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J Farré

Publications and source records attributed to J Farré.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Effect of losartan on human platelet activation by thromboxane A2].

INTRODUCTION AND OBJECTIVES: Previous studies have demonstrated that losartan, an AT-1 receptor antagonist of angiotensin II (Ang II) could block the receptor of thromboxane A2 (TXA2) in the vascular wall. The aim of the present study was to assess the effect of losartan on human platelet activation. MATERIALS AND METHODS: Platelets were obtained from 15 healthy men between the age 26 and 40. Platelet activation was measured by changes in the light transmission of platelet-rich plasma stimulated by a synthetic TXA2 analogue, U46619 (5 x 10(-6) mol/l). RESULTS: The U46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-response manner. Only a high dose of EXP 3174 (5 10-5 mol/l), the in vivo active metabolite of losartan, was able to attenuate U46619-induced platelet activation. Captopril, an angiotensin I-converting inhibitor failed to modify U46619-induced platelet aggregation. Despite the platelets expressing AT-1 type receptors, of Ang II exogenous Ang II did not modify platelet aggregation induced by U46619. The binding of U46619 to platelets was competitively inhibited by losartan in dose-dependent manner. However, only a high dose of EXP 3174 reduced the binding of U46619. Captopril failed to modify the binding of U46619 to platelets. CONCLUSIONS: Losartan decreased platelet aggregation by a TXA2-dependent mechanism. EXP 3174 showed a lesser potency than losartan to reduce TXA2-platelet activation. Captopril and exogenous angiotensin II had no effect on human platelet activation. These results suggest that losartan reduced TXA2-dependent platelet activation independently of the blockade of AT-1 receptors.

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

A 4-trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function.

BACKGROUND: The thrombotic process is a multicellular phenomenon in which not only platelets but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal, a 4-trifluoromethyl derivative of salicylate, reduced platelet aggregation not only by inhibiting thromboxane A2 production but also by stimulating nitric oxide (NO) generation by neutrophils. The aim of the present study was to evaluate whether oral treatment of healthy volunteers with triflusal could modify the ability of their neutrophils to produce NO and to test the role of the NO released by neutrophils in the modulation of ADP-induced platelet aggregation and alpha-granule secretion. METHODS: The study was performed in 12 healthy volunteers who were orally treated with triflusal (600 mg day-1) for 5 days. Flow cytometric detection of platelet surface expression of P-selectin was used as a measure of the ability of platelets to release the contents of their alpha-granules. RESULTS: After treatment with triflusal, there was an increase in NO production by neutrophils and an increase in endothelial nitric oxide synthase (eNOS) protein expression in neutrophils. A potentiation of the inhibition of platelet aggregation by neutrophils was reversed by incubating neutrophils with both an L-arginine antagonist, NG-nitro-L-arginine methyl ester (L-NAME) and an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO). A slight decrease in P-selectin surface expression on platelets was found which was not modified by the presence of neutrophils and therefore by the neutrophil-derived NO. Exogenous NO released by sodium nitroprusside dose-dependently inhibited both ADP-stimulated alpha-granule secretion and platelet aggregation. Therefore, platelet aggregation showed a greater sensitivity to be inhibited by exogenous NO than P-selectin expression. CONCLUSION: Oral treatment of healthy volunteers with triflusal stimulated NO production and eNOS protein expression in their neutrophils. After triflusal treatment, the neutrophils demonstrated a higher ability to prevent ADP-induced platelet aggregation. However, the neutrophils and the endogenous NO generated by them failed to modify P-selectin expression in ADP-activated platelets.

Administration, Oral↗
PubMed2000

Doxazosin modifies Bcl-2 and Bax protein expression in the left ventricle of spontaneously hypertensive rats.

BACKGROUND: Increased apoptosis has recently been reported in the heart of spontaneously hypertensive rats (SHRs). OBJECTIVE: To investigate the molecular basis of apoptosis in the left ventricle of SHRs in terms of the expression of Bcl-2 protein (which protects from apoptosis) and Bax protein (which acts as an apoptotic promoter). In addition, we analysed the involvement of alpha -adrenergic receptors in the left ventricular apoptosis of SHRs. METHODS: The study was performed in untreated SHRs (n=16) and SHRs that were orally treated with doxazosin (10 mg/kg body weight per day, for 15 days), a selective alpha1-receptor blocker (n=16). A group of Wistar-Kyoto (WKY) rats (n=16) was used as the control. RESULTS: The left ventricles of untreated SHRs showed a significant increase in Bcl-2 protein expression and a reduced presence of Bax protein. The ratio of Bcl-2:Bax in SHRs was higher than in WKY rats, suggesting an anti-apoptotic state. Paradoxically, both the number of apoptotic cardiac cells and the cleavage of an 85-kDa fragment of the poly (ADP-ribose) polymerase (PARP), a marker of caspase-3 activity, were higher in the left ventricle of SHRs than in WKY rats, suggesting an apoptotic situation. Bax promotes cell apoptosis when it is bound to Bcl-2. We then determined the abundance of Bax-Bcl-2 complexes in the left ventricle of the two groups of animals. Bax-Bcl-2 complexes were more abundant in SHRs than WKY rats. In a second set of experiments, we analysed the role of alpha1-adrenergic blockade by doxazosin in the above-described mechanisms. Doxazosin treatment reduced the formation of Bax-Bcl-2 complexes in the left ventricle of SHRs, and this was accompanied by a decrease in the levels of 85kDa PARP and a reduction in apoptotic left ventricular cells. CONCLUSIONS: The present work suggests that the presence of Bax-Bcl-2 complexes in the left ventricle could be a more reliable marker of the apoptotic state than the determination of the absolute expression of Bcl-2 and Bax proteins. Moreover, the inhibition of alpha1 -adrenergic receptors by doxazosin decreased the abundance of BaxBcl-2 complexes and promoted a reduction of apoptosis in the left ventricle of SHRs.

Animals↗
PubMed2000

Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation.

A recent study has shown that losartan, an AT-1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of this study was to analyze the ability of different angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers. Platelets were stimulated with the TxA2 analogue, U46619 (10(-6) M). U46619-stimulated platelet activation was significantly reduced by both losartan and irbesartan in a dose-dependent manner. Only maximal doses of valsartan (5 x 10(-6) M) and the main metabolite of losartan, EXP3174 (5 x 10(-6) M), reduced U46619-induced platelet activation. Whereas the active form of candesartan cilexetil (candesartan, CV-11974) failed to modify platelet activation involved by TxA2, telmisartan showed a higher effect than valsartan and EXP3174 but lower than either losartan and irbesartan. Losartan or irbesartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed with lower ability with the other AT-1 antagonists. Although platelets expressed AT-1-type receptors, exogenous Ang II did not modify platelet activation. This effect was not modified by blocking the AT-2 receptor with PD123319. These results suggest that some AT-1-receptor antagonists reduce TxA2-dependent activation independent of Ang II involvement.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Estrogen stimulates neuronal nitric oxide synthase protein expression in human neutrophils.

Recent studies have postulated the contribution of nitric oxide (NO) released by the endothelium to the beneficial effects of estrogen. Despite a neuronal-type NO synthase (nNOS) described in neutrophils, less is known about the effect of estrogen in these cells. The aim of the present study was to analyze the expression of nNOS protein in human neutrophils under different estrogenic conditions. We first analyzed nNOS expression in neutrophils obtained from premenopausal women. During the first 2 days of the follicular phase (low circulating estrogen concentrations), nNOS expression in neutrophils was reduced with respect to that found in neutrophils obtained from the same donors during the ovulatory phase (high circulating estrogen concentrations). Moreover, the expression of nNOS protein in neutrophils obtained from postmenopausal women after transdermal estrogen therapy was markedly enhanced with respect to that observed before the treatment. In vitro incubation of neutrophils derived from men for 6 hours with 17beta-estradiol (10(-10) to 10(-8) mol/L) upregulated the expression of nNOS protein. The 17beta-estradiol receptor antagonists, tamoxifen (10(-8) mol/L) and ICI 182780 (10(-8) mol/L), inhibited the upregulation of nNOS protein induced by 17beta-estradiol. The putative functional implication was denoted by a reduced expression of the CD18 antigen on the surface of 17beta-estradiol-incubated neutrophils, which was accompanied by a decreased adhesive capacity. Both effects were prevented by an NO antagonist. In conclusion, the in vivo levels of circulating estrogen concentrations seem to be associated with the level of nNOS protein expression in neutrophils from women. Moreover, low doses of 17beta-estradiol upregulate nNOS protein expression in neutrophils from men. The increased ability of 17beta-estradiol-incubated neutrophils derived from men to produce NO reduced their adhesive properties.

Adult↗
PubMed1999

Navigation in the mega-trials waters: reflections on the Multicenter Automatic Defibrillator Implantation Trial and the Antiarrhythmics Versus Implantable Defibrillators Study.

Today, cardiology seems to be driven by mega-trials and meta-analyses. Guidelines published by scientific and professional cardiovascular societies, such as the American Heart Association, the American College of Cardiology, and the European Society of Cardiology, follow the rules of evidence-based medicine. Such evidence is not always sufficiently conclusive to practice clinically helpful medicine. Sometimes, relatively small trials, such as the Multicenter Automatic Defibrillator Implantation Trial and the Antiarrhythmics Versus Implantable Defibrillators study, may be taken as guides for current clinical decisions and as inspiration for future investigations. Large mega-trials with a great lack of homogeneity among the recruited patients are less important for clinically helpful medicine than studies enrolling well-defined, high-risk patients. It is probably important to acknowledge that the best possible treatment for many patients with ventricular tachyarrhythmias remains obscure. Among these situations are the following: (1) sustained ventricular tachycardia (VT) in patients without coronary artery disease; (2) sustained, nonsyncopal VT in patients with coronary artery disease and left ventricular dysfunction; (3) post myocardial infarction survivors with an ejection fraction < or = 35%, frequent/complex ventricular arrhythmias, depressed heart rate variability, and inducible sustained ventricular tachyarrhythmias during electrophysiologic study. Many studies are being conducted to add light where uncertainty exists, but probably only a few will contribute to the practice of clinically helpful medicine, although some will be used to produce meta-analysis to sustain evidence-based medicine.

Anti-Arrhythmia Agents↗
PubMed1999

Amiodarone and "primary" prevention of sudden death: critical review of a decade of clinical trials.

Several trials have evaluated the role of amiodarone in decreasing mortality in patients at high risk of developing sudden death. Current evidence does not support the prophylactic use of amiodarone in myocardial infarction (MI) survivors with a depressed left ventricular function and/or frequent or complex ventricular ectopy. Some postinfarction trials (e.g., the Spanish Study of Sudden Death [SSSD]) found mortality rates in controls much lower than the expected figures. Other postinfarction trials--the European Amiodarone Myocardial Infarction Arrhythmia Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT)--despite observing a 2-year mortality rate of about 15% as expected, could not demonstrate a significant reduction in mortality. Amiodarone decreases the risk of sudden death in postinfarction patients by about 35%. In patients with a history of heart failure and left ventricular dysfunction, evidence is not sufficiently strong to use amiodarone for prevention of sudden death. The 2 major trials on such patients, Group for the Study of Survival in Heart Failure in Argentina (Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina or GESICA) and the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure (STAT-CHF), arrived at conflicting results. Meta-analyses have been performed to overcome the small sample size of these trials, with the aim of assessing the benefit of amiodarone on total mortality. Differences among the recruited populations make it difficult to extract clinically applicable conclusions from these overviews. Even accepting that amiodarone might decrease total mortality by 10%, it is difficult to identify the patients for whom such a beneficial effect applies. A practical consequence of amiodarone trials is that this drug can be used rather safely in patients with left ventricular dysfunction of any etiology as, in contrast to some class I agents, it does not increase mortality. Therefore, amiodarone is the drug of choice when antiarrhythmic drug treatment is indicated in patients with left ventricular dysfunction.

Aged↗
PubMed1999

[Expression of inducible nitric oxide synthase in the carotid of rats after endothelial skinning: the effects of platelets and treatment with abciximab].

BACKGROUND: Functional evidence suggests that endothelial denudation stimulates inducible nitric oxide synthase (iNOS) activity in the vascular wall. In vitro studies done in our laboratory have shown that iNOS expression in smooth muscle cells is reduced by endothelial cells. The object of this study was to analyze the iNOS protein expression in the arterial wall after in vivo deendothelialization, and the role of platelet activation abciximab in the expression of this protein. MATERIALS AND METHODS: Endothelial denudation was performed in the left carotid artery of Wistar rats. The right carotid artery was used as control. RESULTS: iNOS protein was only weakly expressed at 6, 24 and 48 hours after endothelial denudation. Since platelet adhesion and aggregation occur early after endothelial damage, we have analyzed the role of activated platelets in iNOS protein expression during the first two days after angioplasty. Early after in vivo endothelial injury, thrombocytopenic rats showed a marked iNOS protein expression. Similar results were obtained by blocking the platelet glycoprotein IIb/IIIa in rats treated with abciximab (Reopro). CONCLUSIONS: iNOS protein is weakly expressed in the arterial wall after endothelial denudation. Platelets play a crucial role preventing iNOS protein expression early after endothelial damage through a mechanism that depends on GP IIb/IIIa, an effect that can be avoided with glycoprotein IIb/IIIa, blockers, such as abciximab.

Abciximab↗
PubMed1999

Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor-alpha release by cultured smooth muscle cells.

BACKGROUND: Inflammatory related cardiovascular disease, i.e. cardiac allograft rejection, myocarditis, septic shock, are accompanied by cytokine production, which stimulates the expression of inducible nitric oxide (iNOS). MATERIALS AND METHODS: The aim of the present study was to examine whether anti-inflammatory doses of acetylsalicylic acid (aspirin) could regulate iNOS protein expression in bovine vascular smooth muscle cells (BVSMCs) in culture. RESULTS: Interleukin 1 beta (IL-1 beta, 0.03 U mL-1) induced nitric oxide release by BVSMCs. Aspirin inhibited nitric oxide release from IL-1 beta-stimulated BVSMCs in a dose-dependent manner. In addition, aspirin significantly inhibited iNOS protein expression in BVSMCs and reduced the translocation of the nuclear factor-kappa B (NF-kappa B). Furthermore, aspirin and the blockade of NO generation by BVSMCs reduced the production of tumour necrosis factor alpha (TNF-alpha) by these cells. CONCLUSION: High doses of aspirin inhibited iNOS protein expression in BVSMCs and decreased NF-kappa B mobilization. The inhibition of iNOS expression by aspirin was further associated with a reduced ability of BVSMCs to produce TNF-alpha. This study could provide new mechanisms of action for aspirin in the treatment of the inflammation-related cardiovascular diseases.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Effect of losartan on human platelet activation.

OBJECTIVE: Previous studies have demonstrated that losartan can block the thromboxane A2 receptor on the vascular wall. The aim of the present study was to assess the effect of losartan on human platelet activation. METHODS: Platelets were obtained from 15 healthy men, aged 26-40 years. Platelet activation was measured by changes in the light transmission of platelet-rich plasma stimulated by the thromboxane A2 analog U46619 (5 x 10(-6) mol/l) or ADP (10(-5) mol/l). RESULTS: U46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-dependent manner. Only a high dose of EXP 3174 (5 x 10(-5) mol/l), the in vivo active metabolite of losartan, was able to attenuate U46619-induced platelet activation. Captopril, an angiotensin I converting inhibitor, failed to modify U46619-induced platelet aggregation. Furthermore, the binding of [3H]-U46619 to platelets was competitively inhibited by losartan, whereas only a high dose of EXP 3174 reduced the binding of [3H]-U46619. Captopril failed to modify the binding of [3H]-U46619 to platelets. Losartan also reduced the platelet activation induced by ADP (10(-5) mol/l), a platelet agonist partially dependent on thromboxane A2. In addition, when thromboxane A2 generation was blocked by aspirin, ADP-induced platelet aggregation was inhibited to a similar degree to the inhibition induced by losartan. Exogenous angiotensin II did not elicit any modification of either U46619- or ADP-stimulated platelet aggregation. CONCLUSIONS: Losartan decreased platelet aggregation by a thromboxane A2-dependent mechanism. EXP 3174 was less potent than losartan in reducing thromboxane A2-dependent platelet activation. Captopril and exogenous angiotensin II had no effect on human platelet activation. These results suggest that losartan reduced thromboxane A2-dependent platelet activation independently of its effect on angiotensin II.

Adult↗
PubMed1999

NO from smooth muscle cells decreases NOS expression in endothelial cells: role of TNF-alpha.

Despite the evidence that cytokines stimulate nitric oxide (NO) production by inducible nitric oxide synthase (iNOS), several reports recently demonstrated that the hypotensive response related to endothelial nitric oxide synthase (eNOS) activity could be inhibited by the same cytokines. The aim of the present work was to analyze whether NO generated by vascular smooth muscle cells (VSMC) could modify eNOS protein expression in endothelial cells. Bovine aortic endothelial cells (BAEC) and bovine VSMC (BVSMC) in coculture were used for the study. Interleukin-1beta (IL-1beta, 10 ng/ml)-treated BVSMC, which expressed iNOS protein, decreased eNOS protein expression in BAEC. The presence of NO antagonists N(omega)-nitro-L-arginine methyl ester (10(-3) mol/l) or N(G)-monomethyl-L-arginine (10(-3) mol/l) prevented the decrease in eNOS protein expression induced by IL-1beta-treated BVSMC. Surprisingly, two different NO donors, 3-morpholinosydnonimine (10(-4) mol/l) and S-nitroso-N-acetyl-D,L-penicillamine (10(-4) mol/l), failed to modify eNOS expression in BAEC, suggesting the existence of a diffusible mediator released from IL-1beta-treated BVSMC that acts on endothelial cells by reducing eNOS expression. The presence of NO antagonists reduced tumor necrosis factor-alpha (TNF-alpha) production by IL-1beta-stimulated BVSMC. This effect was also produced in the presence of a protein kinase G inhibitor, guanosine-5'-O-(2-thiodiphosphate) trilithium salt. A polyclonal antibody against TNF-alpha prevented eNOS expression in the BAEC-BVSMC coculture. In conclusion, NO by itself failed to modify eNOS protein expression in endothelial cells but increased TNF-alpha generation by IL-1beta-stimulated BVSMC and, in this way, reduced eNOS expression in the endothelium.

Animals↗
PubMed1998

Expression of inducible nitric oxide synthase after endothelial denudation of the rat carotid artery: role of platelets.

There is functional evidence suggesting that endothelial denudation stimulates inducible nitric oxide synthase (iNOS) activity in the vascular wall. In vitro studies have shown that iNOS expression in smooth muscle cells is reduced by endothelial cells. In the present study we have analyzed the time course of iNOS protein expression in the arterial wall after in vivo deendothelialization. Endothelial denudation was performed in the left carotid artery of Wistar rats, and the right carotid artery was used as control. Whereas iNOS protein was weakly expressed 6, 24, and 48 hours after endothelial denudation, a marked iNOS expression was found 7, 14, and 30 days after vascular damage. Because platelet adhesion and aggregation occur early after endothelial damage, we studied the role of activated platelets in the negative modulation of iNOS protein expression during the first 2 days after endothelial denudation. Early after in vivo endothelial injury, platelet-depleted rats showed a marked iNOS protein expression in the vascular wall. Similar results were obtained by blocking the platelet glycoprotein (GP) IIb/IIIa. Although iNOS protein is present in the arterial wall several days after endothelial denudation, early after arterial wall injury iNOS protein is weakly expressed. Platelets play a crucial role in preventing iNOS protein expression early after endothelial damage, an effect that can be avoided with GP IIb/IIIa blockers. Although iNOS protein was weakly expressed in vivo in the rat carotid artery wall 6, 24, and 48 hours after balloon endothelial denudation, a marked iNOS expression was found 7, 14, and 30 days after arterial damage. iNOS expression could be increased early after endothelial injury by removing circulating platelets and by an antibody against the GP IIb/IIIa. In conclusion, platelets prevent iNOS protein expression early after endothelial balloon damage, an effect that can be avoided with GP IIb/IIIa blocking agents.

Animals↗
PubMed1998

Capillary zone electrophoresis with indirect UV detection of haloacetic acids in water.

A capillary zone electrophoresis (CZE) system for determining haloacetic acids in water was optimized with indirect photometric detection. Two different carrier electrolytes, potassium hydrogenphthalate and sodium 2,6-naphthalenedicarboxylate, were evaluated in terms of sensitivity and two different electroosmotic flow modifiers, tetradecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide, were tested. Parameters such as electrolyte concentration and pH, and the concentration of the electroosmotic flow modifiers, which affect the CZE separations, were investigated. The method was used to determine haloacetic acids in chlorine tap water using the liquid-liquid extraction process.

Acetates↗
PubMed1998

Comparison of in vitro effects of triflusal and acetysalicylic acid on nitric oxide synthesis by human neutrophils.

Recent studies have suggested that the protective anti-ischemic effects of acetylsalicylic acid are stronger than the inhibition of platelet thromboxane A2 synthesis. Since ischemic events still occur in acetylsalicylic acid-treated patients, the development of new drugs with more powerful protective effects is needed. We compared the effects of a new platelet antiaggregating drug, 2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and of acetylsalicylic acid on the interaction between human neutrophils and platelets, examining the capability of neutrophils to generate nitric oxide (NO). Triflusal, in the presence of neutrophils, showed a greater antiplatelet potency than acetylsalicylic acid to inhibit thrombin-induced platelet activation. Significant stimulation of NO-mediated mechanisms in the presence of acetylsalicylic acid or triflusal was demonstrated by the following findings: (1) increased metabolism of arginine to citrulline, (2) increase of cGMP in the platelet/neutrophil system and (3) the inhibitory action of the L-arginine (L-Arg) competitive analogue, NG-nitro-L-arginine-methyl ester (L-NAME), which was reversed by L-Arg. Triflusal increased the stimulation of NO synthesis by neutrophils more than did of acetylsalicylic acid. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), alone or in combination with acetylsalicylic acid, did not modify NO production by neutrophils. Therefore, the whole molecule of triflusal is needed to stimulate NO production by neutrophils. Our results show that, in the presence of neutrophils, triflusal exerts an antiplatelet effect greater than that of acetylsalicylic acid, demonstrating a more powerful stimulation of the NO/cGMP system. The present results indicate that it is possible to develop new and more potent acetylsalicylic acid-related antiplatelet drugs for the prevention of the myocardial ischemic/reperfusion processes.

Aspirin↗
PubMed1998

[Thrombosis and coronary disease: neutrophils, nitric oxide and aspirin].

In recent years, relevant changes have occurred in the knowledge of the cellular mechanisms regulating platelet aggregation and adhesion to the endothelial surface. In particular, major aspects of the interactions between platelets and endothelial cells and neutrophils have been clarified. These interactions involve not only thrombosis-promoting or thrombosis-inhibiting properties but also several aspects of the regulation of vascular function. A new concept has progressively emerged showing thrombosis as a multicellular event in which cell-to cell interactions between platelets, neutrophils, and endothelium regulate the size of a growing thrombus. In brief, there is consistent evidence showing that two vasodilating mediators produced by endothelial cells and neutrophils (nitric oxide and prostacyclin) have antiaggregating platelet effects. Platelet activation is particularly relevant in myocardial ischemia, and several pharmacological strategies have been devised to prevent intravascular platelet activation. Aspirin remains a keystone of these preventive and damage-limiting strategies. Current knowledge maintains that low doses of aspirin decrease in vivo platelet aggregation by a selective inhibitory effect on thromboxane A2 production by platelets with maintenance of prostacyclin production by the endothelium. We have recently focussed our research on the basis that the antiaggregating effect of aspirin could be explained not only by the above-mentioned effects on thromboxane A2 synthesis, but also through its action on neutrophils. Our in vitro and ex vivo studies have demonstrated that neutrophils enhance the antiaggregating effects of acetylsalicilic acid on platelets. We have shown that acetylsalicilic acid stimulates nitric oxide production on neutrophils inhibiting the aggregating effects of thrombin, ADP or epinephrine on platelets. the role of the neutrophils in ischemic events enhancing the tissue damage through the release of several proteases, reactive oxygen species and tumor necrosis factor-alpha has been extensively demonstrated. In an experimental model of acute ischemia/reperfusion in rabbits, we have shown that acetylsalicilic acid is able to enhance the nitric oxide production by neutrophils providing a potential mechanism for the beneficial action of aspirin in the myocardial infarction. Further research is needed to assess the mechanisms of the action of aspirin during the thrombotic phenomena and its effects on the different types of cells that compound the microvascular environment.

Aspirin↗
PubMed1998

[Endothelial dysfunction: a global response].

The endothelium is a dynamic organ involved in the genesis and development of the cardiovascular diseases. Nitric oxide (NO) is one of the factors released from endothelium. NO is generated by endothelial cells through the activity of a constitutive nitric oxide synthase (cNOS). Smooth muscle cells generate NO by an inducible NOS isoform (iNOS). NO regulates vascular tone, different mechanisms involved in the interaction of blood cells to the vascular wall, the growth of smooth muscle cells and the matrix protein synthesis. The lack of an endothelium-dependent vasodilatory response has been defined as endothelial dysfunction. It has been demonstrated a reduced endothelium-dependent vasodilation response in hypertension, aging, atherosclerosis ... and in patients without evident coronary disease. Although the cNOS has been initially described as constitutive, in recent years it has been demonstrated that several pathophysiological stimuli such as hypoxia, chronic exercise, cytokines regulate its level of expression. Our laboratory has demonstrated that an endothelial cytosolic protein regulates the half-lives of eNOS mRNA. This endothelial cytosolic protein could be a target for specific drugs to prevent endothelial dysfunction.

Endothelium, Vascular↗