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St Thomas' Hospital cardioplegic solution is commonly used to arrest hearts during surgery. Pursuing the hypothesis that the cardioprotective properties of adenosine could be a beneficial adjunct to a solution containing high K+ and Mg2+, we tested a low and a high adenosine concentration added to this cardioplegic solution, aiming at improved recovery of function and energy status. We arrested 18 working rat hearts by a 3-minute infusion with the solution without or with 50 microM or 5 mM adenosine. We induced 30 minute stop-flow ischemia at 37 degrees C, followed by 10 minute washout (Langendorff mode) and 20 minute reperfusion (working heart). Control cardioplegia induced electrical arrest in 19.8 +/- 5.5 s. This took 9.1 +/- 0.9* and 12.7 +/- 1.8 s in the presence of 50 microM and 5 mM adenosine, respectively (*p < 0.05 vs no adenosine). During reperfusion a regular electrocardiogram appeared after 1.9 +/- 0.3 minutes in controls, after 1.0 +/- 0.0* and 1.7 +/- 0.2 minutes in hearts treated with low and high-dose adenosine, respectively (*p < 0.05 vs no adenosine). After 20 minute reperfusion, the pressure-rate product had recovered to 65 +/- 17% in controls, and to 107 +/- 11** and 72 +/- 11% of preischemic values in hearts treated with 50 microM and 5 mM adenosine, respectively (**p < 0.05 vs other groups). There was a good correlation between reperfusion function recovery and the postischemic release of creatine kinase, an index for irreversible cellular damage. This association was absent with ATP content, which increased with the adenosine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Controversy exists as to whether hibernating myocardium is ischemic (with evidence of lactate production and ATP breakdown) during sustained coronary hypoperfusion or whether the oxygen supply is balanced by the oxygen requirements of contractile function. To investigate the mechanical and metabolic response to a moderate reduction in regional coronary blood flow, selective coronary perfusion was performed by a carotid-coronary shunt using a small roller pump circuit in six pigs. Flow was reduced for 45 minutes to 40% of base line followed by 2 hours reperfusion at normal blood flow. No hemodynamic changes occurred during flow reduction and reperfusion. Reduction of coronary blood flow to 40% resulted in a reduction in wall motion to 40.8 +/- 6.1% of base line. Two hours of reperfusion resulted in myocardial stunning shown by persistence of wall motion abnormalities (reduction to 64.6 +/- 6.0% of base line) without histologic and electron microscopic evidence of necrosis. The metabolic response to hypoperfusion varied from nil to substantial, measured as nucleotide catabolism and lactate production. We found no correlation between the base line normoxic contractile state and the magnitude of ischemic metabolite efflux. The efflux of lactate, inosine and uridine did not correlate with wall motion at each time during coronary flow reduction. Initial contractile recovery correlated with maximal lactate and uridine efflux during hypoperfusion. The results provide evidence that, in the in-vivo porcine myocardium, moderate coronary hypoperfusion can exist without metabolic evidence of ischemia.

In several species, xanthine oxidoreductase activity seems to be a major source of free radicals in myocardial tissue. Its activity changes during development and aging, at least in the rat heart. Hardly any data are available about its activity in two important diseases, hypertension and hypercholesterolemia, in which the production of free radicals induced by xanthine oxidoreductase activity could play a role. Therefore we measured the activity of xanthine oxidase and dehydrogenase in myocardial tissue of spontaneously hypertensive. Wistar (control hypertensive), Yoshida (hypercholesterolemic) and Brown Norway (control hypercholesterolemic) rats of various ages. Cytosolic fractions were incubated at 30 degrees C, pH 8.3, with 60 microM xanthine, and the formation of urate was measured with high performance liquid chromatography. In the Wistar group, xanthine oxidoreductase activity was relatively constant during aging (about 1.8 U/g protein). In the hypertensive group, the activity increased gradually from 1.7 to 2.3 U/g at 18 months (p < 0.05 compared with Wistar at 18 months). Xanthine oxidase was about twice as high in both groups at 18 months (p < 0.001 compared with 2 and 6 months). The ratio of xanthine dehydrogenase to xanthine oxidase had decreased 42% at this age (p < 0.001). In the Yoshida and Brown Norway groups, xanthine oxidoreductase activity was similar, with a peak at 6 months. These data suggest that the hypercholesterolemic state does not influence xanthine oxidoreductase activity. In contrast, in hypertrophied myocardium, xanthine oxidoreductase activity was higher than in the control, suggesting a different potential for free-radical generation.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of repeated short anoxic or ischemic periods on ATP breakdown and cardiac function remains controversial. To analyze this issue further and to study the regulation of adenine nucleotide breakdown during recurrent cardiac anoxia, we compared two different protocols of intermittent anoxia. Four rat hearts, perfused according to Langendorff, were exposed to 12 periods of anoxia, each lasting 1 minute, with reoxygenation periods of 3 minutes (protocol A). A second group of 8 hearts were made anoxic for 6 periods of anoxia, each lasting 1 minute, followed by 6 periods of anoxia, each lasting 2 minutes, with the same reoxygenation periods (protocol B). Adenosine production was studied with high performance liquid chromatography, ventricular contraction was monitored using a force transducer. During anoxia a substantial vasodilation and immediate fall in strength of ventricular contraction occurred. They were most pronounced during the first anoxic period and during the change from 1 to 2 minute periods of anoxia. Adenosine production was about 1 nmol/min during the first 1-minute anoxic period, decreasing during the following 1-minute anoxic periods. During the first 2-minute anoxic period, a new and much higher adenosine peak was observed (6 nmol/min), decreasing during the following 2-minute anoxic periods. Total purine release followed a pattern similar to that of adenosine. The concentration of ATP at the end of protocol B was 18.5 mumol/g dry tissue, which is significantly lower than that in protocol A (21.6 mumol/g). The results show that ATP breakdown during intermittent anoxia gradually decreases, notwithstanding the presence of substantial amounts of ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

Reports on enhanced nucleotide regeneration by purines during reperfusion are conflicting. We have, therefore, evaluated the effects of inosine or adenine, administered after ischemia, on adenine nucleotide levels and function in isolated rat hearts. The hearts were perfused with a Tyrode solution, containing 10 mM D-glucose, with or without 5 mM pyruvate. After 15 minutes without flow, the hearts were reperfused for 45 minutes with 20 microM purine and 0.5 mM D-ribose. Adenine nucleotide levels tended to recover better in the purine-treated groups. The purines decreased the ATP/ADP ratio by 10-15% (p less than 0.05) if pyruvate was absent. The IMP level in the inosine/glucose group exceeded that in all other groups by a factor of two (p less than 0.001). Inosine increased the adenosine concentration in the effluent sixfold (p less than 0.005). The hypoxanthine concentration rose up to four times following adenine treatment (p less than 0.05). The administration of purine, with or without pyruvate, did not affect mechanical recovery, heart rate or coronary flow. We conclude that inosine and adenine failed to improve cardiac function and hardly affected nucleotide levels in the reperfused heart.