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Biomedical subjects

R Xhonneux

Publications and source records attributed to R Xhonneux.

At least 19 recordsLinked to original sources
PubMed1992

Cardiac and hemodynamic effects of intravenous R80122, a new phosphodiesterase III inhibitor, in a canine model of myocardial ischemia and heart failure.

The cardiac and hemodynamic effects of R80122, a new specific phosphodiesterase III inhibitor, were studied in a closed-chest canine model of acute global left ventricular ischemia complicated by heart failure. The results obtained were compared with those obtained with milrinone. Intravenous infusion of the compounds (0.005 mg/kg/min for both) was started when stable heart failure had developed and was continued for 50 min followed by a washout period of 60 min. Both R80122 and milrinone improved the function of the acutely failing heart, as indicated by the increase in the values of the variables related to left ventricular function, but differences existed. The most striking differences were the normalization of the left ventricular external mechanical efficiency with R80122, but not with milrinone, and the maintenance of aortic blood pressure during infusion of R80122, which decreased during infusion of milrinone. Milrinone tends to induce ventricular tachycardia more frequently than R80122. It can be concluded that R80122 and milrinone improve the function of the acutely failing heart, but that the changes induced by R80122 are better balanced, i.e., enhancement of external mechanical efficiency with maintenance of aortic blood pressure.

Animals↗
PubMed1991

Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries.

In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7), or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However, such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.

Animals↗
PubMed1990

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer.

In this study the effect of l-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of l-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg.kg-1 d-nebivolol. The potentiating effect of l-nebivolol was seen at doses higher than 0.16 mg.kg-1. At 1.25 mg.kg-1 d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by l-nebivolol in doses up to 1.25 mg.kg-1. Higher doses of l-nebivolol (2.5 and 5.0 mg.kg-1) in combination with 1.25 mg.kg-1 d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced beta 1-adrenoceptor blocking properties. This is probably disadvantageous, because d,l-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal beta 1-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% l-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.

Adrenergic beta-Antagonists↗
PubMed1989

Nebivolol is devoid of intrinsic sympathomimetic activity.

Nebivolol is a chemically novel, potent and selective beta 1-adrenoceptor-blocking agent that acutely lowers arterial blood pressure in hypertensive patients and rats without depressing, or even enhancing, left ventricular function. These properties could be compatible with a partial agonistic effect of beta-adrenoceptor-blocking agents. It was the aim of the present study to investigate whether nebivolol has intrinsic sympathomimetic properties. The study was performed on reserpinized dogs and spontaneously hypertensive rats, and on various isolated tissues from various species. Unlike pindolol and practolol, nebivolol did not exert a stimulating effect on the heart rate and left ventricular function in reserpinized animals and/or in isolated atria of reserpinized rats at doses that are clinically active. Nebivolol did not induce relaxation of isolated coronary arteries and saphenous veins at concentrations that block beta-adrenoceptors. These findings indicate that nebivolol is devoid of intrinsic sympathomimetic activity at clinically relevant doses.

Adrenergic beta-Antagonists↗
PubMed1989

An improved method to correct the QT interval of the electrocardiogram for changes in heart rate.

The adequacy of the Bazett formula to correct for heart rate-induced changes in the QT interval of the electrocardiogram has been frequently questioned. In the present study, a simple linear equation was derived, which in anesthetized dogs corrects more adequately for changes in heart rate than the Bazett formula. Regression analysis of experimental data yielded the following equation: QTc = QT - 0.087 (RR - 1000) = QT - 87 (60/HR - 1). The reliability of this equation was investigated in experiments on anesthetized dogs with different cardioactive drugs with a known mechanism of action.

Amiodarone↗
PubMed1988

Cardiovascular effects of dl-nebivolol and its enantiomers--a comparison with those of atenolol.

In the present study, we investigated the cardiovascular effects of dl-nebivolol, a newly synthetized, chemically novel, beta 1-adrenoceptor antagonist and its enantiomers, d-nebivolol (SRRR) and l-nebivolol (RSSS), in closed-chest anesthetized dogs, using atenolol as a reference substance. Results from preliminary studies in vitro indicate that d-nebivolol is the beta 1-adrenoceptor antagonist and that l-nebivolol is practically devoid of beta-adrenoceptor-blocking properties. Unlike atenolol, dl-nebivolol does not depress left ventricular function and slightly, but significantly, reduces peripheral vascular resistance over the dose range from 0.0025 to 0.04 mg.kg-1 i.v. These observations are likely to be clinically relevant because one daily oral dose of 5 mg dl-nebivolol effectively lowers arterial blood pressure in patients with hypertension. The favorable hemodynamic profile of dl-nebivolol can be ascribed to the l-enantiomer because the cardiovascular effects of this enantiomer are similar to those of the racemate. The cardiovascular profile of the d-enantiomer is similar to that of atenolol, albeit that its depressant effect on left ventricular function occurs at higher doses.

Animals↗
PubMed1988

Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist.

The pharmacological profile of nebivolol (N), a chemically novel beta-adrenergic antagonist, was assessed in investigations on isolated tissues, awake spontaneously hypertensive rats (SHR), closed-chest anesthetized dogs, and humans. In vitro, N was found to be a potent antagonist of beta 1-adrenergic receptors (A2 value, 5.8 X 10(-9) M) and only a weak beta 2-adrenergic antagonist (A2 value, 1.7 X 10(-6) M). The selectivity for the beta 1-adrenergic receptor was higher for N than for any of the reference compounds. In dogs--similarly with atenolol--N was more potent in blocking the isoprenaline (I)-induced increases in left ventricular performance than the I-induced decrease in arterial pressure. In dogs, as compared with propranolol, N (0.025 and 0.01 mg.kg-1 i.v.) increased cardiac output and stroke volume, lowered systemic vascular resistance, and had no significant effect on the variables related to left ventricular contraction. In contrast to other beta-adrenergic antagonists, N acutely lowered arterial blood pressure in SHR (1.25 mg.kg-1 i.p.) and in hypertensive patients (1 oral dose of 5 mg) for several hours. In healthy volunteers N (5 mg) lowered systemic vascular resistance during daily oral treatment and did not negatively affect left ventricular function. In conclusion, N is a potent and selective beta 1-adrenergic blocking agent with an interesting hemodynamic profile. In hypertensive subjects and SHR, a single dose lowers arterial blood pressure for substantial periods of time.

Adrenergic alpha-Antagonists↗
PubMed1988

Interaction between S2-serotonergic and alpha 1-adrenergic receptor activities at vascular sites.

Serotonin enhances (amplifies) the vasoconstrictor effect of norepinephrine not only on isolated large blood vessels and isolated perfused vascular beds but also in vivo. This amplification can be observed with endogenous serotonin released from aggregating platelets and with endogenous norepinephrine released from the adrenergic nerves in the blood vessel wall. It is due to an interaction between S2-serotonergic and alpha 1-adrenergic mechanisms. Combined S2-serotonergic and alpha 1-adrenergic antagonism is more effective than either one alone against contractions evoked with the combination of serotonin and an alpha 1-adrenergic agonist. In spontaneously hypertensive rats, S2-serotonergic antagonism alone does not reduce blood pressure but combined S2-serotonergic and alpha 1-adrenergic blockade lowers blood pressure more than alpha 1-adrenergic blockade alone. This suggests that the interaction between S2-serotonergic and alpha 1-adrenergic vasoconstrictor responses may play a role in the maintenance of high blood pressure.

Animals↗
PubMed1987

Electrophysiologic, antiarrhythmic and hemodynamic effects of transcainide.

Transcainide was selected as an antiarrhythmic drug with potential clinical application. In isolated dog, sheep and rabbit Purkinje fibres, in dog and guinea-pig trabecular preparations and in the guinea-pig right auricle, transcainide decreases the rate of rise of the transmembrane action potential, with no effect on normal spontaneous activity and calcium-mediated action potentials; it inhibits early after-depolarizations. The effect on the rate of rise is very slow in onset. In vivo a prolongation of QRS duration is observed. In dogs, the drug is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. Hemodynamic studies in anaesthetized and unaesthetized dogs indicate that transcainide moderately decreases contractility, while slightly increasing frequency. No major side effects are seen. Preliminary data on the pharmacokinetics suggest that in the dog the observed effects after i.v. infusion are related to the parent drug. Transcainide is an antiarrhythmic of the local anaesthetic type, with very slow kinetics. It is characterized by a good oral absorption and a long duration of action.

Action Potentials↗
PubMed1987

Changes in ultrastructure and Ca2+ distribution in the isolated working rabbit heart after ischemia. A time-related study.

Ultrastructural changes in cardiac muscle of isolated working rabbit hearts after various periods of ischemia are described and compared with distributional changes in calcium. The effects of reperfusion on these structural parameters were also investigated. The purposes of this study were to relate the role of calcium in the degeneration of cardiac muscle; to determine whether Ca2+ localizations could serve as additional criteria to determine more closely the point of no return; and to investigate the contributory role of reoxygenation to the development of myocardial damage. This study shows the existence of topographic differences in the tolerance to ischemia in the mid area, subendocardium, and subepicardium; that the sequestration of Ca2+ by mitochondria is an energy-requiring (active) process that occurs only during reperfusion; the loss of the sarcolemma's ability to bind Ca2+ during ischemia to coincide with increased Ca2+ entry during postischemic reperfusion (this Ca2+ is scavenged by mitochondria as long as sufficient energy remains available; these changes are interpreted as being at the edge of irreversibility); and the lack of additional damage and and lack of Ca2+ accumulation in mitochondria during reperfusion in cells that are damaged to such an extent that mitochondria possess flocculent densities already at the end of the ischemic insult.

Animals↗
PubMed1986

Changes in creatine phosphate, inorganic phosphate, and the purine pattern in dog hearts with time of coronary artery occlusion and effect thereon of mioflazine, a nucleoside transport inhibitor.

A detailed analysis was made of the changes in canine myocardium, with time of occlusion, in several important metabolites such as creatine phosphate and adenosine triphosphate (luminometry), inorganic phosphate (spectrophotometry), and most of the purines and nicotinamide adenine dinucleotide (high performance liquid chromatography). Within 1 min there was a significant reduction in creatine phosphate and a significant increase in inorganic phosphate, adenosine diphosphate, and adenosine monophosphate. A decrease in adenosine triphosphate became apparent after 4 min, concomitant with a progressive rise in the nucleosides, which reached almost 50% of the total purines after 64 min of occlusion. The formation of hypoxanthine was detectable in 50% only of all animals, suggesting a lack of active nucleoside phosphorylase in the others. Nicotinamide adenine dinucleotide, although decreasing slightly, was by far the most constant of all variables measured during at least 30 min of ischaemia. Therefore, this component is suggested to be a useful internal standard, thus minimising analytical and biological variations. Mioflazine, a potent nucleoside transport inhibitor (I50 3 X 10(-8) mol X litre-1), when given orally at 2.5 mg X kg-1, did not affect any of the changes with the exception of the nucleosides, where the drug completely inverts the adenosine to inosine ratio. The contribution of adenosine to the total nucleosides changed from 20% in the controls to 80% with treatment during at least 16 min of occlusion, there being no overlap between the groups. It is concluded therefore that adenosine is not deaminated in the cell where it is produced. It is not yet clear how this notable effect of mioflazine could be linked to its remarkable protective effect against ischaemia.

Animals↗
PubMed1985

Cardiovascular effects of ketanserin in closed-chest anesthetized dogs.

The cardiovascular effects of the selective 5 HT2-serotonergic antagonist Ketanserin (cumulative doses of 0.01, 0.04, 0.16, 0.64 and 2.5 mg.kg-1 i.v. at 30 min intervals) were investigated in closed-chest, anesthetized dogs with spontaneously beating hearts (n = 7) and in dogs with a fixed heart rate (n = 7). Besides, the effects of Ketanserin (0.04 mg.kg-1 i.v.) during serotonin infusion (median: 20 micrograms kg-1.min-1 i.v.) were studied (n = 7). Ketanserin, starting at 0.04 mg.kg-1, lowers arterial blood pressure through a decrease in systemic vascular resistance. The increase in heart rate after the injection of 0.16 mg.kg-1 and higher doses is likely reflexogenic in nature and secondary to the decrease in systemic vascular resistance. Ketanserin also induces a positive inotropic effect, starting at a dose of 0.16 mg.kg-1 as indicated by the increase in LV dP/dt max, LV dP/dt max/P and maximum aortic blood flow velocity at constant heart rate and in the presence of no change or a slight decrease in left ventricular end-diastolic pressure. Whether this is an intrinsic property of the compound remains subject to further investigation. Except for the increase in the variables related to left ventricular function, Ketanserin (0.04 mg.kg-1) blocks the serotonin induced circulatory and respiratory changes. The inhibition of serotonin induced pulmonary hypertension and bronchoconstriction was especially marked. The positive inotropic properties of serotonin were not blocked by Ketanserin, suggesting that this property of the amine is not 5 HT2-receptor mediated.

Anesthesia↗
PubMed1984

Cardiovascular and some respiratory effects of high doses of alfentanil in dogs.

The cardiovascular and some respiratory effects of alfentanil, a potent and short-acting morphinomimetic, were studied in conscious (n = 6) and anaesthetized, artificially ventilated dogs (n = 7). The compound was injected intravenously in increasing doses of 12.5, 12.5, 25, 50, 100, 200, 400 and 800 micrograms X kg-1 in the conscious dogs and of 0.16, 0.32, 0.64, 1.25, 2.5 and 5 mg X kg-1 in the anaesthetized animals. In the conscious dogs, the heart rate decreased significantly reaching a maximum decrease after the injection of 400 micrograms X kg-1 X PCO2 and arterial and venous lactate concentrations increased, while PO2, pH and base excess decreased significantly. At higher dose levels (100-400 micrograms X kg-1) short periods of convulsions were seen. The most pronounced change in the anaesthetized dogs was a significant fall in LVdP/dt max and LV dP/dt max/P, associated with a rise in left ventricular end-diastolic pressure following the injection of 5 mg X kg-1, suggesting negative inotropic properties at this high dose level. Most of the animals showed A-V dissociations which disappeared at higher doses. All animals survived. These findings indicate that alfentanil is a safe analgesic as far as the effects on the cardiovascular system are concerned. High doses are tolerated well, especially when the animals are artificially ventilated. The short periods of convulsions, seen only in the awake dogs, may have been facilitated by the low PO2 levels reached (median value: 9 kPa).

Alfentanil↗
PubMed1984

Cardioprotective effects of mioflazine during 1 h normothermic global ischaemia in the canine heart.

The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were investigated in 41 anaesthetised open chest Beagle dogs subjected to 1 h normothermic global myocardial ischaemia. The severity of the model is evidenced by the finding that only one out of 20 control dogs could be weaned from extracorporeal bypass. Oral pretreatment with mioflazine (2.5 mg X kg-1) resulted in complete functional recovery in 17 out of 20 animals. Biochemical analysis of left ventricular biopsies taken before, during and after aortic cross clamping showed a preservation of purines and a better recovery of ATP, ATP/ADP X Pi ratio and energy charge (p less than 0.05) in the pretreated animals. Morphological and cytochemical assessment of the myocardium demonstrated that the ultrastructure of the sarcolemma and its calcium binding capacity is remarkably well preserved in the drug treated animals. These results indicate a strong cardioprotective effect of mioflazine. The biochemical, cytochemical and ultrastructural findings suggest an interaction of the drug with the sarcolemma.

Animals↗
PubMed1984

Cardiac and haemodynamic effects of intravenous administrations of flunarizine in closed-chest anaesthetized mongrel dogs.

This study was performed to evaluate the cardiac and haemodynamic effects of 1-cinnamyl-4-[bis(p-fluorophenyl)methyl]piperazine dihydrochloride (flunarizine, Sibelium ). The compound was dissolved in distilled water acidified with tartaric acid in a concentration of 2 mg/ml (pH 1.8) and administered intravenously in cumulative doses of 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Flunarizine induced systemic vasodilatation dose- relatedly starting with a dose of 0.1 mg/kg i.v. as indicated by the decrease in systemic vascular resistance, while this compound had no vasodilating properties in the pulmonary circulation. Flunarizine caused an increase in heart rate following the administration of the higher doses. This effect is probably reflexogenic in nature and secondary to the decrease in aortic blood pressure. As a consequence the oxygen demand of the myocardium enhanced after these high doses of flunarizine as indicated by the increase in pressure-rate product. Flunarizine did not affect the contractility and the conduction of the heart in the doses of 0.03 up to and including 1.0 mg/kg i.v., but could have some negative inotropic properties at the highest dose used. The end-tidal CO2 concentration in the expired air increased after the administration of 0.3 up to and including 3.0 mg/kg i.v. From these results, it is concluded that flunarizine has systemic vasodilating properties without any cardiac effects at doses from 0.03 up to and including 1.0 mg/kg i.v.

Animals↗
PubMed1984

Beneficial effect of mioflazine in limiting myocardial infarct size in the anesthetized dog.

The effect of mioflazine (R 51 469) on infarct size was studied in anesthetized dogs subjected to 24 h of LAD (left anterior descending) coronary artery occlusion. The myocardium normally supplied by the occluded coronary artery (perfusion area, PA) was delineated by perfusion of the arterial bed distal to the occlusion with colorless fluid while the remainder of the heart was simultaneously perfused with an Evans blue solution. After sectioning the heart, infarct areas (IA) could be visualized by incubation of the slices in triphenyl-tetrazolium-chloride (TTC). Quantification of the areas was performed using a Quantimet 900 image analysis system. The animals either received mioflazine (2.5 mg X kg-1 orally) or a same volume of 20% polypropylene glycol, the solvent of mioflazine 2.5 h before the start of the surgical procedure. For perfusion areas greater than 20% of the left ventricle infarct size was significantly reduced in mioflazine pretreated animals compared with the control group, both expressed as per cent of the left ventricle (10.6 +/- 2.3 vs 19.2 +/- 1.5, p less than 0.005) and as per cent of the perfusion area (35.1 +/- 7 vs 64.4 +/- 5, p less than 0.005).

Anesthesia↗
PubMed1981

Cardioprotective effects of lidoflazine during 1-hour normothermic global ischemia.

The cardioprotective effects of lidoflazine, a drug with calcium homeostatic properties, were investigated in dogs subjected to 1 hour of normothermic global ischemia, followed by reperfusion. None of the eight control dogs could be weaned from the extracorporeal bypass, confirming the severity of the ischemic model. All eight acutely pretreated dogs showed rapid recovery from the prolonged ischemic arrest and could support their own circulation. Recovery of preischemic values was 95% for systolic aortic pressure, 71% for diastolic aortic pressure, 99% for left ventricular dP/dt max and 80% for cardiac output. Light and electron microscopy and calcium cytochemistry were performed on left ventricular biopsies taken before, during and after ischemic arrest. In the control dogs, loss of structural integrity of the sarcolemma and mitochondria was prominent at the end of the ischemic period. Intracellular edema, hypercontraction of sarcomeres and great accumulation of calcium in severely damaged mitochondria occurred after 5 and 30 minutes of reperfusion. In the lidoflazine-treated dogs, such lesions were largely prevented during the ischemic period and completely reversed after reperfusion. These observations suggest that the tolerance of ischemia is markedly augmented by lidoflazine.

Animals↗