Functional and metabolic effects of adenosine in cardioplegia: Role of temperature and concentration

Annals of Thoracic Surgery (USA), 1997, 63/2 (449-455)

Background. Addition of adenosine to cardioplegic fluid has been shown to improve myocardial tolerance to ischemia. This study was designed to investigate further this phenomenon to evaluate the dose-response and the temperature dependence of the effect of addition of adenosine to St. Thomas' Hospital cardioplegic solution. Methods. The isolated working rat heart model was used in this study. After the assessment of control function, hearts (6 in each group) were subjected to infusions of cardioplegic solution containing 0.0 (control), 0.1, 5.0, 10.0 or 20.0 mmol/L adenosine followed by 3 hours of ischemic arrest at temperatures of 20degreeC, 10degreeC, or 4degreeC with multidose (3 minutes every 30 minutes) cardioplegic infusion. Results. After ischemic arrest at 20degreeC, the recovery of cardiac output (expressed as percent of preischemic baseline) was 35.4 plus or minus 5.11 (control) 45.0 plus or minus 5.51 (0.1 mmol/L), 53.1 plus or minus 2.9 (5.0 mmol/L), 61.8 plus or minus 3.7 (10.0 mmol/L), and 57.6 plus or minus 2.3 (20.0 mmol/L). Hearts receiving 5.0 to 20.0 mmol/L adenosine had significantly greater recovery of cardiac output thanion;

The effect of glutathione, superoxide dismutase and adenosine triphosphate on venous flap survival

European Journal of Plastic Surgery (Germany), 1996, 19/4 (170-173)

Oxygen-derived free radicals and the energy supply for resynthesis are important factors that affect flap survival. An experimental rabbit model was designed to investigate the effects of the free radical scavengers? glutathione (GSH), superoxide dismutase (SOD), and adenosine triphosphate (ATP-MgCl2), on venous flap survival. Four 4 x 6 cm flaps were elevated in each animal along the axis of the thoraco-epigastric veins. Postoperatively, the agents were administered intravenously and relative flap survival was measured after two weeks. Mean flap survival, using the free radical scavengers, ranged between 76 and 87%, which showed a significant improvement over saline controls (68.73%, p < 0.01). The respective mechanisms of the individual agents are discussed.

The effect of ATP (adenosine triphosphate) on heart function of patients with chronic ischemic heart disease after aortocoronary bypass surgery

ANESTEZIOL. REANIMATOL. (Russian Federation), 1993, -/6 (3-8)

Using thermodilution technique, 110 patients have been examined during aortocoronary bypass surgery. Cardiac output, pump coefficient, cardiac index, stroke index, mean and edge pulmonary pressure, and other parameters of peripheral hemodynamics have been determined. At the end of the operation upon heart function recovery the test patients were administered intravenously a 1% ATP solution at a dose of 0.05 and 0.025 mg/kg/min. In control patients inotropic drugs were not used, cardiac function recovered spontaneously. A thorough clinical analysis of central hemodynamic data in the control and test groups has been performed. A number of positive effects of intravenous 1% ATP solution in the postperfusion period have been revealed. The data obtained indicate that myocardium protection during heart arrest is insufficient and an additional administration of substrates that form energy and recover adequate coronary flow and oxygen consumption is necessary upon heart function recovery in all the cases. The first results of intravenous ATP administration make it possible to consider the above technique absolutely safe and especially useful for the improvement of some central hemodynamic parameters.

Adenosine partially prevents cirrhosis induced by carbon tetrachloride in rats

HEPATOLOGY (USA), 1990, 12/2 (242-248)

Adenosine administration was tested in rats with carbon tetrachloride-induced hepatic fibrosis and was able to partially prevent the enlargement of liver and spleen induced by the toxin. This amelioration of the hepatomegaly was accompanied by a 50% reduction of the liver collagen deposition and preservation of content of glycosaminoglycans. A stimulated hepatic collagenase activity is apparently the mechanism for reduction of collagen accumulation. These effects were associated with a striking improvement in liver function. Adenosine treatment did not modify the late hepatotoxic effect of the carbon tetrachloride; however, the stimulatory effect of the nucleoside on energy state appeared to counteract the drastic decreases in adenine nucleotides, ATP, ATP/ADP ratio and energy charge elicited by the hepatotoxin. Moreover, a possible beneficial action of enhanced hepatic oxygenation caused by the vasodilator properties of adenosine cannot be ruled out. Regardless of the mechanism, adenosine seems to change the cellular response to the injury induced by the hepatotoxin.

Experimental and clinical study on ATP-MgClsub 2 administration for postischemic acute renal failure

CLIN. EXP. DIAL. APHERESIS (USA), 1983, 7/1-2 (37-47)

The present study was undertaken to investigate the effect of ATP-MgClsub 2 on the recovery of renal function following renal ischemia. Bilateral renal ischemia was produced for 90 minutes in dogs. Immediately after the release of ischemia, ATP-MgClsub 2 (50 mumoles/kg) was given intravenously. Serum creatinine and FeNa were measured following the release of ischemia. Renal cellular energy charge, glomerular endothelial thickness and per cent circularity of interstitial cells were measured. Creatinine and FeNa were significantly lower in ATP-MgClsub 2 treated dogs compared to those in saline treated controls. Changes in energy charge, glomerular endothelial thickness and per cent circularity indicated ischemically induced renal cellular edema was reversed with ATP-MgClsub 2 through the improvement of energy metabolism. Taking those experimental data into consideration, ATP-MgClsub 2 was given to 16 acute renal failure patients and 13 patients survived. ATP-MgClsub 2 administration is effective for the treatment of acute renal failure.

Studies on the mechanism of beneficial effects of ATP-MgClsub 2 following hepatic ischemia

AM. J. PHYSIOL. (USA), 1983, 13/5 (R695-R702)

Infusion of ATP-MgClsub 2 following hepatic ischemia significantly improves the survival of animals. To determine the subcellular effects of infused ATP-MgClsub 2 and whether such effects are mediated through vasodilation, global hepatic ischemia in rats was produced for 90 min followed by reperfusion. The rats then received iv 0.5 ml of saline, dopamine, papaverine, or ATP-MgClsub 2. At various intervals following reflow, hepatic mitochondria were isolated. ADP-to-O ratio and respiratory control ratio (RCR) were significantly lower 1 h following reflow, and there was a further decrease in these parameters 3 h after reflow in mitochondria from saline-treated rats. Dopamine and papaverine treatment did not improve RCR, however, ATP-MgClsub 2 treatment resulted in a progressive and significantly higher ADP/O and RCR following reflow. Hepatic ATP levels in saline, dopamine, and papaverine-treated rats were found to be 50% lower 3 h following reflow. However, treatment with ATP-MgClsub 2 resulted in significantly higher ATP levels and energy charge. Hepatic blood flow was markedly depressed 1 h following reflow in the saline-treated rats but was significantly higher in the ATP-MgClsub 2 group. Three hours following reflow, hepatic blood flow decreased further in the saline-treated rats, whereas in the ATP-MgClsub 2-treated rats there was a progressive increase in flow. Dopamine treatment resulted in an initial restoration in flow, however, this, effect was not sustained. Hepatic ultrastructure deteriorated progressively following reflow in the saline-treated rats, however, it was normal in the ATP-MgClsub 2-treated rats 1 h as well as 20 h following reflow. These results lead us to conclude that infused ATP-MgClsub 2 improves mitochondrial and cellular functions either directly or by way of long-term improvement in microcirculation but not through vasodilatation.

Purine metabolism in ischaemic kidney tissue

DAN. MED. BULL. (DENMARK), 1982, 29/1 (1-26)

Acute ischaemia or hypoxia result, in the majority of tissues including kidney tissue, in pronounced metabolic changes. A rapid fall occurs in the tissue content of ATP, due to an inhibition of the oxidative phosphorylation, and with this a falling 'adenylate energy charge': the latter regulates most of the cellular turn-over. The total purine nucleotide and adenine nucleotide content falls slowly owing to a further catabolization to purine nucleosides, purine bases as well as in the organism as a whole, to uric acid. The transformation of hypoxanthine to uric acid does not take place in isolated kidney tissue owing to a very low xanthine oxidase activity. The purine nucleosides and purine bases thus formed are in contrast to purine nucleotides, diffusible and will rapidly pass out of the ischaemic kidney tissue to the blood in connection with reimplantation or to the perfusion fluid during in vitro kidney preservation. This will represent an intracellular loss of purines. It has been found in agreement with the above, that the postischaemic regeneration of adenine nucleotides in rabbit kidney tissue is very slow and dependent only on the prior ischaemic purine loss. The regeneration in kidney tissue appears to occur only as de novo synthesis, which is a process requiring much energy and therefore inexpedient. The accumulation of the purine nucleotide catabolites, hypoxanthine-xanthine in ischaemic kidney tissue has both during normothermia (37degr. C) and hypothermia (4degr.C) been found to be closely correlated to the ischaemic trauma. The wash-out of hypoxanthinexanthine to the perfusate during simple cold-preservation of rabbit kidneys, with subsequent transplantation, has also been found to be a prospective measure of the posttransplantatory functional regenerative ability of the tissue. A prospective measure which would appear applicable to clinical kidney transplantation. The addition of exogenous purines, such as adenosine to purine depleted ischaemic rabbit kidney tissue has been found to stimulate the postischaemic adenine nucleotide synthesis, a fact that appears to prove the existence of a 'biochemical purine deficit' in ischaemic kidney tissue. Definite direct evidence that the ischaemic purine loss is causally related to the ischaemic cell degeneration and with this the existence of an ischaemic 'purine deficit syndrome' is not available at present due to the considerable variation in experimental results. The administration of ATP, adenosine, inosine and allopurinol has, however, in a few investigations, been found to increase ischaemic tolerance in both isolated organs and intact organisms. Adenosine administered to ischaemic rabbit kidneys has been found to have considerable side-effects such as vasoconstriction and possibly disturbance of the cellular RNA and DNA synthesis, factors which make the investigation of exogenous addition of purine less attractive. An inhibition of the membrane bound phosphomonoesterase activity in intact kidneys (rat) in vitro with methyl xanthine (theophylline) has been found to produce a reduction in the ischaemic purine loss, due to an inhibition of the dephosphorylation of the diffusible purine nucleotide monophosphates to diffusible purine nucleosides. In agreement with this, inhibition of phosphomonoesterase during normothermia in a preliminary study has brought about an increase in kidney tissue tolerance to ischaemia. Inhibition of phosphomonoesterase and with this a reduction in the ischaemic purine loss has thus the possibility of providing definite evidence of an 'ischaemic purine deficit syndrome' and may possibly contribute to an improvement in clinical organ preservation.

Alterations in cell function with ischemia and shock and their correction

ARCH. SURG. (CHICAGO) (USA), 1981, 116/10 (1309-1317)

Progressive cell injury occurs with shock and ischemia, beginning with functional changes in the cell and cell membrane. Membrane transport and potential decrease, Nasup + enters and Ksup + leaves cells; Nasup +-Ksup + adenosine triphosphatase is activated, adenosine triphosphate (ATP) is used, and mitochondria are stimulated as increased lactate produces acidosis. Energy and cyclic adenosine monophosphate levels decrease, Casup 2sup + regulation is compromised, and nuclear function and protein synthesis are depressed. The cell swells, and further membrane changes occur with altered hormonal effects and mitochondrial uncoupling. Finally, lysosomes leak, intracellular and mitochondria disruption occurs, and the cell is destroyed. Based on these changes, attempts were made to directly support cell function during low-flow states. After volume replacement and vasoactive agents, other modalities, eg, substrates, membrane-stabilizing solutions, osmotic agents, and energy compounds were used. The use of ATP-MgClsub 2 was helpful in many experimental low-flow states, with an improvement in cell function mediated by microcirculatory, cell membrane, or energy-recycling effects. Clinical examples of altered cell and organ function with ischemia and shock are numerous and play a critical role in the development of multiple systems failure. The potential for biochemical support and correction of these problems is now recognized. Benefits have already been achieved in myocardial preservation during cardiac operations, kidney preservation for transplantation, and circulatory and metabolic support of the injured and septic patient.

Evidence for enhanced uptake of ATP by liver and kidney in hemorrhagic shock

AM. J. PHYSIOL. (USA), 1977, 2/2 (83-88)

It has been shown that infusion of ATP-MgClsub 2 proved beneficial in the treatment of shock; however, it is not known whether this effect is due to improvement in the microcirculation or direct provision of energy or a combination of the above or other effects. To elucidate the mechanism of the salutary effect of ATP-MgClsub 2, the authors have now examined the in vitro uptake of ATP by liver and kidney of animals in shock. Rats were bled to a mean arterial pressure of 40 Torr and so maintained for 2 h. After the rats were killed, liver and kidney were removed and slices of tissue (0.3-0.5 mm thick) were incubated for 1 h in 1.0 ml of Krebs-HCOsub 3 buffer containing 10 mM glucose, 5 mM MgClsub 2, and 5 mM (8-sup 1sup 4C) ATP or 5 mM (8-sup 1sup 4C) ADP, or 5 mM (8-sup 1sup 4C) AMP, or 5 mM (8-sup 1sup 4C) adenosine in 95% Osub 2-5% COsub 2 and then homogenized. Tissue and medium samples were subjected to electrophoresis to separate and measure the various nucleotides. The uptake of (sup 1sup 4C) ATP but not that of (sup 1sup 4C) ADP or (sup 1sup 4C) adenosine by liver and kidney slices from animals in shock was 2.5 times greater than the corresponding uptake by control slices. Thus, the beneficial effect of ATP-MgClsub 2 in shock could be due to provision of energy directly to tissue in which ATP levels were lowered. The acutely ischaemic myocardium rapidly depletes its endogenous reserves of adenosine triphosphate (A.T.P.) and creatine phosphate (C.P.). It releases inorganic phosphate potassium and intracellular enzymes. These biochemical changes are accompanied by structural changes and the initially reversible injury becomes irreversible when the process of energy production can no longer maintain cellular integrity. The effect of artificial elevation of local levels of A.T.P., C.P., and the infusion of methylprednisolone into an area of acutely ischaemic myocardium has been studied in 60 New Zealand white rabbits in vivo. Changes in plasma levels of cardiac enzymes, potassium, inorganic phosphate have been measured along with the rise in the artificial pacing threshold in muJ during the 1-6 hours after coronary ligation. The ultrastructure has been studied after perfusion fixation of the ischaemic myocardium. Significantly improved levels were found in C.P.K. (p<0.001); L.D.H. (p<0.05); Ksup + (p<0.05); inorganic phosphate (p<0.001); and the pacing threshold (p<0.001) at 6 hours after coronary ligation in those animals where A.T.P. was infused locally. Methylprednisolone infusion significantly reduced the release of C.P.K. (p<0.001): Ksup + (p<0.05); and inorganic phosphate (p<0.005). C.P. infusion offered significant improvement 1-4 hours post coronary ligation. The study has shown that an increase in 'local levels of A.T.P.' significantly delays the onset of irreversible injury and offers better protection of ischaemic myocardium than C.P and methylprednisolone.

Exogenous adenosine in cardioplegia

Zeitschrift fur Kardiologie (Germany), 1996, 85/SUPPL. 6 (201-204)

The nucleoside adenosine is used clinically for the treatment of paroxysmal atrioventricular junctional tachycardia. Surgically oriented experimental studies indicate an improvement of myocardial protection when adenosine is administered as an adjunct to cardioplegic protection. This regards both postischemic functional recovery and the regeneration of myocardial energy-rich phosphates. However, as yet it remains to be determined which of the various effects of adenosine is truly protective. Likewise it is still unclear if the beneficial effects of 'ischemic preconditioning' may be simulated by administration of adenosine. Current knowledge about this substance warrants careful evaluation of its protective capabilities in clinical studies during open-heart surgery.