Search

In a double-blind, randomized, placebo-controlled trial, the possible anti-ischemic effect of metoprolol during percutaneous transluminal coronary angioplasty was tested. Electrocardiograms, hemodynamics, and metabolism were studied in 27 patients with a stenosis in the left anterior descending coronary artery. Measurements took place before angioplasty, after each of four 1-minute occlusions and 15 minutes after the last balloon deflation. Patients were randomly given placebo or metoprolol (15 mg as a bolus intravenously, followed by an infusion of 0.04 mg/kg/hr). At the end of the procedure, the rate-pressure product had decreased by 15% (NS) and 23% (p = 0.001) in the placebo and metoprolol groups, respectively, mainly due to similar decreases in heart rate. Metoprolol tended to lower chest pain and reduce precordial ST-segment elevation due to angioplasty, but the effects were not statistically significant. Lactate, hypoxanthine, and urate release immediately after deflation was similar in both groups. Metoprolol reduced arterial plasma hypoxanthine throughout the procedure by about 30% (p < or = 0.02 vs. placebo). Thus, intravenous infusion of metoprolol did not significantly attenuate chest pain and ST-segment elevation, and failed to decrease cardiac lactate and oxypurine release. It did, however, reduce arterial hypoxanthine concentrations during angioplasty, possibly indicating that the beta-blocker inhibits extracardiac ATP catabolism.

Xanthine oxidase is the pathological form of xanthine oxidoreductase, which generates free oxygen radicals, when it converts (hypo)xanthine to urate. We studied 1. developmental changes in rat heart, 2. urate production in catheterized patients, and 3. species differences of cardiac xanthine oxidase. First, we measured the activity of the enzyme at various ages. In rat-heart homogenate, xanthine oxidoreductase increased from 0.5 mU/g (newborn) to 25 mU/g (15 weeks, P less than 0.001). In the second part of the study, we demonstrated that patients undergoing coronary angioplasty showed some cardiac urate production. In the last part of our investigations we showed that in explanted human hearts perfused with hypoxanthine, the enzymatic activity was low, contrasting findings in some other species. The apparent xanthine oxidoreductase activity (mU/g) was: 33 (mouse), 28 (rat), 14 (guinea pig), 0.59 (rabbit), less than 0.1 (pig), 0.31 (man) and 3.7 (cow). We conclude that in several species, cardiac damage due to xanthine oxidase cannot be excluded; however in man it is unlikely to occur.

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.

Our earlier work on reperfusion showed that adult rat hearts released almost twice as much purine nucleosides and oxypurines as newborn hearts did [Am J Physiol 254 (1988) H1091]. A change in the ratio anabolism/catabolism of adenosine could be responsible for this effect. We therefore measured the activity of adenosine kinase, adenosine deaminase, nucleoside phosphorylase and xanthine oxidoreductase in homogenates of hearts and myocytes from neonatal and adult rats. In hearts the activity of adenosine deaminase and nucleoside phosphorylase (10-20 U/g protein) changed relatively little. However, adenosine kinase activity decreased from 1.3 to 0.6 U/g (P less than 0.025), and xanthine oxidoreductase activity increased from 0.02 to 0.85 U/g (P less than 0.005). Thus the ratio in activity of these rate-limiting enzymes for anabolism and catabolism dropped from 68 to 0.68 during cardiac development. In contrast, the ratio in myocytes remained unchanged (about 23). The large difference in adenosine anabolism/catabolism ratio, observed in heart homogenates, could explain why ATP breakdown due to hypoxia is lower in neonatal than in adult heart. Because this change is absent in myocytes, we speculate that mainly endothelial activities of adenosine kinase and xanthine oxidoreductase are responsible for this shift in purine metabolism during development.

The possible cardioprotective effect of diltiazem during ischemia caused by percutaneous transluminal coronary angioplasty was tested. Electrocardiograms and myocardial lactate, hypoxanthine and urate production were determined in 26 patients with a stenosis in the left anterior descending artery without angiographically demonstrable collaterals. Measurements took place before angioplasty, after each of 4 occlusions and 15 minutes after the last balloon inflation. Patients were randomly given placebo or DL-diltiazem (0.4 mg/kg as a bolus intravenously, followed by an infusion of 15 mg/hr). During angioplasty the ST-segment elevation for the anterior wall leads V2, V4 and V6, and the intracoronary lead was similar for both groups, as was lactate release. Diltiazem significantly reduced cardiac hypoxanthine release immediately after angioplasty from 63 to 88% (p less than 0.05). The drug diminished urate production after the last dilatation by 82% (p less than 0.05). In conclusion, intravenous infusion of diltiazem reduced cardiac adenosine triphosphate breakdown during angioplasty as shown by diminished hypoxanthine and urate production. In contrast, diltiazem was unable to attenuate ST-segment elevation and lactate release.

Xanthine oxidoreductase has been demonstrated in the heart of various species. However, its presence in human heart is still debated. In the literature, high to undetectable levels have been reported. We studied the arterial-venous urate difference across the heart of patients undergoing both routine cardiac catheterization and percutaneous transluminal coronary angioplasty. Urate is the end product of the reaction catalysed by xanthine oxidoreductase. In 10 patients, studied before angioplasty, the plasma urate level in the great cardiac vein exceeded the arterial one by 26 +/- 10 nmol/ml (P = 0.028). In a further 13 patients, urate production was maximal immediately after the last of four consecutive occlusions (23 +/- 8 nmol/ml, P = 0.018) and concomitant with increased coronary sinus hypoxanthine levels. We conclude that xanthine oxidoreductase is probably present in the heart of patients, suffering from ischemic heart disease, and responsible for the increase in urate production during transient myocardial ischemia.

We studied the effect of the calcium entry blocker nisoldipine on ATP catabolism in the rat heart, perfused according to Langendorff. Even 1 nM nisoldipine induced vasodilatation; concentrations of 30 nM and higher caused significant negative inotropy. The drug had a very strong affinity for silicon rubber tubing. Myocardial ischaemia was induced by lowering the perfusion pressure, which reduced flow without nisoldipine by 85%. The efflux of purine nucleosides and oxypurines rose 14 fold. Nisoldipine reduced this efflux of ATP catabolites dose-dependently. The highest concentration, 300 nM, suppressed ischaemic purine production completely. The action of the drug was antagonized by an increase in Ca2+-concentration in the perfusion fluid. We also showed the protective effect of nisoldipine on adenine nucleotides in freeze-clamped hearts. A concentration of 20 nM partially prevented the reduction of ATP and adenylate energy charge due to ischaemia. We conclude that relatively low doses of nisoldipine effectively prevent ATP breakdown in ischaemic rat heart.

Calcium entry blockers seem useful for energy conservation in the ischemic heart. Their exact mechanism of action, however, remains uncertain. In this study we investigated the effect of 30 nM nisoldipine on carbohydrate metabolism in isolated rat heart perfused with glucose-containing medium. Nisoldipine increased flow 1.5-fold and reduced apex displacement 60%. We induced ischemia by lowering the perfusion pressure from 72 to 14 mm Hg, which resulted in a flow reduction in untreated hearts by 80%. Lactate production rose 16-fold, glucose utilization increased fourfold, and the heart glycogen content decreased by 32%. Nisoldipine treatment diminished ischemic lactate release by 77%. It decreased glucose utilization to normoxic levels and reduced glycogen breakdown to a value intermediate to the ischemic and normoxic ones. We conclude that nisoldipine reduces glycolysis in the ischemic heart. Consequently, it appears that the ATP-saving effect of nisoldipine during ischemia, reported elsewhere, is due to a lower energy demand rather than increased ATP production.

Although inosine has been used clinically to support the myocardium, no data are available on the fate of exogenous inosine in the human heart. We therefore infused six patients, catheterised for coronary angiography, with inosine (5 mg.kg-1.min-1 intravenously) for 6 minutes. Before infusion, the arterio-venous difference of inosine, hypoxanthine and xanthine across the heart was nil. During infusion, arterial inosine increased substantially, exceeding the coronary sinus concentration by a maximum of 200 (SEM 53) mumol.litre-1, p = 0.02, at the fourth minute. Arterial hypoxanthine and xanthine also increased, while the arterio-venous difference became 16(11) and 10(3) (p = 0.04) mumol.litre-1, respectively. Left ventricular dP/dtmax increased by 22(7)% (p = 0.04) at the end of infusion. Thus, there seemed to be substantial uptake of inosine by the human heart, followed by improvement in haemodynamics.

Twelve patients with proximal stenosis of the left anterior descending artery, normal myocardial wall motion but without angiographically demonstrable collateral circulation, were studied during transluminal occlusion. Prior to the first transluminal occlusion before crossing the lesion with the balloon, patients were randomly given 0.2 mg nifedipine or its solvent in the left mainstem. The same dose was repeated via the balloon catheter, positioned across the lesion, immediately prior to the second transluminal occlusion. In all patients great cardiac venous flow and ST-elevation were monitored during and after each transluminal occlusion. The lactate extraction ratio A-GCV/A (A = arterial, GCV = great cardiac vein) was determined prior to the angioplasty procedure, 10-15 seconds after each transluminal occlusion and 10 minutes after the third transluminal occlusion. Great cardiac venous flow rose significantly to an average of 160% of basal flow when nifedipine was administered into the mainstem before the angioplasty procedure while its solvent had no effect. During each transluminal occlusion, great cardiac venous flow diminished on average by 30% in those who received nifedipine and by 28% in those who received only its solvent. This difference was statistically not significant. After angioplasty great cardiac venous flow was slightly, but not significantly, increased in both groups with respect to basal flow (104% resp. 120% of control). Patients who received nifedipine in the post-stenotic area just before the second transluminal occlusion, had significantly lower lactate production, measured immediately after the transluminal occlusion compared with the patients who received only its solvent (P less than 0.01). The ST-elevation during the second transluminal occlusion was significantly lower in the nifedipine group (0.1 mm in nifedipine group versus 1.4 mm in solvent group; P less than 0.05, unpaired t-test). Nifedipine given intracoronary in the post-stenotic area just before coronary angioplasty reduces lactate release and electrocardiographic signs of myocardial ischemic injury. This regional cardioprotective effect seems not due to an enhanced collateral flow, but to a regional cardioplegic effect, which precedes the ischemic event.