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Biomedical subjects

Lucas Liaudet

Publications and source records attributed to Lucas Liaudet.

At least 19 recordsLinked to original sources
PubMed2005

Nitrosative stress and pharmacological modulation of heart failure.

Dysregulation of nitric oxide (NO) and increased oxidative and nitrosative stress are implicated in the pathogenesis of heart failure. Peroxynitrite is a reactive oxidant that is produced from the reaction of nitric oxide with superoxide anion and impairs cardiovascular function through multiple mechanisms, including activation of matrix metalloproteinases (MMPs) and nuclear enzyme poly(ADP-ribose) polymerase (PARP). Recent studies suggest that the neutralization of peroxynitrite or pharmacological inhibition of MMPs and PARP are promising new approaches in the experimental therapy of various forms of myocardial injury. In this article, the role of nitrosative stress and downstream mechanisms, including activation of MMPs and PARP, in various forms of heart failure are discussed and novel emerging therapeutic strategies offered by neutralization of peroxynitrite and inhibition of MMPs and PARP in these pathophysiological conditions are reviewed.

Enzyme Activation↗
PubMed2005

Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium.

OBJECTIVE: A distinctive feature of sepsis is a pleiotropic modification of membrane protein expression in the vascular endothelium, associated with diminished endothelium-dependent relaxation (endothelial dysfunction). In cultured endothelial cells, inflammatory stimuli alter expression of connexins (Cx), proteins that make up the gap junctions responsible for intercellular communication. In the present study, we tested whether the polymicrobial sepsis induced by cecal ligation and perforation in the rat alters the expression of the connexins present in the vascular endothelium (i.e., Cx37, Cx40, and Cx43). We also examined a possible association between such changes and endothelial dysfunction in this model. DESIGN: Animal study, with two parallel groups. SETTING: Animal research facility. SUBJECTS: One hundred four male adult Wistar rats. INTERVENTIONS: Rats underwent either cecal ligation and perforation to induce sepsis or a sham operation and were killed after a variable time, mostly 24 hrs. MEASUREMENTS AND MAIN RESULTS: Experiments designed to test for the impact of sepsis on connexin expression disclosed a three-fold increase in Cx40 messenger RNA and protein in the aorta, an effect that peaked at 24 hrs after cecal ligation and perforation, was specific to this connexin (i.e., levels of Cx37 and Cx43 did not vary), and was restricted to the aortic endothelium. Experiments designed to test the permeability of interendothelial gap junctions using the scrape-loading method did not show a change in function in the septic group. Finally, a time-course study was designed to test for a possible association of enhanced Cx40 expression with endothelial dysfunction. Endothelium-dependent relaxation was diminished in rings of aorta when harvested from septic rats before (6 hrs after surgery) but not at the time when enhanced Cx40 expression occurred (12 and 24 hrs). CONCLUSION: In this experimental model, recovery from an early transient dysfunction of the aortic endothelium is associated with an enhanced expression of aortic endothelial Cx40.

Animals↗
PubMed2004

Local heating of human skin causes hyperemia without mediation by muscarinic cholinergic receptors or prostanoids.

Local changes in surface temperature have a powerful influence on the perfusion of human skin. Heating increases local skin blood flow, but the mechanisms and mediators of this response (thermal hyperemia response) are incompletely elucidated. In the present study, we examined the possible dependence of the thermal hyperemia response on stimulation of muscarinic cholinergic receptors and on production of vasodilator prostanoids. In 13 male healthy subjects aged 20-30 yr, a temperature-controlled chamber was positioned on the volar face of one forearm and used to raise surface temperature from 34 to 41 degrees C. The time course of the resulting thermal hyperemia response was recorded with a laser-Doppler imager. In one experiment, each of eight subjects received an intravenous bolus of the antimuscarinic agent glycopyrrolate (4 microg/kg) on one visit and saline on the other. The thermal hyperemia response was determined within the hour after the injections. Glycopyrrolate effectively inhibited the skin vasodilation induced by iontophoresis of acetylcholine but did not influence the thermal hyperemia response. In a second experiment, conducted in five other subjects, 1 g of the cyclooxygenase inhibitor aspirin administered orally totally abolished the vasodilation induced in the skin by anodal current but also failed to modify the thermal hyperemia response. The present study excludes the stimulation of muscarinic receptors and the production of vasodilator prostaglandins as essential and nonredundant mechanisms for the vasodilation induced by local heating in human forearm skin.

Acetylcholine↗
PubMed2004

Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failure.

Aging is associated with profound changes in the structure and function of the heart. A fundamental understanding of these processes, using relevant animal models, is required for effective prevention and treatment of cardiovascular disease in the elderly. Here, we studied cardiac performance in 4- to 5-mo-old (young) and 24- to 26-mo-old (old) Fischer 344 male rats using the Millar pressure-volume (P-V) conductance catheter system. We evaluated systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), maximal slope of the systolic pressure increment (+dP/dt), and its relation to end-diastolic volume (+dP/dt-EDV) as well as the time constant of left ventricular pressure decay, as an index of relaxation. The slope of the end-diastolic P-V relation (EDPVR), an index of left ventricular stiffness, was also calculated. Aging was associated with decrease in left ventricular systolic pressure, +dP/dt, maximal slope of the diastolic pressure decrement, +dP/dt-EDV, PRSW, ejection fraction, stroke volume, cardiac and stroke work indexes, and efficiency. In contrast, total peripheral resistance, left ventricular end-diastolic volume, left ventricular end-diastolic pressure, and EDPVR were greater in aging than in young animals. Taken together, these data suggest that advanced aging is characterized by decreased systolic performance accompanied by delayed relaxation and increased diastolic stiffness of the heart in male Fischer 344 rats. P-V analysis is a sensitive method to determine cardiac function in rats.

Aging↗
PubMed2004

A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging.

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension, and aging. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury, circulatory shock, and aging. Here, we investigated the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar's new Aria pressure-volume conductance system and isolated aortic rings. Young adult (3 months old) and aging (24 months old) Fischer rats were treated for 2 months with vehicle, or the potent PARP inhibitor INO-1001. In the vehicle-treated aging animals, there was a marked reduction of both systolic and diastolic cardiac function and loss of endothelial relaxant responsiveness of aortic rings to acetylcholine. Treatment with INO-1001 improved cardiac performance in aging animals and also acetylcholine-induced, nitric oxide-mediated vascular relaxation. Thus, pharmacological inhibition of PARP may represent a novel approach to improve cardiac and vascular dysfunction associated with aging.

Aging↗
PubMed2004

Effects of poly(ADP-ribose) polymerase inhibition on inflammatory cell migration in a murine model of asthma.

BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1), a monomeric nuclear enzyme present in eukaryotes, plays a role in cell death, inflammatory mediator expression, and mononuclear cell recruitment in various experimental models of inflammation and reperfusion injury. Part of the molecular mechanism of this function involves the regulation of cytokine and chemokine production. Since chemokines are principal regulators of mononuclear and polymorphonuclear cell trafficking in asthma, we investigated the possibility whether PARP modulates chemokine production and cell recruitment in a murine model of asthma. MATERIAL/METHODS: We studied ovalbumin-sensitized mice challenged with a single dose of ovalbumin. RESULTS: PARP inhibition with the phenanthridinone-based PARP inhibitor PJ34 suppressed inflammatory cell migration. These effects were associated with downregulation of the CC chemokine MIP-1alpha, but not the CXC chemokine MIP-2. The production of TNF- alpha and IL-12, but not IL-5 or IL-13, was also suppressed by PARP inhibition. CONCLUSIONS: Our results demonstrate the pathogenetic role of PARP activation in a murine model of asthma. PARP selectively regulates the production of certain chemokines and cytokines in this experimental model, which may be responsible for some of the observed protective effects seen in the current murine asthma model.

Animals↗
PubMed2004

Poly(ADP-ribose) polymerase activation in the reperfused myocardium.

The activation of poly(ADP-ribose) polymerase (PARP) is now considered a final common effector in various types of tissue injury including systemic inflammation, circulatory shock and ischemia/reperfusion. Free radical and oxidant production and related cytotoxicity during ischemia/reperfusion leads to DNA strand breakage which activates the nuclear enzyme PARP and initiates an energy-consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. During the last 5 years, a growing number of experimental studies demonstrated the beneficial effects of PARP inhibition in cell cultures through rodent models and more recently in pre-clinical large animal models of regional and global ischemia/reperfusion injury. The objective of the current review is to provide an overview of the experimental evidence implicating PARP as a pathophysiological modulator of myocardial injury in vitro and in vivo.

Animals↗
PubMed2004

Acetylcholine-induced vasodilation and reactive hyperemia are not affected by acute cyclo-oxygenase inhibition in human skin.

OBJECTIVE: To examine whether prostaglandins are involved in endothelium-dependent vasodilatory responses of the skin microcirculation. METHODS: Twenty-three young male volunteers were studied on 2 different days 1-3 weeks apart. On each experimental day the forearm skin blood flow response to iontophoretically applied acetylcholine (Ach, an endothelium-dependent vasodilator) was determined with laser Doppler imaging following the intravenous administration of either the cyclo-oxygenase inhibitor lysine acetylsalicylate (L-AS), 900 mg, or the oral intake of indomethacin, 75 mg. Acetylcholine was iontophoresed both in presence and in absence of surface anesthesia. In some subjects, the effects of L-AS on skin reactive hyperemia were also assessed. RESULTS: Acute cyclo-oxygenase inhibition with either drug influenced neither the skin blood flow response to 4 different doses of Ach (0.28, 1.4, 7, and 14 mC/cm2) nor reactive hyperemia. The peak vasodilatory response to Ach was significantly increased by skin anesthesia, regardless of whether the subjects received the cyclo-oxygenase inhibitor or not. For example, the mean response (+/-SD) to the largest dose of Ach (tested in 6 subjects, expressed in perfusion units) were as follows: in absence of anesthesia: L-AS 339 +/- 105, placebo 344 +/- 68; with anesthesia: L-AS 453 +/- 76, placebo 452 +/- 65 (p <.01 for effect of anesthesia). CONCLUSIONS: These data give no support for a contribution of prostaglandins to acetylcholine-induced vasodilation or to reactive hyperemia in the skin microcirculation. In this vascular bed, local anesthesia seems to amplify acetylcholine-induced vasodilation via a prostaglandin-independent mechanism.

Acetylcholine↗
PubMed2004

Dose-dependent vasodilatory effects of acetylcholine and local warming on skin microcirculation.

The assessment of the skin microvasculature response to iontophoretically applied acetylcholine (ACh) and local warming makes it possible to explore noninvasively in humans the functional integrity of endothelium. The present study aimed to examine whether these two stimuli of nitric oxide (NO) release have a dose-dependent vasorelaxant activity. For this purpose we assessed in healthy subjects using a laser-Doppler imaging system the increase in forearm blood flow following transdermal application of increasing amounts of ACh [with an iontophoretic current of either 0.28 mC/cm2 (n = 18), 0.56 mC/cm2 (n = 14), 1.4 mC/cm2 (n = 26), 7 mC/cm2 (n = 14), 28 mC/cm2 (n = 14), or 48 mC/cm2 (n = 6)] or graded warming of the skin [to either 37 degrees C (n = 8), 39 degrees C (n = 4) or 41 degrees C (n = 12)]. The maximal vasodilation was significantly smaller with the lowest dose than with the higher doses of ACh, and a plateau was reached with the 1.4 mC/cm2 dose. The skin blood flow responses to ACh were not dependent on the pulsed or continuous pattern of iontophoretic administration. The hyperemia induced by the local heating to 41 degrees C was significantly greater than that observed with the other temperatures. When measured in the same subjects, the magnitude of the maximal ACh-mediated skin blood flow increase was significantly smaller than the vasodilation associated with the warming to 41 degrees C. In summary, transdermally applied ACh and local heating of the skin induce a dose-dependent vasorelaxation. These techniques represent a unique means to investigate noninvasively the functional vasodilatory capacity of the skin microvasculature.

Acetylcholine↗
PubMed2004

Carboxyhemoglobin formation as an unexpected side effect of inhaled nitric oxide therapy in severe acute respiratory distress syndrome.

OBJECTIVE: To report an unexpected cause of carboxyhemoglobinemia associated with inhaled nitric oxide therapy in severe acute respiratory distress syndrome. DESIGN: Case report. SETTING: Medical critical care unit at Lausanne University Hospital. PATIENT: One female patient with acute respiratory distress syndrome treated with inhaled nitric oxide, who developed a simultaneous increase in blood methemoglobin and carboxyhemoglobin. CONCLUSIONS: Potential pathophysiologic mechanisms linking acute respiratory distress syndrome, inhaled nitric oxide, methemoglobin, and carboxyhemoglobin are discussed. Since carboxyhemoglobin has a negative influence on oxygen-carrying capacity, this effect may potentially offset the beneficial influence (if any) of inhaled nitric oxide on arterial PO2. This observation does not support the use of inhaled nitric oxide in the treatment of acute respiratory distress syndrome.

Administration, Inhalation↗
PubMed2004

Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity.

Matrix metalloproteinase (MMP) activation contributes to the development of various pathophysiological conditions, including dilated cardiomyopathy, congestive heart failure, and reperfusion injury. Increased oxidative and nitrosative stress have been implicated in the activation of MMPs and also in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Thus, we hypothesized that MMP activation occurs in DOX-induced cardiotoxicity. Male Balb/c mice received a single injection of DOX (25 mg/kg i.p.) and were sacrificed 12 h, 1, 2, 3 and 4 days later. Hearts and aortae were harvested for MMP zymography. DOX induced time-dependent activation of MMPs both in the heart and in the aortic tissue with an earlier onset in the latter. These results demonstrate that MMP activation is an early event in DOX-induced cardiotoxicity and raises the possibility that MMP inhibitors may influence the outcome of this severe complication.

Animals↗
PubMed2004

[Heart arrest: which reality and which training for the practitioner?].

Sudden death related to out-of hospital cardiac arrest is an important cause of mortality, which is mainly caused by ventricular fibrillation, a potentially reversible condition. The prognosis of out-of-hospital cardiac arrest remains dismal despite well developed emergency medical services. Witnessed arrest, ventricular fibrillation as the initial arrhythmia, cardiopulmonary resuscitation and early defibrillation are systematically associated with better survival. Key interventions must therefore be enforced to improve survival from out-of-hospital cardiac, introducing the concept of a "chain of survivals". The aim of the present article, which is illustrated by local results, is to review this important public health issue, to emphasize the role of the general practitioner in the chain of survival, and to promote education and training of basic and advanced life support.

Family Practice↗
PubMed2004

[New therapeutic strategies in severe sepsis and septic shock].

Severe sepsis and septic shock are an important cause of mortality. Until recently, in spite of major progresses in our understanding of the pathogenic mechanisms of this syndrome, clinicians had only a limited therapeutic arsenal. Considerable efforts have been made in the past few years to develop novel therapeutic interventions to reduce mortality in sepsis. So far, five specific therapies have proven their efficacy to achieve such goal in large randomised controlled trials: early goal-directed therapy, recombinant activated protein C, moderate doses of steroids, low tidal volume ventilation in acute respiratory distress syndrome and intensive insulin therapy to control hyperglycemia. This review will focus on these recently acquired therapeutic modalities, that are presently available to clinicians for the treatment of severe sepsis and septic shock.

Humans↗
PubMed2004

[Value of non-invasive ventilation in intensive care].

Noninvasive ventilation (NIV) refers to the delivery of mechanical ventilation using a nasal or facial mask. Compared to mechanical ventilation with endotracheal intubation, the occurence of complications, mainly infectious, is reduced by NIV. Reduction of respiratory workload and improvement of gas exchange are achieved with the use of NIV. In patients with exacerbations of chronic obstructive pulmonary disease (COPD), NIV reduces the need for endotracheal intubation, the length of ICU stay and the mortality. It is equally effective in acute cardiogenic pulmonary edema and for ventilatory weaning of patients with COPD. In selected groups of patients with acute hypoxemic respiratory failure, NIV diminishes the rate of endotracheal intubation and improves survival. The purpose of this article is to review the mechanisms, the technical aspects and the indications of NIV for the treatment of acute respiratory failure.

Critical Care↗
PubMed2004

[Infective endocarditis: update].

The pathogenesis of infective endocarditis (IE) is being dissected at the molecular level, which should help redefine new preventive and therapeutic strategies against IE. In spite of improving health care, the incidence of IE has not decreased over the last decades. While classical predisposing conditions such as rheumatic heart disease were being eradicated, new features of IE have emerged. These include IE in intravenous drug users, IE in elderly patients with sclerotic valve disease, prosthetic valve IE and nosocomial IE. The epidemiology, pathogenesis, diagnosis, prevention and treatment of IE are being reviewed in this article.

Endocarditis, Bacterial↗