a non-toxin derivative of LPS, strongly suggest that iNOS-derived NO in the rat heart does not act as an immediate mediator of the cardioprotection but rather as a trigger of long-term protective mechanisms. Thus, the present data reveal the important role of adventitial cells as a site of iNOS expression and activity in intact blood vessels. The induction of adaptive mechanisms in the heart and the formation of releasable NO stores in blood vessels are examples of long-term consequences of iNOS induction. These new information are relevant for a better understanding of the circumstances in which NO overproduction by iNOS may play either a beneficial or deleterious role in these tissues.

Animals↗
PubMed1999

Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice.

Poly (ADP-ribose) polymerase-1 is a nuclear DNA-binding protein that participates in the DNA base excision repair pathway in response to genotoxic stress in mammalian cells. Here we show that PARP-1-deficient cells are defective in NF-kappaB-dependent transcription activation, but not in its nuclear translocation, in response to TNF-alpha. Treating mice with lipopolysaccharide (LPS) resulted in the rapid activation of NF-kappaB in macrophages from PARP-1(+/+) but not from PARP-1(-/-) mice. PARP-1-deficient mice were extremely resistant to LPS-induced endotoxic shock. The molecular basis for this resistance relies on an almost complete abrogation of NF-kappaB-dependent accumulation of TNF-alpha in the serum and a down-regulation of inducible nitric oxide synthase (iNOS), leading to decreased NO synthesis, which is the main source of free radical generation during inflammation. These results demonstrate a functional association in vivo between PARP-1 and NF-kappaB, with consequences for the transcriptional activation of NF-kappaB and a systemic inflammatory process.

3T3 Cells↗
PubMed1999

Induction of nitric oxide synthase and dual effects of nitric oxide and cyclooxygenase products in regulation of arterial contraction in human septic shock.

BACKGROUND: The role of endogenous nitric oxide (NO) and cyclooxygenase metabolites was investigated in contractile responses of small omental arteries from patients with hyperdynamic septic shock. METHODS AND RESULTS: Expression of inducible NO synthase (immunostaining) and a high but variable level of NO production (NO spin trapping) was detected in arteries from patients with septic shock. In these vessels, ex vivo contractile responses to the thromboxane A2 analogue U46619 and to low concentrations of norepinephrine (NE) (up to 10 micromol/L) were not significantly different from controls. However, higher concentrations of NE caused pronounced fading of contraction in septic but not in nonseptic arteries. Exposure to either the NO synthase inhibitor NG-nitro-L-arginine methyl ester or the cyclooxygenase inhibitor indomethacin had no effect in control vessels. However, both inhibitors increased the response to the contractile effects of the 2 agonists only in patients with septic shock. In contrast to NG-nitro-L-arginine methyl ester, which decreased the threshold concentration of the fading effect of NE, indomethacin abolished this effect in arteries from septic patients. CONCLUSIONS: These results provide direct evidence for the induction of NO synthase in small arteries from patients with septic shock. They suggest that in these arteries, increased production of NO, in conjunction with vasodilatory cyclooxygenase metabolites, contributes to counteract hyperreactivity to agonists and decreases the cyclooxygenase product-mediated pronounced fading of contraction caused by a high concentration of NE.

Adult↗
PubMed1999

The inducible nitric oxide synthase in vascular and cardiac tissue.

Expression of the inducible form of nitric oxide synthase (iNOS) has been reported in a variety of cardiovascular diseases. The resulting high output nitric oxide (NO) formation, besides the level of iNOS expression, depends also on the expression of the metabolic pathways providing the enzyme with substrate and cofactor. NO may trigger short and long term effects which are either beneficial or deleterious, depending on the molecular targets with which it interacts. These interactions are governed by local factors (like the redox state). In the cardiovascular system, the major targets involve not only guanylyl cyclase, but also other haem proteins, protein thiols, iron-non-haem complexes, and superoxide anion (forming peroxynitrite). The latter has several intracellular targets and may be cytotoxic, despite the existence of endogenous defence mechanisms. These interactions may either trigger NO effects or represent releasable NO stores, able to buffer NO and prolong its effects in blood vessels and in the heart. Besides selectively inhibiting iNOS, a number of other therapeutic strategies are conceivable to alleviate deleterious effects of excessive NO formation, including peroxynitrite (ONOO-) scavenging and inhibition of metabolic pathways triggered by ONOO-. When available, these approaches might have the advantage to preserve beneficial effects of iNOS induction. Counteracting vascular hyper-responsiveness to endogenous vasoconstrictor agonists in septic shock, or inducing cardiac protection against ischaemia-reperfusion injury are examples of such beneficial effects of iNOS induction.

Animals↗
PubMed1999

Triggering role of nitric oxide in the delayed protective effect of monophosphoryl lipid A in rat heart.

1. The main objective of the present study was to further evaluate the role of nitric oxide (NO) in delayed cardiac protection against ischaemia-reperfusion injury induced by monophosphoryl lipid A (MLA). 2. For this purpose, rats were administered with either 0.5 or 2.5 mg kg(-1) MLA (i.p.). Eight or 24 h later, in vivo NO production in the heart was analysed by electron paramagnetic resonance (EPR) spin trapping technique. In parallel experiments, hearts were removed and perfused according to Langendorff. Functional ventricular parameters and incidence of ventricular fibrillation (VF) were determined after 30 min global ischaemic insult (37 degrees C) followed by 30 min reperfusion. Vascular reactivity of aortic rings was also assessed. 3. Hearts from rats pretreated with 2.5 mg kg(-1) MLA for 24 h (but not those from rats treated with 0.5 mg kg(-1) MLA for 8 and 24 h, or with 2.5 mg kg(-1) MLA for 8 h) exhibited preservation of ventricular function (LVDP, +/-dP/dtmax) and a reduced incidence of VF (25% vs 87.5% in vehicle control) during reperfusion. At the cardioprotective dose of 2.5 mg kg(-1) (for 8 or 24 h), MLA did not produce alterations of the contractile response of aortic rings to noradrenaline. 4. An increased formation of NO was detected in hearts removed from rats pretreated with 2.5 mg kg(-1) MLA for 8 h, but not in those from rats treated for 24 h (or with 0.5 mg kg(-1) MLA). 5. Pretreatment of the animals with the inhibitors of inducible NO-synthase, aminoguanidine (2x300 mg kg(-1)) or L-N6-(1-Iminoethyl)-lysine (L-NIL, 10 mg kg(-1)) abolished both MLA (2. 5 mg kg(-1))-induced rise of NO production (observed 8 h after MLA) and cardioprotection (observed 24 h after MLA). However MLA-induced cardioprotection was not attenuated when the hearts were perfused with aminoguanidine (150 microM) for 30 min before the ischaemic insult. 6. Altogether, the present data suggest that NO acts as a trigger rather then a direct mediator of the delayed cardioprotective effect of MLA in rat heart.

Adjuvants, Immunologic↗
PubMed1999

Mechanism of endothelial nitric oxide-dependent vasorelaxation induced by wine polyphenols in rat thoracic aorta.

The mechanisms by which red wine polyphenolic compounds (RWPCs) induced endothelium-dependent relaxation were investigated in rat thoracic aorta rings with endothelium. RWPCs produced relaxation that was prevented by the nitric oxide (NO) synthase inhibitor, N(omega)-nitro-L-arginine-methyl-ester. This relaxation was abolished in the absence of extracellular calcium in the medium or in the presence of the Ca2+ entry blocker, La3+, but it was not affected by the nonselective K+ channels blocker, tetrabutylammonium. N-Ethyl-maleimide (NEM), a sulfhydryl alkylating agent, abolished vasorelaxation produced by RWPCs and acetylcholine but not that produced either by the sarcoendoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) pump inhibitor, cyclopyazonic acid (CPA) or the calcium ionophore, ionomycin. Neither pertussis toxin (PTX) nor cholera toxin (CTX) inhibited the vasorelaxant effect of RWPC. The effect of RWPC was not affected by the phospholipase C (PLC) blocker, L-alpha-glycerophospho-D-myo-inositol 4-monophosphate (Gro-pip), and the phospholipase A2 pathway blockers, quinacrine and ONO-RS-082. Finally, the protein kinase C (PKC) inhibitor, GF 109203X, and tyrosine kinase inhibitors, tyrphostin A-23 and genistein, did not impair the response to RWPCs. These results suggest that RWPCs produce endothelium-NO-derived vasorelaxation through an extracellular Ca2+-dependent mechanism via an NEM-sensitive pathway. They also show that PTX- or CTX-sensitive G proteins, activation of PLC or PLA2 pathways, PKC, or tyrosine kinase may not be involved.

Animals↗
PubMed1999

Mechanism of Ca2+ release and entry during contraction elicited by norepinephrine in rat resistance arteries.

The intracellular Ca2+ stores and the mechanisms of Ca2+ entry produced by norepinephrine (NE) were investigated in small mesenteric resistance arteries of the rat. In Ca2+-free medium, NE (10 microM) elicited a transient increase in both intracellular free Ca2+ concentration ([Ca2+]i) and tension that were both drastically reduced by caffeine and only partially reduced by the two sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) blockers thapsigargin and cyclopiazonic acid, despite the presence of SERCA2a and SERCA2b isoforms in the medial smooth muscle layer of the artery. After depletion of intracellular Ca2+ stores with 10 microM NE, addition of exogenous CaCl2 (2.5 mM) produced large and sustained increases in both [Ca2+]i and contraction of the arteries provided that the agonist was continuously present. In these conditions, the responses to CaCl2 were inhibited by the voltage-dependent Ca2+ entry blocker nitrendipine (1 microM), the putative inhibitor of receptor-operated Ca2+ entry SKF-96365 (30 microM), and NiCl2 (1 mM). The inhibition produced by SKF-96365 and NiCl2 was greater than that of nitrendipine. Also, the responses to CaCl2 were greatly reduced or abolished in the presence of the Na+/Ca2+ exchanger inhibitors 1,3-dimethyl-2-thiourea, 3',4'-dichlorobenzamil, MgCl2, and amiloride or after omission of NaCl in the medium. Also, protein kinase C inhibitors, calphostin C and staurosporine, and tyrosine kinase inhibitors, genistein and tyrphostin 23, both reduced the responses to CaCl2. The inhibitory effect of protein kinase C inhibitor and tyrosine kinase were additive. These results suggest that NE releases Ca2+ from intracellular stores that are caffeine sensitive and partially sensitive to SERCA inhibitors. They indicate that in addition to Ca2+ influx via nitrendipine-sensitive and SKF-96365-sensitive channels, Na+/Ca2+ exchanger participates in the CaCl2-induced contraction produced in NE-exposed vessels. The pathway leading to Ca2+ entry probably involves tyrosine kinase and protein kinase C. All the above mechanisms require ongoing receptor stimulation.

Animals↗
PubMed1999

Endothelial no release caused by red wine polyphenols.

Epidemiological studies have suggested that moderate consumption of red wine might reduce the risk of cardiovascular disease. Red Wine Polyphenolic Compounds (RWPC), a complex extract obtained from red wine, causes endothelium-dependent vasorelaxation in rat aortic rings pre-contracted with noradrenaline. This effect is associated with marked formation of NO in the vessel (directly shown by electron paramagnetic resonance spectroscopy) and it is abolished by the NO synthase inhibitor N(G)-nitro-L-arginine methylester (300 microM). It is mimicked by some defined polyphenols (like the anthocyanin delphinidin) but not by others (malvidin, cyanidin, quercetin, catechin, epicatechin), despite close structures. In addition, RWPC causes an extracellular Ca(2+)-dependent increase in [Ca2+]i in endothelial but not in smooth muscle cells. The efficiency of RWPC in inducing NO production in the aorta and increase in [Ca2+]i, in endothelial cells is comparable to those of carbachol and bradykinine, respectively. These findings provide evidence that RWPC and polyphenols with selective structures can activate an undefined target in endothelial cells. The resulting increase in [Ca2+]i activation of NO-synthase and enhanced formation of NO may be involved in cardiovascular protection.

Animals↗
PubMed1998

Nitric oxide-related cyclic GMP-independent relaxing effect of N-acetylcysteine in lipopolysaccharide-treated rat aorta.

1. We have recently demonstrated the formation of protein-bound dinitrosyl-iron complexes (DNIC) in rat aortic rings exposed to lipopolysaccharide (LPS) and shown that N-acetylcysteine (NAC) can promote vasorelaxation in these arteries, possibly via the release of nitric oxide (NO) as low molecular weight DNIC from these storage sites. The aim of the present study was to investigate further the mechanism of the relaxation induced by NAC in LPS-treated vessels. 2. In rings incubated with LPS (10 microg ml(-1) for 18 h) and precontracted with noradrenaline (NA, 3 microM) plus N(omega)-nitro-L-arginine methylester (L-NAME, 3 mM), the relaxation evoked by NAC (0.1 to 10 mM) was abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM, a selective inhibitor of soluble guanylyl cyclase) but not affected by Rp-8-bromoguanosine 3'5'-cyclic monophosphorothioate (Rp-8BrcGMPS, 60 microM a selective inhibitor of cyclic GMP-dependent protein kinase). Tetrabutylammonium (TBA, 3 mM, as a non selective K+ channels blocker) or elevated concentration of external KCl (25 or 50 mM) significantly attenuated the NAC-induced relaxation. Selective K+ channels blockers (10 microM glibenclamide, 0.1 microM charybdotoxin, 0.5 microM apamin or 3 mM 4-aminopyridine) did not affect the NAC-induced relaxation. The relaxing effect of NAC (10 mM) was not associated with an elevation of guanosine 3':5' cyclic monophosphate (cyclic GMP) in LPS-treated rings. 3. In aortic rings precontracted with NA (0.1 microM), low molecular weight DNIC (with thiosulphate as ligand, 1 nM to 10 microM) evoked a concentration-dependent relaxation which was antagonized by ODQ (1 microM) and Rp-8BrcGMPS (150 microM) but not significantly affected by TBA (3 mM) or by the use of KCl (50 mM) as preconstricting agent. The relaxation produced by DNIC (0.1 microM) was associated with an 11 fold increase in aortic cyclic GMP content, which was completely abolished by ODQ (1 microM). 4. Taken together with our previous data, the main finding of the present study is that the vascular relaxation induced by NAC in LPS-treated aorta, although probably related to NO through an interaction via preformed NO stores, was not mediated by activation of the cyclic GMP pathway. It may involve the activation of TBA-sensitive K+ channels. The differences in the mechanism of relaxation induced by NAC and by exogenous DNIC suggest that the generation of low molecular weight DNIC from protein-bound species does not play a major role in the NAC-induced relaxation observed in LPS-treated rat aorta. In addition, it is suggested that ODQ may display other properties than the inhibition of soluble guanylyl cyclase.

Acetylcysteine↗
PubMed1998

Role of adventitial nitric oxide in vascular hyporeactivity induced by lipopolysaccharide in rat aorta.

This study was designed to elucidate the role of the adventitia in NO-mediated vascular effects of lipopolysaccharide (LPS). After incubation of rat aorta with LPS, the adventitia generated 3.5 times more nitrite plus nitrate than a corresponding segment of media. Control media covered by adventitia from LPS-treated aortic rings exhibited a 4 fold elevated level of cyclic GMP. Medial layers from LPS-treated aortic rings (like LPS-treated adventitia-intact rings) exhibited a decrease in sensitivity to noradrenaline (NA) that was reversed by 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (1 microM) or N omega-nitro-L-arginine methylester (0.3 mM). However, in contrast to LPS-treated adventitia-intact rings, medial layers showed no reduction in maximal contraction to NA and virtually no relaxation to L-arginine. These data indicate that in blood vessels exposed to LPS, the adventitia is a more powerful source of NO than the media. The adventitia-derived NO can reach soluble guanylyl cyclase in the medial layer and contribute greatly to vascular hyporeactivity and L-arginine-induced relaxation observed in blood vessels exposed to LPS.

Animals↗
PubMed1998

Natural dietary polyphenolic compounds cause endothelium-dependent vasorelaxation in rat thoracic aorta.

This study investigated the possible active principles which support the endothelial nitric oxide-dependent relaxation produced by red wine and other plant polyphenolic compounds in thoracic aorta from male Wistar rats (12-14 wk old). Relaxation experiments were recorded isometrically on vessels precontracted with norepinephrine. Ten different chromatographic fractions (3-18 mg) isolated from red wine polyphenolic compounds (RWPC) and some available defined polyphenols (10-15 mg) were tested. Fractions enriched into either anthocyanins or oligomeric condensed tannins exhibited endothelium-dependent vasorelaxant activity (maximal relaxation in the range of 59-77%) comparable to the original RWPC. However, polymeric condensed tannins elicited a weaker vasorelaxant activity than the original RWPC (maximal relaxation ranged between 20-47%, P < 0.01). Moreover, the representative of either phenolic acid derivatives (benzoic acid, vanillic acid, gallic acid), hydroxycinnamic acid (p-coumaric acid, caffeic acid) or the flavanol [(+)-epicatechin] classes failed to induce this type of response. Among the anthocyanins, delphinidin (maximal relaxation being 89%), but not malvidin or cyanidin, showed endothelium-dependent vasorelaxation. These results show that anthocyanins and oligomeric-condensed tannins exhibited a pharmacological profile comparable to the original RWPC. These compounds may be involved in the reduction of cardiovascular mortality related to the presence of wine, fruits and vegetables in the diet.

Animals↗
PubMed1998

Molecular mechanisms underlying the role of nitric oxide in the cardiovascular system.

In the cardiovascular system, nitric oxide (NO) is involved in the short and long-term regulation of haemodynamics, and in a number of their pathological alterations. Investigation into the biochemistry of NO-synthase isoforms has confirmed that they also all produce superoxide anion (O(*)). The free radical NO can interact with many targets on which novel information has been recently obtained. The major results of these interactions are not only the well known activation of guanylyl cyclase, but also the formation of potentially cytotoxic peroxynitrite (ONOO(-)), and the formation of S-nitrosothiols and non-haem iron-dinitrosyl dithiolate complexes. Tissue O(2), O(*), low molecular weight thiols and transition metals (especially FeII) play a pivotal role in directing NO towards targets responsible for biological effects, or storage or release from these stores. In addition, circulating forms of NO have been proposed with S-nitrosation of blood proteins. All these mechanisms provide potential pharmacological targets for future therapeutic strategies.

Journal Article↗