To explore the role of oxygen free radicals produced by the xanthine oxidase pathway on infarct size and left ventricular function, the effect of oxypurinol, an active metabolite of allopurinol and a potent noncompetitive inhibitor of xanthine oxidase, was assessed in a 90 min, closed-chest, canine preparation of occlusion-reperfusion. Animals were randomized to receive 25 mg/kg iv oxypurinol (n = 13) or saline (n = 13) 60 min after occlusion. Regional myocardial blood flow was measured with radioactive microspheres and regional ventricular function with contrast ventriculography. Hemodynamic variables, regional myocardial blood flow, and size of the occluded bed were similar in the two groups. Oxypurinol failed to reduce infarct size 24 hr after reperfusion when expressed as a percentage of the area at risk (36.3 + 4.9% vs 36.0 + 5.6%; p = NS). Both groups exhibited comparative radial shortening at baseline and similar degrees of dyskinesia 1 hr into occlusion ( -6.6 + 1. 2% vs -4.9 ± 1.0%). However, oxypurinol-treated animals demonstrated an improved regional ventricular function at 3 hr after reperfusion (0.7 ± 2.6% vs -2.8 + 2.0%) and a significant improvement at 24 hr (5.4 + 2.5% vs -3.2 + 1.7%; p < .05). A reduced neutrophil infiltrate was observed in the border zone in treated animals. These findings suggest that oxygen free radicals derived from the xanthine oxidase pathway contribute to stunning of reversibly damaged myocardium but do not determine the final extent of myocardial necrosis in a canine preparation of reperfusion. Circulation 76, No. 3, 678-686, 1987. FREE RADICALS are reactive compounds that are toxic to cellular membranes and organelles and that are thought to be involved in the pathogenesis of ischemicreperfusion injury.1, 2Oxygen free radicals have been implicated in the death of potentially salvageable myocardium when blood flow is restored to ischemic areas ("reperfusion injury") and more recently have been shown to contribute to the prolonged left ventricular dysfunction ("myocardial stunning") that occurs in reversibly injured myocytes.38The cellular origin of and metabolic pathways involved in free radical generation in the heart remain speculative. One potential source of the superoxide free radical (2 -) in reperfused myocardium is the enzyme xanthine oxidase, which catalyzes the first irreversible 678step in the degradation of the adenine-based nucleotides.9'0 The effect of allopurinol, a competitive inhibitor of xanthine oxidase, on infarct size after reperfusion has been variable.9 11, 12 However, allopurinol has been shown to improve ventricular function in the ischemic-reperfused canine preparation. 13,14 Oxypurinol is the active metabolite of allopurinol and may be a more potent inhibitor of xanthine oxidase in the setting of ischemia. 1 15, 16The aim of the present study was to assess the effect of oxypurinol administered 60 min after occlusion on infarct size and serial ventricular function in a 90 min canine preparation of occlusion-reperfusion. This duratio...

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The pharmacodynamics of nitroglycerin have been studied in dogs and man. In dogs, intravenous nitroglycerin (TNG) caused a decrease in left ventricular work, myocardial blood flow (MFB), and myocardial oxygen consumption, and no significant change in coronary vascular resistance. Intracoronary artery TNG in dogs caused an immediate increase in MBF and a decrease in coronary vascular resistance that persisted until arterial pressure fell. In man, sublingual TNG (0.4 mg.) caused a decrease in left ventricular work, MBF, and myocardial oxygen consumption, and no significant decrease in coronary vascular resistance in patients with and without arteriographically proven coronary artery disease. The injection of doses of 0.1 to 0.2 mg. of TNG directly into the coronary artery in man caused an immediate increase in MBF and a decrease in coronary vascular resistance in patients with and without arteriographically proven coronary artery disease. The hypothesis proposed for the mechanism of action of TNG in the relief of angina pectoris is first, a decrease in coronary vascular resistance due to its effect on the coronary circulation, and, secondly, a decrease in cardiac work due to its effect on the systemic circulation.

Thromboxane A2 (TxA2), an arachidonic acid metabolite causing vasoconstriction and platelet aggregation, is a putative mediator of coronary-artery vasospasm. To determine whether platelet-released TxA2 causes coronary arterial vasospasm, we measured plasma thromboxane B2 (TxB2, the inactive hydration product of TxA2) in the radial-artery and coronary-sinus blood of seven patients and performed therapeutic trials of antiplatelet agents in nine. Although coronary-sinus TxB2 levels rose from the base line approximately fivefold with spontaneous ischemia, samples drawn early in ischemia showed no rise over base-line values. Although a 150 mg dose of aspirin reduced urinary dinor-TxB2 levels by over 75 per cent, it had no effect on the course of the chronic recurrent form of angina pectoris due to vasospasm ("vasotonic angina"). Similarly, indomethacin had no effect on the frequency or duration of ischemia. TxA2 is unlikely to cause vasotonic angina, but it may be released during coronary vasospasm.

ANGIOCARDIOGRAPHY and cineangiocardiography are employed with increasing frequency for the diagnosis of cardiovascular diseases. These commonplace technics of cardiovascular radiology depend upon the rapid injection of radiopaque materials into the heart or central circulation. A wide variety of substances are in use, but all are hypertonic and some are considerably more viscous than blood. A variety of studies are available to indicate that the hemodynamic effects can be related to chemical structure, -3 but as newer and safer agents have become available it seems clear that the pharmacodynamic effects are related most importantly to the hypertonicity of these compounds. The effects of the injection of oontrast media can therefore be considered to be the effects of hypertonicity on the circulation, and the study of these effects assumes considerable practical importance.Numerous reports are available that deal with the effects of hypertonic (and radiopaque) materials injected into the right heart and pulmonary circulation in animals,4-10 but comparable systematic studies in man are not available. The hemodynamic consequences associated with the injection of radiopaque ma-From the

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The indicator-dilution principle has been employed to study coronary blood flow and the venous drainage into the coronary sinus ( CS) in the dog. Nine open-chest dogs were prepared to allow separate perfusion and flow measurement of the right and left coronary arteries ( RCAand LCA) as well as simultaneous sampling at two sites in the CS. By injecting indicator at various sites in the arterial tree, it has been demonstrated that the posterior circumflex artery drains chiefly to the CS near the CS ostium; the left anterior descending drains chiefly to the area of the CS far upstream from the CS ostium, and the RCA does not drain to the CS. These drainage data have been used to help determine the adequacy of mixing of dye and blood, and to measure LCA flow. Adequate mixing of dye and blood was frequently achieved by the criteria established, but LCA flow was accurately measured with only a minority of injections. It is likely that pecularities of the anatomy of the coronary vascular bed account for the discrepancies.

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