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Biomedical subjects

L Dumont

Publications and source records attributed to L Dumont.

At least 73 records · Page 4Linked to original sources
PubMed1994

Clentiazem, diltiazem, and cold cardioplegia in isolated ischemic rabbit hearts: relation between additive cardioprotection, physicochemical properties, and preservation of myocardial lipid components.

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Cold cardioplegia and the K+ channel modulator aprikalim (RP 52891): improved cardioprotection in isolated ischemic rabbit hearts.

Cellular potassium extrusion is now considered a natural protective mechanism following myocardial ischemia, and newly synthetized molecules mimicking cellular extrusion of K+ (potassium channel activators) appear promising for cardioprotection, although the underlying mechanisms for their beneficial effects have not been fully characterized. Indeed, the cardioprotective efficacy of K+ channel activators at low temperature or in the presence of the high K+ content of standard cardioplegic solution has never been addressed. Therefore the cardioprotective interaction of the thioformamide K+ channel activator aprikalim (RP 52891) and high K+ content, cold cardioplegia was studied in isolated ischemic rabbit hearts. Isolated hearts were perfused according to the Langendorff procedure at a constant pressure (85 cmH2O; 1 cmH2O = 98.1 Pa); systolic and diastolic left ventricular pressures, coronary flow, and heart rate were monitored throughout the study. Cardiac temperature was monitored through a thermocouple microprobe positioned in the left ventricular free wall. Global ischemia was carried out by completely shutting off the perfusate flow for 90 min, and reperfusion was monitored for 30 min. Several groups of isolated hearts (n = 6 per group) were treated before ischemia with either cold cardioplegia (St-Thomas' Hospital cardioplegic solution, 4 degrees C), aprikalim (10 microM), or glibenclamide (1 microM) alone, or with one of the following combinations: cold cardioplegia + aprikalim, cold cardioplegia + glibenclamide, or cold cardioplegia + both aprikalim and glibenclamide. A 10 microM infusion of aprikalim significantly increased coronary flow (33 to 63 mL/min, +90%) without negative chronotropic or inotropic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of amrinone and dobutamine on PGF2 alpha-induced pulmonary hypertension in dogs.

The hemodynamic benefits and pulmonary vascular selectivity of amrinone, dobutamine and amrinone + dobutamine were assessed in a canine model of vasoconstrictive pulmonary hypertension. Dogs were equipped with central and peripheral catheters and with an electromagnetic flow probe placed around the ascending aorta for the measurement of cardiac function. Through a laparotomy, an arteriovenous fistula was created between the abdominal aorta and the inferior vena cava. Gradual opening of this fistula, which permitted construction of pressure-flow curves (mean pulmonary artery pressure over the cardiac index, PAP/CI), was utilized to identify the pulmonary vascular effects of amrinone and dobutamine. PGF2 alpha, prostaglandin derivative, induced stable pulmonary hypertension along with significant reduction in CI. The resultant pulmonary hypertension translated into a significant increase in both the slope and pressure intercept of the PAP/CI curve. The bipyridine derivative, amrinone, did not reverse the CI reduction observed with PGF2 alpha: both mean arterial pressure and PAP were decreased as was the intercept of the PAP/CI curve. Dobutamine, a beta-agonist, reversed the CI decline elicited by PGF2 alpha but the elevated pulmonary pressure remained unaffected; dobutamine reduced the slope of the PAP/CI curve. When combined, amrinone and dobutamine demonstrated additive beneficial hemodynamic effects and improved lung perfusion. Their additive effects were also indicated by data on the PAP/CI curve: both the slope and the pressure intercept were significantly reduced. These results suggest that amrinone and dobutamine interact at different sites of the pulmonary vasculature and that their association might be beneficial in vasoconstrictive pulmonary hypertension although no significant pulmonary vascular selectivity could be observed.

Amrinone↗
PubMed1994

Elastolytic activity of MAP1, a protease from Myxococcus xanthus.

MAP1, a protease isolated from Myxococcus xanthus, is demonstrated to be an elastase. Although its elastolytic activity is lower than that of other well-known elastases, the size distribution of solubilized elastin peptides is similar. MAP1 as pancreatic elastase releases peptides with molecular weights higher than 10,000. However, the specificity of MAP1 is different since this enzyme cannot hydrolyze alanine oligomers as do pancreatic and Pseudomonas aeruginosa elastases.

Animals↗
PubMed1994

Experimental evidence that rejection, but not transplantation, modulates coronary reactivity to direct and indirect vasodilation.

OBJECTIVE: To investigate the coronary response to direct and indirect vasodilation in a canine model of orthotopic heart transplantation because of the potential benefits of preserved vascular function during rejection. In cardiac transplants, reversal of vascular abnormalities is considered to be of prime importance for recovery from graft failure and rejection. DESIGN: Cardiac function and coronary bloodflow were monitored with electromagnetic flow probes. Hemodynamic data were collected either postoperatively, at the height of the recovery period, or during the severe rejection phase. Nitroglycerin (n = 7) as a 5 micrograms/kg intravenous bolus and diltiazem (n = 5) as a 150 micrograms/kg intravenous bolus were administered as direct stimulants of the coronary vasculature. Ouabain (n = 7), a digitalis derivative, at 20 micrograms/kg/min and calcium gluconate (n = 9) at 0.05 mEq/kg were given as indirect coronary vasodilators. Amrinone (n = 6), having both vasodilator and inotropic properties, was also studied (0.75 mg/kg intravenous bolus followed by a 200 micrograms/kg infusion). RESULTS: Under control conditions, all drugs significantly increased coronary bloodflow: nitroglycerin +47%, diltiazem +33%, ouabain +25%, calcium gluconate +36% and amrinone +65%. Coronary vascular resistance was reduced by a similar magnitude in all cases. In the rejection phase, ouabain and calcium gluconate, despite increasing stroke work, failed to induce significant changes in coronary bloodflow. Among the direct vasodilators used, only nitroglycerin augmented coronary perfusion (+38%) during rejection; the magnitude of its action on coronary vascular resistance was similar to that observed under control conditions. CONCLUSIONS: These results suggest that transplantation per se does not interfere with the response to either direct or indirect coronary dilation. Severe rejection blunted indirect coronary dilation. In these conditions, inotropic challenges appear to be detrimental. The observation that the coronary vasculature remained sensitive to nitroglycerin despite severe rejection suggested that a drug-specific coronary vasodilator reserve is still present. This study provides valuable arguments for the use of vasodilator therapy during graft rejection since rejection and ischemia are intimately related.

Amrinone↗
PubMed1993

Immunosuppressive properties of the benzothiazepine calcium antagonists diltiazem and clentiazem, with and without cyclosporine, in heterotopic rat heart transplantation.

In vitro studies have shown that calcium channel blockers (CCB) exert inhibitory effects on immunocompetent cells but conflicting results have been reported as to the translation of these effects into significant in vivo immunosuppression. In this study we evaluated the effects of the benzothiazepine-like calcium blockers diltiazem and clentiazem, given alone or associated with cyclosporine on survival improvement of heterotopic rat heart transplants. Inbred male rats of the Lewis strain were used as recipients and Wistar-Furth as donors. Following abdominal implantation of the graft, recipients were randomly divided into 9 groups (n = 5). Group 1 were control isografts (Lew-Lew); group 2 were control allografts (WFu-Lew), and group 3 were allografts treated with low-dose oral cyclosporine 2 mg/kg/day. Groups 4 and 5 were allografts treated with oral diltiazem 0.25 and 2.50 mg/kg/day. Groups 6 and 7 were treated with oral clentiazem, 0.25 and 2.50 mg/kg/day. Groups 8 and 9 consisted of allografts receiving low-dose cyclosporine with either diltiazem or clentiazem 2.50 mg/kg/day, all drugs were administered daily by gavage. Graft function was monitored by transabdominal palpation, and rejection was considered to be complete when no contraction of the graft could be detected. Mean survival time of untreated allografts was 6.4 +/- 0.5 days. Cyclosporine alone increased the mean survival time to 10.6 +/- 2.7 days (P < 0.05 vs. group 2). At all doses studied, diltiazem and clentiazem significantly increased mean survival time of allografts, clentiazem being slightly more potent than diltiazem. In addition, the observed beneficial effects of the benzothiazepine-like calcium channel blockers were dose-dependent. When combined with cyclosporine, diltiazem and clentiazem interacted synergistically (mean survival time increased to 16.8 +/- 3.4 days for diltiazem and 15.8 +/- 1.4 days for clentiazem). These results demonstrate that the benzothiazepine-like calcium channel blockers, as opposed to phenylalkylamines or dihydropyridines, afford significant immunosuppression when used alone. These observations, and the fact that they beneficially interact with cyclosporine, suggest that the benzothiazepine-like calcium antagonists should be considered the drugs of choice when CCBs are to be selected in transplanted patients.

Animals↗
PubMed1993

[Validation of the virus inactivation capacity of a procedure of human plasma albumin purification by chromatography].

Almost the whole of the human plasma albumin preparations intended for clinical or biological uses is at present fractionated by cold ethanol precipitation technics based on the Cohn method. However, ion-exchange chromatographic processes have been recently developed. The aim of this work was the evaluation of the viral inactivation efficacy of an automated industrial chromatographic process allowing fractionation of 350 to 400 l of plasma per cycle (one precipitation step, three ion-exchange chromatography steps using the Spherodex-Spherosil gels--Sepracor-IBF, Villeneuve la Garenne, France--and one pasteurization step. Three relevant viruses were selected for this validation study: the hepatitis B virus (HBV), the poliomyelitis virus and the human immunodeficiency virus (HIV). In order to comply with EEC and FDA regulatory documents, significant amounts of the tested viruses were spiked into the different fractions obtained during the various purification steps and their removal or inactivation during the subsequent step were determined. The validation study was performed under conditions which mimic the manufacturing process using fractions obtained during a semi-industrial fractionation. Moreover, residual viral infectivity was checked on after elution and washing of the columns for each chromatographic step. Results have pointed out: a) an overall reduction of 4.4 log 10 for HBV. Infectivity is judged by a combination of several markers and the DNA polymerase activity is the most affected particularly during the three ending purification steps; b) an overall reduction in virus titer > 10 log 10 for the poliomyelitis virus; c) an overall reduction in virus titer > 10 log 10 for HIV (four of the five steps have an important potential to inactivate this virus increasing the safety of the process). Moreover, no residual viral infectivities were detected after washing of the columns. In conclusion, this study showed the viral safety of human albumin purified using the chromatographic Spherodex-Spherosil process. As had been observed for fractionation by means of ethanol, the pasteurization step is necessary to ensure inactivation of two of the three viruses tested (HBV and poliomyelitis virus). This validation study allowed the preparation of a manufacturing and controls document for albumin and a marketing authorization has been issued by the "Laboratoire National de la Santé" (LNS, France).

Chromatography, Ion Exchange↗
PubMed1992

Mechanism of halothane attenuation of isometric tension induced by serotonin in isolated canine coronary artery rings.

We explored the mechanism of halothane's interaction with the serotoninergic contractile response of isolated canine coronary artery rings. The serotoninergic contractile response of both intact and denuded rings was measured with and without halothane. In some experiments, rings were pretreated with methiothepin, a 5-HT1 and 5-HT2 antagonist, or ketanserin, a 5-HT2 antagonist. The contractile responses to 5-carboxamidotryptamine (5-CT) and alpha-methylserotonin, a 5-HT1 and a 5-HT2 receptor agonist, respectively, were measured with and without halothane. Finally, the response to prostaglandin F2-alpha, another spasm mediator, was also measured with and without halothane. Halothane attenuated the coronary artery response to serotonin (5-hydroxytryptamine, 5-HT), and specific 5-HT1 and 5-HT2 agonists, and prostaglandin F2 alpha (PGF2 alpha). Its inhibitory effect on the serotoninergic response was abolished in vessels pretreated with either 5-HT1 or 5-HT2 blockers. These data suggest that halothane is not a direct smooth muscle depressant, that it is not a specific 5-HT1- or 5-HT2-subtype antagonist in canine coronary arteries, and that it might interfere with intracellular pathways activated by agonist-receptor interactions.

Animals↗
PubMed1992

The effect of a new calcium channel blocker (TA-3090) on lipoprotein profile and intestinal lipid handling in rodents.

Recent interest has focused on findings that drugs used to lower blood pressure may adversely modify plasma lipids and lipoprotein metabolism. This observation may explain why pharmacologic control of hypertension has failed to reduce the incidence of morbidity and mortality from coronary artery disease. The present study aims to evaluate the effect of TA-3090, a new calcium channel blocker, on fasting plasma lipids and lipoproteins, as well as on processes of intestinal fat absorption. Rats were treated by gavage with TA-3090 (10 mg/kg twice daily) for 4 days and compared with controls (n = 6 per group). Plasma cholesterol was increased in the treated group to (mean +/- SE) 74 +/- 2 vs 60 +/- 4 mg/dl (P less than 0.01), due mainly to an increased high density lipoprotein-cholesterol level (50 +/- 2 vs 37 +/- 3 mg/dl, P less than 0.005). Notably plasma triglycerides (TG) and low density lipoprotein-cholesterol were not significantly affected. Another group of TA-3090-treated animals was given an intraduodenal fat meal, and the rise in plasma TG and chylomicrons followed over 4 hr. Postprandial hypertriglyceridemia and chylomicronemia were significantly lower at 2 hr (P less than 0.05) and 3 hr (P less than 0.01) compared with controls. In a separate group of animals, the addition of TA-3090 to a 2% intralipid infusion intraduodenally was associated with significantly reduced TG and chylomicron-TG transport into lymph (P less than 0.05). Furthermore, experiments in rats pretreated with TA-3090 intraperitoneally and then given 2% intralipid intraduodenally were shown to have a significant decrease in mean flow rate (27%), TG transport (31%) and chylomicron-TG output (37%), when compared with controls. In vitro studies using jejunal organ culture to examine the effect of TA-3090 on intracellular lipid synthesis and secretion revealed that the addition of the drug to the medium resulted in significantly decreased TG synthesis and secretion. These data suggest that TA-3090 could be effective in increasing HDL-cholesterol and reducing postprandial chylomicronemia. Our findings support a role for TA-3090 directly on enterocyte absorption and/or intracellular lipid transport, and thus indicate the importance of intracellular calcium on these processes.

Animals↗
PubMed1991

Beneficial effects of volatile anesthetics on decrease in coronary flow and myocardial contractility induced by oxygen-derived free radicals in isolated rabbit hearts.

Oxygen-derived free radicals have been implicated in reperfusion injury whereas volatile anesthetics have been shown to enhance myocardial recovery during reperfusion. To explore the mechanism by which these agents improve myocardial recovery, we measured the effect of volatile anesthetics on the free radical-induced reduction in left ventricular pressure (LVP), coronary flow, and endothelium-dependent dilation induced by acetylcholine (Ach). Isolated rabbit hearts were perfused in a Langendorff apparatus. Isovolumetric LVP and coronary flow were measured throughout the study. Oxygen-derived free radicals were produced by the electrolysis (direct current of 0.6 mA) of the perfusate. The following volatile anesthetics were used: halothane 0.5 or 1.0%, isoflurane 0.7 or 1.4%, and enflurane 1.0 or 2.0%. Oxygen free radicals induced a significant decrease in systolic LVP and coronary flow. Pretreatment of the heart with enflurane 1.0 or 2.0%, halothane 1.0%, or isoflurane 0.7% attenuated the effect of the free radicals on both systolic LVP and coronary flow. Free radicals reduced the dilating response induced by 0.1 microM Ach with or without addition of volatile anesthetics. These data suggest that the volatile agents have beneficial effects on the free radical cell damage pathway and that this protection is not related to the preservation of endothelium-dependent dilation.

Anesthetics↗
PubMed1991

Peripheral vasodilator and cardiac properties of the 1,5-benzothiazepine calcium antagonist analog, TA-3090, in dogs.

Diltiazem, a 1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous cardiovascular diseases. TA-3090, a newly synthetized 1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of TA-3090 (n = 16) or diltiazem (n = 15) (15, 50, 200, and 400 micrograms/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both TA-3090 and diltiazem elicit slight peripheral and coronary vasodilator properties at low doses (15 and 50 micrograms/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between TA-3090 and diltiazem indicates that both drugs elicit coronary vasodilator selectivity and TA-3090 has a prolonged duration of action compared with that of diltiazem. A straightforward relationship is demonstrated between vasodilator properties and plasma levels of either TA-3090 or diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with TA-3090. Changes of heart rate were not correlated with plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Acute hypercalcemia and increased work load in canine transplanted heart. Coronary blood flow adjustments.

Coronary vasodilator adjustments following cardiac transplantation might be adversely affected during severe rejection. We studied the coronary blood flow response following intravenous bolus administration of calcium (0.04-0.05 mEq/kg) in canine cardiac transplants. Fifteen dogs were submitted to orthotopic heart transplantation and equipped with electronic implants for monitoring of hemodynamic parameters. Of these animals, 9 were not immunosuppressed, while 6 were treated with ciclosporin, azathioprine, and prednisone. The effects of calcium administration upon cardiac function were evaluated during the postoperative period, at recovery (2-3 days after transplantation) and during severe rejection (7-10 days after transplantation), and also in immunosuppressed animals. Rapid calcium administration elicits brief increases in arterial pressure, cardiac index, stroke work, and coronary blood flow. There were significant differences in these effects, depending on the hemodynamic status of these animals. Coronary blood flow was significantly increased in all experiments, except when severe rejection was evidenced. These results indicate that changes in myocardial metabolic demand (work load) are not adequately matched with coronary blood flow adjustments in the presence of severe rejection.

Acute Disease↗
PubMed1989

Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs.

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.

Amrinone↗