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H Van Belle

Publications and source records attributed to H Van Belle.

At least 19 recordsLinked to original sources
PubMed1998

Physiological red blood cell kinetic model to explain the apparent discrepancy between adenosine breakdown inhibition and nucleoside transporter occupancy of draflazine.

A physiological red blood cell (RBC) kinetic model is proposed for the adenosine (ADO) transport into erythrocytes and its subsequent intracellular deamination into inactive inosine (INO) and further breakdown into hypoxanthine (HYPO). The model and its parameters were based on previous studies investigating the kinetics of the biochemical mechanism of uptake and metabolism of ADO in human erythrocytes. Application of the model for simulations of the breakdown of ADO in a RBC suspension revealed that the predicted adenosine breakdown inhibition (ABI) of draflazine corresponded well with the ABI measured ex vivo. The model definitely explained the apparent discrepancy between the ex vivo measured ABI and the nucleoside transporter occupancy of draflazine. Intracellular deamination of ADO rather than its transport by the nucleoside transporter is the rate-limiting step in the overall catabolism of ADO. Consequently, at least 90% occupancy of the transporter by draflazine is required to inhibit adenosine breakdown ex vivo substantially. Simulations on basis of the validated model were performed to evaluate the ABI for different experimental conditions and to mimic the clinical situation. The latter may be very helpful for the design of optimal dosing schemes of draflazine. It was demonstrated that the short half-life of released ADO was prolonged substantially in a dose-related manner after a continuous infusion of draflazine. Finally, the previously found different sigmoidal Emax relationships between the measured ABI and the concentrations of draflazine in plasma and whole blood could be explained by the ADO transport and breakdown RBC kinetic model and the capacity-limited specific RBC binding characteristics of draflazine.

Adenosine↗
PubMed1997

Population analysis of the non linear red blood cell partitioning and the concentration-effect relationship of draflazine following various infusion rates.

AIMS: To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured adenosine breakdown inhibition (ABI). METHODS: Draflazine was administered to healthy volunteers as a 15-min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately followed by an infusion of the same dose over 1 h. Plasma and whole blood concentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The capacity-limited specific binding of draflazine to the nucleoside transporter located on the erythrocytes was evaluated by a population approach. RESULTS: The estimate of the population parameter typical value (%CV) of the binding constant Kd and the maximal specific binding capacity (Bmax) was 0.385 (3.5) ng ml-1 plasma and 158 (2.1) ng ml-1 RBC, respectively. The non-specific binding was low. The specific binding to the erythrocytes was a source of non-linearity in the pharmacokinetics of draflazine. The total plasma clearance of draflazine slightly decreased with increasing doses, whereas the total clearance in whole blood increased with increasing doses. The sigmoidal Emax equation was used to relate the plasma and whole blood concentration of draflazine to the ex vivo determined ABI. In plasma, typical values (%CV) of Emax, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml-1 and 1.06 (3.4), respectively. The relationship in whole blood was much steeper with population parameter typical values (%CV) of Emax, IC50 and Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml-1 and 4.47 (5.5), respectively. The RBC occupancy of draflazine did not coincide with the ex vivo measured ABI. The observed relationship between RBC occupancy and ABI was not directly proportional but similar for all studied infusion schemes. CONCLUSIONS: The findings of this study show that the occupancy of the nucleoside transporter by draflazine should be at least 90% in order to inhibit substantially adenosine breakdown in vivo. On the basis of these findings it is suggested that a 15 min infusion of 1 mg draflazine followed by an infusion of 1 mg h-1 could be appropriate in patients undergoing a coronary artery bypass grafting.

Adenosine↗
PubMed1996

The implications of non-linear red blood cell partitioning for the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine.

1. Draflazine, a nucleoside transport inhibitor, was administered as a 15 min i.v. infusion of 2.5 mg to eight healthy male subjects. Plasma and whole blood concentrations were measured up to 32 h post-dose, and were related to adenosine breakdown inhibition (ABI) measured ex vivo, which served as a pharmacodynamic endpoint. 2. The red blood cell/plasma distribution of draflazine was non-linear and characterized as a capacity-limited specific binding to the nucleoside transporter on the red blood cells. The binding (dissociation) constant Kd was 0.87 ng ml-1 plasma and the maximal specific binding capacity (Bmax) was 164 ng ml-1 RBC, which corresponds to about 14,000 specific binding sites per erythrocyte. Non-specific binding amounted to less than 15% of the total binding. 3. The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pharmacokinetic model. The pharmacokinetic parameters (mean +/- s.d.) were: clearance 22.0 +/- 8.0 ml mm-1, volume of distribution at steady-state 39.8 +/- 4.7 l and terminal half-life 24.0 +/- 9.4 h. Concentrations in plasma were much lower, and could only be determined accurately in pooled plasma samples with a red blood cell binding assay. The pharmacokinetic parameters in pooled plasma were: clearance 551 ml min-1, volume of distribution at steady-state 349 l and terminal half-life 10.7 h. 4. A non-linear relationship was observed between the plasma or blood concentration of draflazine and the ABI determined ex vivo. This relationship was characterized by the sigmoidal Emax pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were Emax 100%, IC50 10.5 ng ml-1 and Hill factor 0.9. When using whole blood concentrations, the relationship was much steeper with values (mean +/- s.d.) Emax 92.4 +/- 5.6%, IC50 76.0 +/- 15.3 ng ml-1 and Hill factor 3.5 +/- 0.9. 5. Binding to the nucleoside transporter on red blood cells is an important determinant of the pharmacokinetics of draflazine and a high degree of occupancy of the transporter by draflazine is required to inhibit adenosine breakdown ex vivo. It is suggested that red blood cell nucleoside transporter occupancy may serve as a useful pharmacodynamic endpoint in dose ranging studies with draflazine.

Adenosine↗
PubMed1996

Presynaptic inhibition of norepinephrine release from sympathetic nerve endings by endogenous adenosine.

ATP is coreleased with norepinephrine from sympathetic nerve endings and subsequently broken down to adenosine. In animal preparations, adenosine can inhibit norepinephrine release by stimulation of presynaptic receptors. We tested this feedback mechanism in humans by using a specific nucleoside transport inhibitor (draflazine) as a pharmacological tool to allow accumulation of endogenous adenosine in the synaptic cleft. In a dose-finding study on draflazine infusions into the brachial artery (n=10), we identified an optimal dose of 250 ng/min per deciliter of forearm tissue that induced considerable local nucleoside transport inhibition (approximately 40%) without systemic effects. In the main study, we investigated the effects of this draflazine dose on sympathetic-mediated norepinephrine spillover during lower body negative pressure (-25 mm Hg) by the use of the [3H]norepinephrine isotope dilution technique (n=25). Lower body negative pressure induced a significant increase in total body norepinephrine spillover, forearm norepinephrine appearance rate, forearm vascular resistance, and heart rate. During draflazine infusion into the brachial artery, the responses to lower body negative pressure were preserved for all parameters, with the exception of the median increase in forearm norepinephrine appearance rate, which was reduced from 54% to 2% (P <.05). We conclude that accumulation of endogenous adenosine in the synaptic cleft during sympathetic stimulation can inhibit norepinephrine release from sympathetic nerve endings.

Adenosine↗
PubMed1995

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5 +/- 4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 micrograms/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9 +/- 0.3 ml/100 ml forearm per min for placebo and 1.8 +/- 0.2, 2.0 +/- 0.3, 3.8 +/- 0.9, 6.3 +/- 1.2, 11.3 +/- 2.2, and 19.3 +/- 3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6 +/- 0.2 ml/100 ml forearm per min for placebo and 2.1 +/- 0.3, 3.3 +/- 0.6, 5.8 +/- 1.1, 6.9 +/- 1.4, 14.4 +/- 2.9, and 23.5 +/- 4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the forearm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man.

Adenosine↗
PubMed1995

The effect of ischemia and reperfusion on mitochondrial contact sites in isolated rat hearts.

Contact sites may be described as energy channels between the mitochondria and the cytosol, created by fusion of the inner and the outer mitochondrial membranes, and their number depends highly on the energy state of the cell. The aim of the present study was to examine the early changes of ischemia and reperfusion on the number of mitochondrial contact sites. Therefore isolated rat hearts were subjected to short periods of ischemia followed by reperfusion. The left ventricular pressure (LVP), the contractility (dP/dtmax) and the heart rate were measured. The number of contact sites was morphometrically evaluated. As the flow was stopped, LVP, dP/dtmax and HR declined rapidly and became undetectable after 2 min of ischemia. The number of contact sites fell to a minimum after 10 min of ischemia after an initial increase (1 min of ischemia). A 15 min ischemic period resulted in a high number of contact sites which decreased again after 20 min of ischemia. Reperfusion after 2 min of ischemia caused an immediate functional recovery and a high presence of contact sites. After 15 min of reperfusion, all values returned to control values. Reperfusion after 10 min of ischemia resulted in a slow recovery of the number of contact sites and after 15 min of ischemia the number of contact sites remained low upon reperfusion. We may conclude that mitochondria lose the ability to form contact sites after more than 15 min of ischemia and this might be a first indication of irreversible injury.

Animals↗
PubMed1994

The effect of calcium on mitochondrial contact sites: a study on isolated rat hearts.

Mitochondrial contact sites are dynamic structures created by fusion of the inner and outer mitochondrial membranes. Stimulation of the metabolism results in an increase of the number of contact sites. Functionally, it is shown that mitochondrial creatine kinase (Mi-CK) is active in contact sites and therefore, Mi-CK cytochemistry was performed (using a tetrazolium salt) to improve the visibility of the contact sites. As calcium is involved as an intracellular messenger of hormonal stimulation, the effect of increasing extracellular calcium concentrations on the number of contact sites was investigated. Therefore, isolated rat hearts were perfused with Krebs-Henseleit buffers differing in their calcium content. During the perfusions the heart function was evaluated and at the end of each experiment, the hearts were processed for Mi CK cytochemistry and the number of contact sites was expressed as the ratio of surface densities contact sites to mitochondrial membranes (Ss). At 2.2 mM calcium perfusion, the physiological parameters and the Ss reached a maximum. This was in contrast to the 0.6 and the 3.6 mM of calcium perfusions whereby both the physiological values and the Ss were decreased. Treatment with noradrenaline in vivo, as was done in previous studies or perfusion with 2.2 mM of calcium ends up with similar values for Ss. From these results, it could be suggested that there might be a link between calcium, heart function and the formation of Mi CK active contact sites.

Animals↗
PubMed1994

Ultrastructural localisation of carnitine acetyltransferase activity in mitochondria of rat myocardium.

The acetyl CoA/CoA ratio is an important regulating factor of beta-oxidation in mitochondria and hence of energy production in the myocardium. Carnitine acetyltransferase provides one of the control mechanisms for this ratio during changing energy demand in the heart muscle, possibly by buffering the CoA and carnitine concentration for sustained beta-oxidation. In search for a possible correlation between the activity of this enzyme and ultrastructural changes in heart mitochondria, carnitine acetyltransferase was cytochemically localised in rat myocardium, brought into different metabolic states. In this work we confirm previous observations, namely the formation of contact sites between inner and outer mitochondrial membranes upon catecholaminergic stimulation of the myocardium. It is further shown that this contact site formation might be a prerequisite for carnitine acetyltransferase to demonstrate enzymatic activity and hence control of beta-oxidation in myocardial mitochondria.

Animals↗
PubMed1994

Effects of surgery and asphyxia on levels of nucleosides, purine bases, and lactate in cerebrospinal fluid of fetal lambs.

During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and ATP becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 +/- 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 +/- 0.03 and a base excess of -17.0 +/- 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that 1) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1993

Role of nucleoside transport inhibition and endogenous adenosine in prevention of catecholamine induced death in rabbits.

OBJECTIVE: R 75,231, a potent and specific nucleoside transport inhibitor, largely prevents cardiac damage and death in catecholamine challenged rabbits. The major biochemical effect of nucleoside transport inhibition in ischaemic and reperfused myocardium is a prolonged accumulation of adenosine. The cardioprotection by R 75,231 may be explained if it can be shown that endogenous adenosine plays a role in catecholamine cardiotoxicity and if nucleoside transport inhibition is required for the cardioprotective effect of R 75,231. METHODS: Several groups of rabbits were infused with catecholamines until death. Changes in survival with time of infusion by coinfusion of aminophylline and/or treatment with R 75,231 and its two stereoenantiomers were assessed. RESULTS: Treatment with R 75,231 postponed the time to reach 50% mortality threefold after challenge with adrenaline or noradrenaline. Draflazine, the (-)-enantiomer of R 75,231, was also effective, whereas the (+)-enantiomer, which is devoid of any effect on the transporter, was not cardioprotective. The cardioprotective effect of R 75,231 was dependent on the extent and duration of ex vivo inhibition of the transporter in blood. Co-infusion of aminophylline with adrenaline significantly accelerated the rate of mortality. CONCLUSIONS: Nucleoside transport inhibition is the major, if not the only, determinant for efficacy of R 75,231 and draflazine as cardioprotective agents. Taken together with the evidence for a role of endogenous adenosine, the benefit from nucleoside transport inhibition in this model may be the result of prolonged accumulation of endogenous adenosine.

Adenosine↗
PubMed1993

Metabolic and functional effects of the nucleoside transport inhibitor R75231 in the ischaemic and blood reperfused rabbit heart.

OBJECTIVE: The ability of R75231, a nucleoside transport inhibitor, to influence adenine nucleotide metabolism and enhance postischaemic functional recovery was assessed in the blood perfused rabbit heart. METHODS: Hearts (n = 8 per group) from donor animals were excised and perfused with blood at 37 degrees C from a support rabbit. After 20 min of aerobic perfusion hearts were arrested with St Thomas' Hospital cardioplegic solution (2 min at 37 degrees C) and rendered globally ischaemic for 60 min. This was followed by 60 min of reperfusion. R75231 (0.1 mg.kg-1, intravenously) was given to donor and support rabbits 1 h before the experiment, control rabbits receiving the same volume of vehicle. RESULTS: Treatment with R75231 resulted in a 45% reduction in coronary vascular resistance in aerobically perfused control hearts, an effect that was absent during postischaemic reperfusion. Thus, before ischaemia, coronary flow was greater in R75231 treated hearts [6.6(SEM 0.8) ml.min-1] than in controls [4.3(0.6) ml.min-1; p < 0.05] but during reperfusion no significant difference was observed [4.0(0.6) v 3.6(0.3) ml.min-1]. The mean time to onset and extent of contracture during ischaemia was similar in R75231 treated and control groups, at 42(4) v 41(4) min and 27(3) v 26(6) mm Hg, respectively. Left ventricular developed pressure recovered to approximately 50% of its preischaemic value during the first 40 min of reperfusion in both groups; however, after longer durations of reperfusion, it tended to deteriorate in the R75231 treated group whereas it was maintained at a constant level in the controls [37(10) v 53(6) mm Hg, respectively; NS]. At the end of reperfusion, tissue adenosine content was 13-fold greater in the R75231 treated group, at 0.40(0.09) v 0.03(0.01) mumol.g-1 dry wt in controls; p < 0.05; the nucleotide pool, nicotinamide adenine dinucleotide phosphate content, and the energy charge potential were similar in groups. CONCLUSIONS: R75231 decreased coronary vascular resistance and increased coronary flow during aerobic perfusion in control hearts, an effect that was lost after ischaemia and reperfusion. R75231 also increased greatly the tissue content of adenosine but, despite this, failed to improve either the recovery of cardiac contractile function or the replenishment of the adenine nucleotide pool.

Adenine Nucleotides↗
PubMed1993

The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs.

1. The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs. 2. In closed chest pigs (n = 4), R75231 exerted a moderate dose-dependent decrease in mean arterial blood pressure (from 97 +/- 4 mmHg to 95 +/- 4, 90 +/- 1 and 83 +/- 2 mmHg at 25, 50 and 100 micrograms kg-1 respectively) and produced a dose-related shift to the left of the blood pressure dose-response curve to intravenous bolus doses of adenosine. The degree of inhibition of adenosine uptake by R75231, assessed ex vivo in erythrocyte suspensions, was 43 +/- 5%, 64 +/- 13 and 114 +/- 15% at doses of 25, 50 and 100 micrograms kg-1 respectively. 3. In open chest pigs, intravenous injection of R75231 (50 micrograms kg-1; n = 6 and 100 micrograms kg-1; n = 10) induced a dose-related decrease in both systolic and diastolic arterial blood pressure which was more marked than in closed-chest pigs (mean pressure 86 +/- 4 to 70 +/- 2 mmHg and 88 +/- 6 to 60 +/- 6 mmHg with 50 and 100 micrograms kg-1 respectively), without affecting heart rate or myocardial contractility. Coronary artery occlusion in these pigs caused a secondary decrease in blood pressure. This was not observed in controls (n = 10). The lower dose of R75231 did not exert any antifibrillatory effects, whereas the higher dose significantly reduced the incidence of ventricular fibrillation, from 80% in control pigs to 30%. Neither dose modified the incidence of ventricular tachycardia (33% and 40% with 50 and 100 microg kg-1 respectively, compared to 30% in controls) or had any effect on the total number of ventricular ectopic beats (85 +/- 47 and 130 +/- 31 vs 110 +/- 19 in controls). R75231, at a dose of 100 microg kg-1, also attenuated the ischaemia-induced shortening of QRS-interval, but neither dose modified the ST-segment depression seen following occlusion.4. These results show that the nucleoside transport inhibitor, R75231, exerts an antifibrillatory effect ina model of severe myocardial ischaemia in a dose which completely inhibits adenosine uptake ex vivo.However, while this agent has minimal haemodynamic effects in closed chest animals, the reduction in blood pressure induced by R75231 in open-chest pigs cannot be excluded as a possible contributory mechanism of the antiarrhythmic effects of this drug.

Adenosine↗
PubMed1993

The effect of adenosine transport inhibition on cardiovascular function and survival after severe asphyxia in fetal lambs.

When the energy demand exceeds the energy supply, anaerobic metabolism takes over and the ATP catabolite adenosine is generated. Adenosine acts as a coronary vasodilator, thereby increasing the oxygen supply to the heart. Its potential, however, is poorly exploited due to extensive catabolism. R-75231 inhibits transport of adenosine into endothelial cells, where it is catabolized, resulting in an elevation of interstitial adenosine concentrations. In 14 fetal lambs (3 to 5 d after surgery, gestational age 124.1 +/- 1.1 d), seven fetuses were pretreated with R-75231 (0.1 mg/kg estimated fetal weight as a bolus injection in the inferior vena cava), whereas the other seven served as controls. After 1 h of severe asphyxia, induced by restriction of uterine blood flow, those fetuses treated with R-75231 showed a faster normalization of aortal pH and, in contrast to the control group, did not develop tachycardia. The percentage increase in myocardial blood flow during asphyxia, measured with radioactive microspheres, was significantly higher in the R-75231-treated group compared with the control group (437 and 284%, respectively). In the control group, only three fetuses recovered and survived, whereas in the R-75231 group, all seven animals recovered after severe asphyxia. It is concluded that fetal lambs pretreated with R-75231 before the onset of severe asphyxia have an enhanced increase in myocardial blood flow during asphyxia, recover faster, and survive longer.

Adenosine↗
PubMed1993

Influence of superoxide dismutase on reperfusion injury in donor hearts preserved with Bretschneider-HTK cardioplegic solution.

The ability of superoxide dismutase to prevent reperfusion injury after long-term cold storage of donor hearts was evaluated in canine hearts. Whole blood reperfusion was performed using a 'support animal'. Twelve dog hearts were arrested by a single dose of Bretschneider cardioplegic solution and stored cold (0.5 degrees C) for 24 h. Thereafter they were reperfused for 60 min without (n = 6) or with (n = 6) superoxide dismutase treatment. Myocardial tissue biopsies were taken for determination of high-energy phosphates before explantation, after the preservation period and during reperfusion. Early reperfusion in both groups resulted in an initial recovery of high-energy phosphates and was followed by a decrease during the subsequent reperfusion phase. The latter was associated with the appearance of left ventricular contracture, and cessation of heart beat. Electron microscopic examination of the myocardial tissues after reperfusion revealed a severe reperfusion injury in both groups. It is concluded, that in donor hearts preserved with Bretschneider solution, reperfusion injury cannot be prevented by administration via the perfusate of superoxide dismutase.

Animals↗
PubMed1992

Successful transplantation after long-term preservation of dog hearts.

Nucleoside transport inhibition is a new approach to long-term preservation of donor hearts. To evaluate its effectiveness, the following were tested: 1) the effect of nucleoside transport inhibition on high-energy phosphate content after cardioplegic arrest and during long-term cold storage (group I: cardioplegia, control ]n = 18]; group II: cardioplegia plus nucleoside transport inhibitor [n = 18]); 2) the effect of nucleoside transport inhibition on high-energy phosphates and hemodynamic recovery in a modified blood-perfused Langendorff system (group III: 24-h cold storage followed by reperfusion [n = 6]; group IV: addition of nucleoside transport inhibition to cardioplegia but not during reperfusion [n = 6]; group V: addition of nucleoside transport inhibition during reperfusion [n = 6]; group VI: addition of nucleoside transport inhibition to cardioplegia and during reperfusion [n = 6]); and 3) the effect of nucleoside transport inhibition added to cardioplegia and during reperfusion on high-energy phosphate content and outcome after heart transplantation (group VII: no nucleoside transport inhibitor in cardioplegia and during reperfusion [n = 8]; group VIII: addition of nucleoside transport inhibition to cardioplegia and during reperfusion [n = 8]). The following results were obtained: 1) addition of nucleoside transport inhibition prevented high-energy phosphate depletion during cold storage: after 24 h, adenosine triphosphate content in group I was 9.4 +/- 3.1 mumol/g versus 17.7 +/- 3.6 mumol/g dry weight in group II (P less than 0.05); 2) addition of nucleoside transport inhibition to cardioplegia and during reperfusion resulted in greater high-energy phosphate content (adenosine triphosphate in group III was 7.9 +/- 3.5 mumol/g vs. 17.8 +/- 2.8 mumol/g in group VI [P less than 0.05]) and improved hemodynamics upon reperfusion (hearts in group III did not recover, maximum isometric left ventricular pressure development was 1,635 +/- 577 mmHg/sec in group IV, 1,915 +/- 423 mmHg/sec in group V, and 2,437 +/- 201 mmHg/sec in group VI [P less than 0.05, group VI vs. groups IV and V]); and 3) hearts treated with nucleoside transport inhibition in cardioplegia and during reperfusion (group VIII) could be transplanted successfully in contrast to group VII hearts. These data indicate that nucleoside transport inhibition in dogs is highly effective in long-term preservation of donor hearts.

Adenosine↗