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Biomedical subjects

C Thuillez

Publications and source records attributed to C Thuillez.

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

[Pharmacology of aspirin].

Aspirin (acetylsalicylic acid) is the best-known salicylate and belongs to the non steroid anti-inflammatory drug class. Despite wide use being made since more than 100 years, knowledge about mechanism of action and therapeutic issues continually evolves. The main mechanism of action is prostaglandin synthesis inhibition. This is achieved through inhibition of prostaglandin endoperoxide synthase (PGHS) or cyclooxygenase (COX) synthesis. Most of the therapeutic uses of aspirin are explained by this mechanism. Nevertheless aspirin uses change as time goes by: if the main one during the first fifty years was an analgesic, anti-pyretic and anti-inflammatory one, the last fifty years saw aspirin being used mainly as an anti-thrombotic agent, in primary and secondary thrombo-embolic prevention. Better knowledge of mechanism of action points today at, on one hand, more selective and therefore better tolerated molecules, and, on the other hand, at new therapeutic applications, such as anti-cancer and neurodegenerative diseases prevention.

Adult↗
PubMed2000

Evidence against a role of inducible nitric oxide synthase in the endothelial protective effects of delayed preconditioning.

Preconditioning the heart with brief periods of ischaemia induces delayed endothelial protection against reperfusion injury, but the precise mechanisms involved in this endogenous protein are still unclear. Induction of the type II-nitric oxide synthase (iNOS) acts as a mediator of the preconditioning against myocardial infarction and stunning. The present study was designed to assess whether iNOS also contributes to the delayed endothelial protective effects of preconditioning. Rats were subjected to 20 min ischaemia followed by 60 min reperfusion 24 h after sham surgery or preconditioning (one cycle or 2 min ischaemia/5 min reperfusion and two cycles of 5 min ischaemia/5 min reperfusion). At the end of the reperfusion, coronary segments were removed distal to the site of occlusion and mounted in wire myographs. Ischaemia-reperfusion (I/R) decreased the endothelium-dependent relaxations to acetylcholine (maximal relaxations: sham, 66+/-5%; I/R, 40+/-1%; P<0.05) and this impairment was prevented by preconditioning (maximal relaxation: 61+/-6%). Administration of N-(3-aminomethyl)benzyl)acetaminide (1400W), a highly selective inhibitor for iNOS, 10 min before prolonged ischaemia did not modify the beneficial effect of preconditioning (maximal relaxation: 66+/-5%). These data show that preconditioning induces delayed protection against reperfusion-injury. However, in contrast to the myocytes, these endothelial protective effects of delayed preconditioning do not involve iNOS.

Acetylcholine↗
PubMed2000

Reduced synthesis of inflammatory cytokines by a free radical scavenger after hemorrhagic shock in rats.

OBJECTIVES: Intestinal ischemia/reperfusion during hemorrhage and resuscitation may be a major trigger for cytokine expression. To assess whether free radicals produced on tissue reperfusion may play a role in the inflammatory response after hemorrhage, we tested the effect of a free radical scavenger on the production of inflammatory cytokines in a rat model of hemorrhagic shock. DESIGN: A prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Hemorrhage was induced in anesthetized rats. by bleeding the animal to achieve a mean arterial blood pressure of 40 mm Hg for 60 mins. Resuscitation was then induced by reinjecting shed blood followed by NaCl 0.9% to maintain arterial blood pressure within control values. Treated rats received the free radical scavenger N-2-mercaptopropionyl glycine (MPG; 20mg/kg iv bolus 30 mins before resuscitation followed by 20 mg/kg/hr). MEASUREMENTS AND MAIN RESULTS: MPG reduced the volume of saline necessary to restore blood pressure during resuscitation (untreated 85+/-6; MPG 35+/-5 mL/kg; p < .05). As compared with untreated rats, MPG markedly reduced the systemic and mesenteric plasma concentrations of tumor necrosis factor (TNF)-alpha (as measured by ELISA) and interleukin (IL)-6 (as measured by bioassay), assessed at the end of resuscitation. MPG also reduced TNF-alpha and IL-6 mRNA expression (as measured by reverse transcriptase-polymerase chain reaction) assessed in peritoneal macrophages isolated from shock rats. Finally, in vitro experiments showed that MPG also markedly reduced the mRNA expression and release of TNF-alpha and IL-6 in peritoneal macrophages isolated from normal rats and subjected to hypoxia and reoxygenation. CONCLUSION: Reactive oxygen species contribute to the production of proinflammatory cytokines during posthemorrhage resuscitation. Free radicals scavengers may be a useful treatment in the prevention of the systemic inflammatory response that occurs in shock states.

Animals↗
PubMed2000

Increased endothelium--monocyte interactions in salt-sensitive hypertension: effect of L-arginine.

Although adhesion of monocytes to endothelial cells is considered as one of the initial factors leading in the long term to the development of atherosclerosis, the effects of hypertension on monocyte-endothelial cell interactions are still largely unknown. Thus we evaluated whether hypertension affects adhesion of monocytes on rat carotid endothelium, and whether this adhesion may be modified by long-term treatment with L-arginine, the physiologic precursor of nitric oxide (NO). Hypertension was induced in Dahl rats using a sodium-rich diet (8%), in the absence or the presence of L-arginine (1.25 g/L in drinking water). After 1 month, the carotid arteries were isolated, opened longitudinally, and incubated in the presence of 2 x 10(6) monocytes previously rendered fluorescent by incubation with tetramethyl rhodamine isothiocyanate (TRITC), and adherent cells were counted under fluorescence microscopy. In parallel, the production of NO was evaluated in vitro in isolated aorta and isolated hearts. Hypertension markedly increased adhesion of monocytes on carotid endothelium, and this was reduced by L-arginine. Hypertension also reduced an index of NO release at the level of the aorta and the coronary circulation. This impaired release of NO was partially prevented by L-arginine. Thus hypertension was associated with an increased adhesion of monocytes, which is probably due at least in part to a decreased production of NO. The increased adhesion was partly reduced by L-arginine, possibly secondary to an increased production of NO. Such an increased adhesion of monocytes may contribute the increased cardiovascular risk in hypertension.

Analysis of Variance↗
PubMed1999

Protective effects of preconditioning in cultured rat endothelial cells: effects on neutrophil adhesion and expression of ICAM-1 after anoxia and reoxygenation.

BACKGROUND: Preconditioning with brief periods of ischemia protects the coronary endothelium against acute and chronic reperfusion injury, but the mechanisms of this endothelial protection remain unknown. We hypothesized that preconditioning protects endothelial cells through a decreased production of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), leading to a lesser adhesion of neutrophils to the endothelium. METHODS AND RESULTS: Cultured rat aortic endothelial cells were subjected to 6-hour anoxia followed by various durations of reoxygenation. Preconditioning was induced by 1-hour anoxia and 1-hour reoxygenation. ICAM-1 gene expression was measured by polymerase chain reaction, and the percentage of cells expressing ICAM-1 was assessed by confocal laser fluorescence microscopy. Anoxia/reoxygenation increased expression of ICAM-1, with a peak occurring after 6 hours of reoxygenation for mRNA and 9 hours for protein. Preconditioning prevented the increase in ICAM-1. Similar reductions were observed with the free radical scavenger N-2 mercaptopropionyl glycine (MPG). The inhibitory effect of preconditioning on ICAM-1 expression was abolished by an inhibitor of protein kinase C, an inhibitor of nitric oxide synthesis, and by MPG but was not affected by an adenosine receptor antagonist. Finally, both preconditioning and MPG partially prevented the increased adhesion of human neutrophils to reoxygenated endothelial cells. CONCLUSIONS: Preconditioning prevented reoxygenation-induced, free radical-mediated expression of ICAM-1 by a mechanism involving activation of protein kinase C and production of nitric oxide and free radicals, and this is associated with a lesser adhesion of neutrophils to endothelial cells. Such prevention of neutrophil adhesion may contribute to the protective effect of preconditioning against reperfusion-induced endothelial injury.

Animals↗
PubMed1999

Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress.

BACKGROUND: Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. METHODS AND RESULTS: FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/-3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro-L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise. CONCLUSIONS: CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.

Animals↗
PubMed1999

Induction of haem oxygenase contributes to the synthesis of pro-inflammatory cytokines in re-oxygenated rat macrophages: role of cGMP.

Macrophage activation and the resulting inflammatory response may be a major component of tissue injury upon hypoxia and re-oxygenation. Activation of the haem oxygenase (HO)/carbon monoxide (CO) pathway may be an important regulator of the inflammatory response, through production of cyclic 3', 5'-monophosphate (cGMP). We have assessed whether HO contributes to the increased production of the pro-inflammatory cytokines TNF-alpha and IL-6 in re-oxygenated rat peritoneal macrophages.Hypoxia/re-oxygenation markedly increased levels of HO-1 mRNA and cGMP. The increase in cGMP was reduced by the HO-1 inhibitor tin-protoporphyrin (SnPP-9) given during re-oxygenation. Hypoxia and re-oxygenation also increased IL-6 and TNF-alpha mRNA expression, as well as IL-6 and TNF-alpha concentrations in the cell supernatant. These increases were nullified by SnPP-9 and by Methylene Blue, an inhibitor of guanylate cyclase, but were not affected by L-NNA, an inhibitor of NO synthesis. The inhibitory effect of SnPP on the synthesis of cytokines was reversed by co-administration of the stable analogue of cGMP, 8-Br-cGMP. Our results indicate that activation of haem oxygenase and of the CO/cGMP pathway is a major stimulus for the synthesis and release of pro-inflammatory cytokines in re-oxygenated macrophages. This pathway may play a central role in pathological situations in which local tissue hypoxia/re-oxygenation triggers a systemic inflammatory response, for example in patients with shock.

Animals↗
PubMed1999

Delayed endothelial protective effects of monophosphoryl lipid A after myocardial ischemia and reperfusion in rats.

Monophosphoryl lipid A (MLA) induces delayed (24 h) myocardial protection in various animal models of ischemia/reperfusion injury, and thus mimics the second window of preconditioning against cardiac injury. However, the potential endothelial protective effects of this drug have not been evaluated. The present study was designed to assess whether MLA exerts delayed protective effects against reperfusion-induced coronary endothelial dysfunction in rats, as well as the protective role of iNOS in this protection. Wistar rats received a single i.v. injection of MLA (450 microg/kg) or solvent. Twenty-four hours later, they were anesthetized and subjected to 20 min ischemia with 60 min reperfusion, in the absence or the presence of the iNOS inhibitor aminoguanidine (300 mg/kg i.p.). At the end of reperfusion, 1.5-2 mm coronary segments (average diameter 250 microm) were removed distal to the site of occlusion and mounted in wire myographs. Endothelium-dependent relaxations to acetylcholine were determined in arteries pre-contracted by serotonin. Ischemia/reperfusion induced a marked decrease in the coronary responses to acetylcholine (maximal relaxations: sham 64+/-8%, n=8; ischemia/reperfusion: 41+/-9%, n=8 P<0.05). This impaired response was partially restored by MLA (55+/-4%, n=10 P<0.05 vs ischemia/reperfusion). The effect of MLA was not affected by aminoguanidine (57+/-5%, n=6). Thus, in addition to protecting myocytes, MLA induces a delayed protection against coronary endothelial dysfunction. However, in contrast to its effects on myocytes, the endothelial protective effects do not appear to involve iNOS.

Acetylcholine↗
PubMed1999

[The CAPITOL study (Captopril Post Infarction Tolerance). A trial of progressive titration of captopril after myocardial infarct with left ventricular dysfunction].

The objective of CAPITOL (Captopril Post Infarction Tolerance) multicentre open trial was to study the tolerance of a protocol of titration of Captopril in patients with recent myocardial infarction complicated by left ventricular dysfunction. Five hundred and four patients, with a mean age of 62 +/- 12 years, were included during the hospital period in the 74 participating intensive care units, 9 +/- 6 days after myocardial infarction (ejection fraction 34 +/- 6%). After a 6.25 mg test dose of Captopril, the dosage was progressively increased to the target dose of 150 mg at the end of the first month. Of the 504 patients included, 343 finished the trial and 161 stopped the trial prematurely. At the end of the hospital period, 73% received 75 mg/day: at the first follow-up visit (27 +/- 16 days after inclusion), 59% had attained 150 mg/day, this proportion increasing to 71% at the end of the trial (79 +/- 33 days after inclusion). There was no significant change in blood pressure for the whole study population. However, the systolic blood pressure of the patients receiving 150 mg/day of Captopril at the end of the trial was slightly higher than that observed at the end of the hospital period (126 +/- 17 mmHg and 116 +/- 17 mmHg respectively, p = 0.006). Severe Intercurrent events were observed in 89 patients: 24 deaths, 7 recurrent infarctions, 58 hospital admissions (21 for cardiac failure, 15 for recurrence of angina, 11 aorto-coronary bypass operations, 7 coronary angioplasties, 2 cerebro-vascular accidents, 2 systemic emboli). Of the benign complications, hypotension was observed in 25% of patients, nearly half of which occurred during the hospital admission. The drugs prescribed in association with Captopril were Aspirin (78%), betablockers (57%), nitrate derivatives (42%) and diuretics (27%). Multivariate analysis showed 3 factors associated with good tolerance of the 150 mg dosage of Captopril: Killip Class I or II on admission, an ejection fraction > 30% and an initial systolic blood pressure > 100 mmHg. In conclusion, in this trial of dose titration, 3 out of 4 patients with myocardial infarction and left ventricular dysfunction, tolerated the 150 mg/day dosage of Captopril. Patients in the trial could also be treated with drugs recommended after myocardial infarction, in particular the betablockers. Arch Mal Coeur 1999: 92: 395-403.

Adrenergic beta-Antagonists↗
PubMed1998

Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure.

BACKGROUND: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. CONCLUSIONS: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.

Animals↗
PubMed1998

Different effects of calcium antagonists in a rat model of heart failure.

Calcium antagonists have, to date, shown disappointing effect in chronic heart failure (CHF), possibly due to their cardiodepressant effects and/or reflex increases in sympathetic tone. Mibefradil is a new, selective T-channel calcium antagonist which has no relevant effects on cardiac contractility, sympathetic activity or neurohormonal levels. This study compares the effect of mibefradil with an angiotensin-converting enzyme (ACE) inhibitor on systemic and cardiac hemodynamics, cardiac structure and survival in a rat model of CHF. Rats underwent coronary artery ligation followed by 9 months treatment with mibefradil, cilazapril or no treatment. Both mibefradil and cilazapril increased survival rate to a similar extent over the study treatment period. Both periods reduced systolic blood pressure compared with untreated rats, although the reduction was slightly more marked with cilazapril than mibefradil. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures without any change in the first derivative LV pressure over time or heart rate. Mibefradil decreased LV weight without effecting right ventricular (RV) weight. Both drugs normalized LV collagen density. The data from this study show that long-term treatment with mibefradil results in a survival benefit comparable to that observed with an ACE inhibitor in a rat model of CHF. Mibefradil was also associated with improvements in cardiac hemodynamics, a reduction in LV weight and fibrosis. Mibefradil may be beneficial in the treatment of CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Divergent effects of verapamil and amlodipine at rest and during exercise.

OBJECTIVE: To evaluate, in healthy volunteers, the effects of acute administration of two calcium antagonists with different pharmacological profiles, verapamil and amlodipine, on haemodynamics at rest and during exercise. SUBJECTS AND METHODS: Six healthy volunteers (aged 20-29 years) were randomly assigned to receive single oral doses of amlodipine (5 mg), slow-release verapamil (240 mg) or a placebo during a double-blind cross-over study. Systolic (SAP), diastolic and mean arterial pressures (measured using a cuff sphygmomanometer), heart rate (HR), cardiac index (CI, bioimpedance), rate-pressure product (SAP x HR), and noradrenaline and adrenaline plasma levels were measured at rest before drug administration, and at rest and during graded bicycle exercise (steps of 50, 100 and 150 W during 3, 3 and 4 min, respectively) started 3 h after drug administration. RESULTS: At rest arterial pressure, HR, rate-pressure product and catecholamine plasma levels did not change after verapamil or amlodipine administration, whereas CI significantly decreased after verapamil (from 3.9 +/- 0.4 to 3.3 +/- 0.4 l/min per m2) but not after amlodipine (3.9 +/- 0.3 and 4.1 +/- 0.5 l/m per m2) administration. During exercise the increases in SAP and HR were slightly but not significantly higher after amlodipine than after verapamil administration, rate-pressure product and CI were higher after amlodipine (22 +/- 1 x 10(3) mmHg x beats/min and 13 +/- 2 l/min per m2, respectively) than after verapamil (20 +/- 1 x 10(3) mmHg x beats/min and 10 +/- 2 l/min per m2, respectively) administration. Plasma levels of noradrenaline and adrenaline were similar at rest after each treatment and were slightly more increased after amlodipine administration during exercise. CONCLUSIONS: In contrast to amlodipine, verapamil induced a slight myocardial depressive effect at rest and did not potentiate the myocardial effects of the sympathetic stimulation induced by exercise. The myocardial action of verapamil is such as to induce some decrease in myocardial oxygen demand, both at rest and during exercise.

Adult↗
PubMed1998

[Evaluation of the effects of experimental hypertension on monocyte-endothelial cell interactions].

Adhesion of monocytes to endothelial cells is considered as one of the initial factors leading on the long term to the development of atherosclerosis. We evaluated whether hypertension affects adhesion of monocytes on rat carotid endothelium, and whether this adhesion may be modified by a chronic treatment with L-arginine, the physiological precursor of nitric oxide (NO). Hypertension was induced in Dahl rats using a sodium-rich diet (8%), in the absence or the presence of L-arginine (1.25 mg/kg/day). After 1 month, the carotid arteries were isolated, opened longitudinally, and incubated in the presence of monocytes previously rendered fluorescent by incubation with tetramethyl rhodamine isothiocyanate (TRITC), and adherent cells were counted under fluorescence microscopy. Monocyte adhesion was minimal in carotid arteries isolated from normotensive rats (13 +/- 5, n = 8). Hypertension induced a marked, significant increase in monocyte adhesion (97 +/- 17; n = 10; p < 0.01 vs normotensive). This increased adhesion was significantly reduced by chronic treatment with L-arginine (37 +/- 13; n = 12, p < 0.05 vs untreated hypertensive). Thus, hypertension was associated with an increased adhesion of monocytes, which is probably due to a decrease production of NO. The increased adhesion was partly prevented by L-arginine, possibly secondary to an increased production of NO. Such an increased adhesion of monocytes may contribute to the increased cardiovascular risk in hypertension.

Animals↗
PubMed1997

Delayed coronary endothelial protection 24 hours after preconditioning: role of free radicals.

BACKGROUND: Preconditioning (PC) induces delayed protection against myocardial ischemia/reperfusion (I/R) injury. Whether a similar late protective effect exists in coronary endothelial cells is not known. Thus, we assessed whether PC also induces late protection against endothelial injury after I/R and the potential role of reactive oxygen species as triggers for late PC in this setting. METHODS AND RESULTS: Rats were subjected to sham surgery or to PC with 1 cycle of 2 minutes I/5 minutes R and 2 cycles of 5 minutes I/5 minutes R in the absence or presence of the free radical scavenger N-2-mercaptopropionyl glycine (MPG). Twenty-four hours later, rats were subjected to 20 minutes I/60 minutes R in the absence or presence of MPG. At the end of R, coronary segments (diameter, 200 to 300 microm) were removed distal to the site of occlusion and mounted in wire myographs. I/R reduced the relaxations to acetylcholine (maximal relaxations: sham, 72+/-6%; I/R, 31+/-6%), and this impairment was prevented by MPG (64+/-7%). PC improved the response to acetylcholine (48+/-6%), but this beneficial effect was abolished by MPG (23+/-5%). CONCLUSIONS: PC induces late protection against reperfusion-induced coronary endothelial injury. Moreover, in addition to being mediators of endothelial injury during reperfusion after prolonged ischemia, reactive oxygen species produced during PC also protect the coronary endothelium from reperfusion injury 24 hours later.

Acetylcholine↗
PubMed1997

Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling.

BACKGROUND: Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival. CONCLUSIONS: Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Animals↗
PubMed1997

Early versus delayed angiotensin-converting enzyme inhibition in experimental chronic heart failure. Effects on survival, hemodynamics, and cardiovascular remodeling.

BACKGROUND: The efficacy of ACE inhibitors in congestive heart failure (CHF) might be affected by the pathophysiological status present at the onset of treatment. We compared in a rat model the effects of ACE inhibition (lisinopril, 10 mg.kg-1.d-1) initiated early (1 week) or late (3 months) after myocardial infarction (i.e., at time points corresponding to moderate or severe CHF without or with established cardiac remodeling). METHODS AND RESULTS: Survival was improved by early treatment at 3 months (from 76% to 95%) and by both early and delayed treatment at 9 months (placebo, 28%; early, 90%; delayed, 61%). Delayed treatment was initiated in a more severe pathophysiological context of CHF than early treatment, illustrated in untreated rats by higher left ventricular (LV) end-diastolic and central venous pressures and by increased LV weight and LV cavity circumference. After 9 months, early and delayed treatments reduced systolic, LV end-diastolic, and central venous pressures. Both treatments also similarly decreased LV weight, LV cavity circumference, and LV collagen density. CONCLUSIONS: In this rat model of CHF, early and delayed ACE inhibitor treatments both increase survival and exert similar beneficial effects on cardiac hemodynamics and remodeling. Although early treatment prevents the development of ventricular dysfunction and remodeling, delayed treatment is capable of reversing cardiac hypertrophy and remodeling, as well as ventricular dysfunction. Thus, ACE inhibitors exert marked beneficial effects even when treatment is initiated late into the evolution of heart failure (ie, at a time of established ventricular dysfunction and remodeling).

Analysis of Variance↗
PubMed1997

Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure.

OBJECTIVES: We sought to investigate the effects of mibefradil on survival, hemodynamic variables and cardiac remodeling in a rat model of chronic heart failure (HF) and to compare these effects with those of the angiotensin-converting enzyme (ACE) inhibitor cilazapril. BACKGROUND: The use of calcium channel blocking agents in chronic HF has been disappointing. Most studies have shown that these drugs have either no or even detrimental effects due in part to the negative inotropic effects they induce. Mibefradil is a calcium channel blocker that selectively blocks T channels and displays moderately negative inotropic properties only at high doses. Because T channels are upregulated in the hypertrophied heart and could mediate hypertrophic signals and increase arrhythmogenicity, blockade of these channels might be beneficial in chronic HF. METHODS: Rats were subjected to coronary artery ligation and 9 months of treatment with mibefradil (15 mg/kg body weight per day) or cilazapril (10 mg/kg per day) or no treatment. Survival and systolic blood pressure were assessed over the 9-month treatment period, after which cardiac hemodynamic variables and structure were determined. RESULTS: Mibefradil increased survival rate to the same extent as cilazapril (71% for mibefradil vs. 75% for cilazapril and 44% for no treatment). Mibefradil decreased systolic blood pressure, although to a lesser extent than cilazapril. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures, without any change in the first derivative of LV pressure over time or heart rate. Mibefradil decreased LV weight (although less than cilazapril) without affecting right ventricular weight. Finally, both drugs normalized LV collagen density. CONCLUSIONS: Mibefradil in a rat model improved survival to the same extent as an ACE inhibitor, without impairing LV function, and was associated with a reduction in LV weight and fibrosis. Thus, mibefradil might be beneficial in the treatment of chronic HF.

Animals↗