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Biomedical subjects

R Bolli

Publications and source records attributed to R Bolli.

At least 145 records · Page 8Linked to original sources
PubMed1989

Postischemic mechanical and vascular dysfunction (myocardial "stunning" and microvascular "stunning") and the effects of calcium-channel blockers on ischemia/reperfusion injury.

The purpose of this review is to summarize current concepts regarding the sequelae of myocardial ischemia and reperfusion and the effects of calcium-channel blockers. This article will focus on three topics: (1) the phenomenon of postischemic myocardial dysfunction (myocardial "stunning"); (2) the phenomenon of postischemic vascular dysfunction (microvascular "stunning"); (3) the effects of calcium-channel blockers on myocardial ischemia and reperfusion injury.

Animals↗
PubMed1988

Factors that determine the occurrence of reperfusion arrhythmias.

The determinants of reperfusion arrhythmias were investigated in 63 open-chest dogs undergoing a 25-minute coronary artery occlusion followed by reperfusion. Heart rate correlated positively with the occurrence of reperfusion ventricular tachycardia (VT) and ventricular fibrillation (VF). Collateral flow during ischemia (radioactive microspheres) exhibited a strong negative correlation with the incidence of both VT and VF upon reperfusion. Importantly, a sensitive coupling was present, whereby small differences in flow were associated with large differences in rhythm disorders. The rise in intramyocardial CO2 tension (another index of severity of ischemia) was greater in dogs exhibiting reperfusion VT (p less than 0.001) and VF (p less than 0.08); however, this variable was significantly correlated with collateral flow (r = -0.57, p less than 0.01). The size of the occluded coronary bed, determined by postmortem perfusion, was not consistently related to VT; within a given range of occluded bed sizes, the incidence of VT was inversely related to collateral flow. Thus, reperfusion-induced VT is relatively independent of the size of the occluded bed, and is determined primarily by the degree of myocardial hypoperfusion. In contrast, VF did not develop with occluded beds less than 25% of the left ventricular mass; above this critical occluded bed size, its incidence was inversely related to collateral perfusion. Reperfusion VF is therefore determined by the association of a large occluded bed with a poor collateral flow. This study identifies and systematically analyzes three major determinants of reperfusion arrhythmias: (1) the severity of antecedent ischemia, estimated either from the degree of flow reduction or the rise in intramural CO2 tension; (2) the amount of ischemic/reperfused myocardium; and (3) the heart rate. In addition to conceptual interest and clinical implications, the findings have important implications for the design of future studies aimed at evaluating antiarrhythmic interventions in experimental models.

Animals↗
PubMed1988

Participation of mitochondrial proliferation in morphological differentiation of murine mastocytoma cells.

Proliferation of a cold-sensitive cell-cycle mutant isolated from an undifferentiated murine mastocytoma line is reversibly arrested at the nonpermissive temperature of 33 degrees C, and the arrested cells undergo morphological differentiation as expressed by the formation of metachromatic granules. Following transfer of these mutant cells from the permissive temperature of 39.5 to 33 degrees C, a transient increase in both cytochrome c oxidase and DNA polymerase gamma was observed, the ratio of total mitochondrial volume to cell volume nearly doubled within 6 days, and numbers of mitochondrial cross-sections per cellular cross-section as determined in electron micrographs underwent a threefold increase. Addition of chloramphenicol (100 micrograms/ml) to the mutant cell cultures 6 days prior to transfer from 39.5 to 33 degrees C prevented the increase in the ratio of total mitochondrial to cell volume. Furthermore, chloramphenicol markedly inhibited the increase in granule number per cell that normally is observed after transfer of cultures to 33 degrees C or during treatment with 1 mM butyrate, suggesting that mitochondrial proliferation may be an obligatory step in the process of morphological differentiation of these mastocytoma cells.

Animals↗
PubMed1988

Quantitative assessment of left ventricular wall motion by two-dimensional echocardiography: validation during reversible ischemia in the conscious dog.

This study was designed to test the accuracy of echocardiographic radial shortening measurements during variable degrees of regional dysfunction produced by 14 transient (less than or equal to 10 min) coronary occlusions (8 left anterior descending coronary artery, 6 left circumflex coronary artery) followed by up to 24 h of reperfusion in chronically instrumented conscious dogs. Independent measurement of regional myocardial thickening was obtained using epicardial pulsed Doppler probes and served as a standard for comparison. Radial shortening fraction was derived from two-dimensional short-axis views along 12 equidistant radii. Six reference systems from the epicardial and endocardial centers of geometry (centroids) in a fixed or a floating position were explored. In the ischemic zone, percent thickening fraction averaged 22 +/- 5% at baseline, decreased to -4 +/- 4% during occlusion and gradually returned to baseline values after reperfusion. Percent change in radial shortening correlated significantly with percent change in thickening fraction in the ischemic zone. The worst correlation was seen with the floating endocardial centroid (r = 0.68), and the best was observed with the epicardial floating reference (r = 0.91). Moreover, the epicardial floating reference provided narrower 95% confidence limits of radial shortening and less heterogeneity among radii than did fixed reference systems. Thus, compared with an independent standard, echocardiographic measurement of radial shortening from the short axis provided recognition of discrete grades of regional dysfunction induced by transient reversible ischemia. This technique may be amenable for serial assessment of regional function after interventions on the ischemic myocardium.

Animals↗
PubMed1988

Oxygen-derived free radicals and postischemic myocardial dysfunction ("stunned myocardium").

Experimental studies have demonstrated that myocardium reperfused after reversible ischemia exhibits prolonged depression of contractile function ("stunning"), which is associated with various ultrastructural, biochemical, vascular and other functional abnormalities. Clinical observations suggest that stunning occurs in many situations (for example, rest and exercise-induced angina, myocardial infarction with early reperfusion, open heart surgery, transplantation) and thus may contribute significantly to morbidity among patients with coronary artery disease. In recent years an increasing number of studies have provided indirect evidence that postischemic myocardial dysfunction may be mediated in part by the generation of reactive oxygen species, such as superoxide radical (.O2-), hydrogen peroxide (H2O2) and hydroxyl radical (.OH). Thus, it has been shown that the recovery of the stunned myocardium is enhanced by agents that either scavenge oxygen metabolites, such as superoxide dismutase and catalase, N-2-mercaptopropionylglycine and dimethylthiourea, or prevent their generation, such as allopurinol, oxypurinol and desferrioxamine. More recent experiments utilizing electron paramagnetic resonance spectroscopy have directly demonstrated that reperfusion after a reversible ischemic episode is associated with a burst of free radical production. At present, the evidence supporting the free radical hypothesis is suggestive but not conclusive. Definitive demonstration of the role of oxy-radicals will require careful studies measuring the production of these species in conscious animal models of postischemic dysfunction. If confirmed, the free radical hypothesis will provide not only new important insights into the pathophysiology of ischemic injury, but also a rationale for developing clinically applicable interventions.

Animals↗
PubMed1988

Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile.

Myocardial imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile was investigated as a means to assess myocardial infarct size during coronary occlusion and to quantify the extent of salvaged myocardium after coronary occlusion followed by reperfusion. Open chest dogs underwent either a permanent coronary artery occlusion (Group 1, n = 16) or a 2 h occlusion followed by reperfusion (Group 2, n = 15). Animals in both groups were killed 48 h after occlusion. During coronary occlusion, 23 of the 25 dogs that survived the coronary occlusions had abnormal myocardial scintigrams. The scintigraphic perfusion defect size correlated well with the pathologic infarct size (r = 0.85 and 0.95 by planar and tomographic imaging, respectively). The planar scintigraphic defect size, but not the tomographic defect size, overestimated the pathologic size. The planar scintigraphic defect size observed during coronary occlusion was markedly reduced 48 h after reperfusion (24.8 +/- 12.8% to 10.6 +/- 9.7% of the left ventricle, p less than 0.003). The uptake of technetium-99m hexakis 2-methoxyisobutyl isonitrile in the ischemic myocardium increased significantly 48 h after reperfusion (p less than 0.003) and correlated with the increase in regional myocardial blood flow, as assessed by radioactive microspheres (r = 0.83, p less than 0.01). Thus, myocardial imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile allows reliable demonstration of the presence of acute infarction, estimation of infarct size and quantification of the extent of salvaged myocardium after coronary reperfusion.

Animals↗
PubMed1988

Time course and determinants of recovery of function after reversible ischemia in conscious dogs.

The postischemic recovery of contractile function [measured as systolic wall thickening (WT)] was analyzed in 21 conscious dogs undergoing a 15-min coronary occlusion followed by 7 days of reperfusion (REP). Average WT was still depressed 24 h after REP (85% of base line, P less than 0.001) and returned to base line by 48 h. Analysis of individual dogs, however, revealed marked variability, whereby some recovered completely by 1 h of REP and others required up to 48 h. WT recovered completely within 30 min in dogs with collateral blood flow (CBF) greater than 50% of nonischemic zone flow (NZF) but was still impaired at 24 h (P less than 0.05) in those with CBF less than 25% of NZF. There was a close, curvilinear relation between WT during the first 4 h of REP and transmural CBF, which was described best by an exponential equation WT (as percent of base line) = P0-P1e-P2.CBF(as % of NZF) (r2 = 0.92 at 1 h, 0.76 at 2 h, 0.71 at 3 h, and 0.72 at 4 h), where P0, P1, and P2 are regression coefficients. Importantly, the slope of the regression line was very steep at low CBF, implying that even small differences in CBF produce large differences in postischemic function. Heart rate, systolic pressure, and rate-pressure product during ischemia were also related to WT after REP, but when the effect of CBF was taken into account, the influence of these variables became insignificant. The size of the occluded vascular bed did not correlate with postischemic WT. The presence of hypokinesis or akinesis during ischemia was associated with rapid recovery after REP, but there was no relation between ischemic and postischemic dysfunction when dyskinesis was present during occlusion. Thus, on the average, regional function remains depressed for 24 h after a 15-min ischemic episode, but there is considerable individual variability. This variable rate of recovery is determined primarily by the severity of blood flow reduction during ischemia. Systemic hemodynamics may modulate recovery of function indirectly via their effects on ischemic blood flow.

Animals↗
PubMed1988

Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone.

Recent studies suggest that oxygen free radicals may mediate postischemic myocardial dysfunction ("stunning"), but all the evidence for this hypothesis is indirect. Thus, we used electron paramagnetic resonance (EPR) spectroscopy and the spin trap, alpha-phenyl N-tert-butyl nitrone (PBN), to directly investigate whether free radicals are produced after a 15-min coronary artery occlusion and subsequent reperfusion in 30 open-chest dogs. After intracoronary infusion of PBN, EPR signals characteristic of oxygen- and carbon-centered radical adducts were detected in the venous blood draining from the ischemic/reperfused vascular bed. The myocardial release of PBN adducts began during coronary occlusion but increased dramatically in the first few minutes after reperfusion. After this initial burst, the production of radicals abated but did not cease, persisting up to 3 h after reflow. The EPR spectra (aH beta = 2.67-2.79 G, aN = 14.75-15.00 G) were consistent with the trapping by PBN of secondary oxygen- and carbon-centered radicals, such as alkoxy and alkyl radicals, which could be formed by reactions of primary oxygen radicals with membrane lipids. There was a linear, direct relationship between the magnitude of PBN adduct production and the degree of ischemic flow reduction. Recovery of contractile function (measured as systolic wall thickening) after reperfusion was greater (P less than 0.05) in dogs given PBN than in controls. This study demonstrates that reversible regional myocardial ischemia in the intact animal is associated with prolonged free radical generation, and that the intensity of such generation is related to the severity of ischemia. The results provide direct evidence to support the hypothesis that reactive oxygen metabolites contribute to the persistent contractile dysfunction (myocardial stunning) observed after brief ischemia in vivo.

Animals↗
PubMed1987

Dissociation between global and regional systolic and diastolic ventricular function during coronary occlusion and reperfusion.

Indexes of global ventricular function such as the ejection fraction (EF) and the peak diastolic filling rate (PDFR) are often used to assess the effects of coronary recanalization in patients with myocardial infarction. In this investigation we assessed the relationship between these global indexes and directly measured indexes of regional function during 15 minutes of coronary occlusion followed by 120 minutes of reperfusion in 22 open-chest dogs. A computerized nuclear cardiac probe was used to assess EF and PDFR. Indexes of regional function were measured by Doppler ultrasonic wall-thickening probes. During coronary occlusion, paradoxical systolic thinning occurred and the EF and PDFR decreased an average of 31.6% and 24.4%, respectively. During reperfusion the EF and PDFR improved rapidly and at 60 minutes were similar to baseline. Systolic wall thickening improved more gradually and remained abnormal throughout reperfusion. Likewise, indexes of diastolic function (mean rate to half end-diastolic thinning and late diastolic thinning fraction) recovered slowly and remained abnormal throughout reperfusion (78% and 69.7%, respectively). The correlation between the rate of change of global and regional function was poor during both coronary occlusion and reperfusion. Thus, during coronary occlusion the global and regional indexes of ventricular function undergo directionally similar changes. However, during coronary reperfusion the global indexes do not reflect the slow recovery of the stunned myocardium.

Animals↗
PubMed1987

Effects of exercise tolerance, age, and gender on the specificity of radionuclide angiography: sequential ejection fraction analysis during multistage exercise.

We investigated the factors that determine the left ventricular ejection fraction response to exercise in 57 middle-aged, untrained patients with angiographically normal coronary arteries. The ejection fraction was measured by blood pool radionuclide angiography during each stage of exercise. Stepwise regression analysis was applied to 39 variables, and the resulting significant variables were then included in a logistic regression model to determine which of them would predict a normal ejection fraction response. By stepwise regression analysis, the best model (F = 5.6, p = 0.0004) was obtained by combining four variables: achieving 85% of maximal predicted heart rate, peak heart rate, number of exercise stages performed, and resting pulse pressure. Only the latter two variables were significant by logistic regression analysis. The specificity of greater than or equal to 5 ejection fraction unit increase at peak exercise was 42%, 75%, and 100% in patients who exercised one, two, or three stages, respectively. Furthermore, the increase in ejection fraction during each exercise stage was independent of age or gender. Thus the standard criteria of normality during exercise radionuclide angiography have high specificity only when applied to patients with good exercise performance, regardless of age or gender.

Adult↗
PubMed1987

Activation of the complement system by recombinant tissue plasminogen activator.

Recent trials have shown that recombinant tissue plasminogen activator (rt-PA) is an effective thrombolytic agent in patients with acute myocardial infarction. Because rt-PA converts plasminogen to plasmin, which is known to activate complement in vitro, we tested the hypothesis that rt-PA can induce in vivo activation of complement. Studies were performed in 12 patients with acute myocardial infarction. Six control patients had patent coronary arteries and did not receive rt-PA; these patients had normal values of the components of the complement system C4a (409 +/- 111 ng/ml) and C5a (8.8 +/- 1.8 ng/ml) with a slight elevation of C3a (204 +/- 6.6 ng/ml) in samples collected before coronary arteriography (253 +/- 25 minutes after onset of pain). After coronary arteriography, there was a slight decrease in the values of C4a (224 +/- 37 ng/ml), C5a (7.3 +/- 1.3 ng/ml) and C3a (164 +/- 35 ng/ml). The remaining six patients had complete coronary occlusion and received rt-PA (80 to 150 mg intravenously). In this treated group, before coronary arteriography the values of C4a (406 +/- 51.6 ng/ml) and C5a (8.1 +/- 1.9 ng/ml) were normal, and those of C3a were slightly elevated (250 +/- 76 ng/ml). All complement values obtained before rt-PA were similar to those in the untreated group. However, after administration of rt-PA (but before any angiographically detectable reperfusion), there was a striking increase in C4a (2,265 +/- 480 ng/ml; p less than 0.01), C3a (600 +/- 89 ng/ml; p less than 0.05) and C5a (30.0 +/- 4.5 ng/ml; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1987

End-systolic radius to thickness ratio: an echocardiographic index of regional performance during reversible myocardial ischemia in the conscious dog.

Regional myocardial dysfunction induced by ischemia is associated with less thickening and a larger ventricular radius at end-systole. Thus, end-systolic radius to thickness ratio measured by echocardiography may provide an accurate index of regional left ventricular function that is totally independent of cardiac motion. To test this hypothesis, a total of 14 transient (less than or equal to 10 minutes) coronary artery occlusions (8 left anterior descending, 6 left circumflex) followed by up to 24 hours of reperfusion were performed in six chronically instrumented conscious dogs providing multiple grades of regional ventricular dysfunction. Regional myocardial thickening fraction was determined with epicardial pulsed Doppler probes and served as an independent standard for comparison with simultaneous echocardiographic measurements. End-systolic radius to thickness ratio and radial shortening fraction were derived from the two-dimensional echocardiographic short-axis view along 12 equidistant radii. In the ischemic zone, percent thickening fraction averaged 22 +/- 5% during baseline, decreased to -4 +/- 4% during occlusion with gradual return to baseline after reperfusion. End-systolic radius to thickness ratio averaged 1.39 +/- 0.25 before coronary occlusion and increased to 2.97 +/- 0.48 during occlusion with a gradual return to baseline values. A significant correlation was found between Doppler-determined thickening fraction measurements and echocardiographic end-systolic radius to thickness ratio as well as radial shortening fraction for absolute values (r = -0.83 and 0.75, respectively; n = 65) and percent change from baseline (r = -0.86 and 0.78, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Lipoxygenase inhibitor nafazatrom fails to attenuate postischaemic ventricular dysfunction.

The role of lipoxygenase activation in the genesis of postischaemic myocardial dysfunction was investigated in open chest dogs undergoing a 15 min occlusion of the left anterior descending artery followed by 4 h of reperfusion. Treated animals (n = 9) received nafazatrom, a potent lipoxygenase inhibitor, 10 mg.kg-1 orally 4 h before occlusion followed by intravenous boluses of 1.5 mg.kg-1 and 0.5 mg.kg-1 5 min before occlusion and 1 min before reperfusion respectively. Control animals (n = 10) received saline. No discernible haemodynamic effects were produced by the drug. Collateral flow to the ischaemic zone (radioactive microspheres) was 0.14(0.02) ml.min-1.g-1 in the control group and 0.16(0.05) ml.min-1.g-1 in the treated group. The size of the occluded bed as determined by postmortem perfusion was 25.5(0.8)% of the left ventricle in the control and 24.3(1.3)% in the treated group. Histological examination showed a decrease in neutrophil infiltration of the non-ischaemic myocardium and, to a lesser extent, of the reperfused myocardium in nafazatrom treated animals, suggesting lipoxygenase inhibition. Systolic wall thickening (an index of regional function) was assessed using an epicardial pulsed Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions. Though treated animals showed less dyskinesis during coronary occlusion (p less than 0.05), recovery of function was not enhanced over controls and in both groups the reperfused myocardium was still dyskinetic at 4 h. Thus nafazatrom failed to improve postischaemic ventricular dysfunction, suggesting that leukotrienes do not contribute importantly to this phenomenon.

Animals↗
PubMed1987

Evidence for a pathogenetic role of xanthine oxidase in the "stunned" myocardium.

Recent evidence suggests that postischemic myocardial dysfunction (or myocardial "stunning") may be mediated by oxygen free radicals, but the mechanism for their production remains unknown. To explore the role of xanthine oxidase as a potential source of free radicals, open-chest dogs undergoing a 15-min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received intravenously either allopurinol (50 mg/kg 48 h, 20 h, and 30 min before occlusion, 10 mg/kg 1 min before REP, and 6.25 mg X kg-1 X h-1 throughout REP, n = 13) or saline (n = 14). The two groups were similar with respect to occluded bed size (postmortem perfusion) and collateral flow (radioactive microspheres). In controls, the transcardiac difference in plasma uric acid (great cardiac vein - arterial concentration) increased 199 +/- 70% (means +/- SE) during ischemia (P less than 0.02) and remained elevated for 5 min after REP; no increase was observed in treated dogs. Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. Following REP, however, recovery of contractile function (expressed as percent of preocclusion values) was considerably greater in allopurinol-treated as compared with control dogs: 57 +/- 14 vs. -22 +/- 16 (P less than 0.01) at 1 h, 70 +/- 13 vs. -15 +/- 15 (P less than 0.001) at 2 h, 65 +/- 14 vs. -28 +/- 13 (P less than 0.001) at 3 h, and 68 +/- 13 vs. -17 +/- 14 (P less than 0.001) at 4 h. These differences could not be ascribed to hemodynamic factors. The results suggest that xanthine oxidase is a source of the oxygen free radicals responsible for myocardial stunning following a brief episode of reversible regional ischemia.

Allopurinol↗
PubMed1987

The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction.

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") may be mediated by oxygen free radicals, but the mechanism by which they produce myocellular damage remains unknown. Since iron catalyzes formation of hydroxyl radicals (HO.) as well as HO.-initiated lipid peroxidation, we explored the potential role of this metal in the pathogenesis of myocardial stunning. Open-chest dogs undergoing a 15-min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received the iron chelator desferrioxamine intravenously (10 mg/kg over 45 min beginning 30 min before occlusion, then 1.7 mg.kg-1.h-1 throughout REP, n = 19) or normal saline (n = 17). Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. After REP, however, recovery of contractile function (expressed as percent systolic thickening) as considerably greater in desferrioxamine-treated compared with control dogs: 5 +/- 3 (mean +/- SE) vs. -3 +/- 2% (P less than 0.05) at 1 h, 6 +/- 3 vs. -2 +/- 3% (P less than 0.05) at 2 h, 5 +/- 3 vs. -6 +/- 2% (P less than 0.005) at 3 h, and 6 +/- 3 vs. -6 +/- 2% (P less than 0.002) at 4 h. These differences could not be ascribed to hemodynamic factors. The results suggest that iron-catalyzed reactions (possibly HO. generation) play a significant role in myocardial stunning after a brief episode of reversible regional ischemia.

Animals↗
PubMed1987

The hemodynamic effects of sotalol and quinidine: analysis by use of rest and exercise gated radionuclide angiography.

This placebo-controlled, double-blind trial compared the hemodynamic effects of sotalol and quinidine with the use of rest and exercise gated radionuclide angiography. Patients had frequent ventricular premature depolarizations (greater than or equal to 30 VPDs/hour) and depressed cardiac function (mean ejection fraction 43 +/- 15%). Resting left ventricular ejection fraction and stroke volume index increased (p less than .002, p less than .001, respectively) during sotalol therapy, associated with a concomitant fall in heart rate (p less than .001). Quinidine also increased mean left ventricular ejection fraction, but less so than did sotalol (p less than .05). Quinidine significantly decreased left ventricular end-diastolic (p less than .05) and end-systolic (p less than .002) volumes, but had no effect on stroke volume index or heart rate. Neither drug affected cardiac index. Quinidine resulted in no symptomatic deterioration in left ventricular function or serious arrhythmia aggravation. In contrast, five patients on sotalol developed either decompensated congestive heart failure (two patients), arrhythmia aggravation (two patients), or hypotension associated with bradyarrhythmia (one patient). These patients had a unique hemodynamic profile that can be used to identify patients likely to have a poor outcome on sotalol. This profile reflected a lack of cardiac reserve, characterized by an inability to increase stroke volume and cardiac output with supine bicycle exercise.

Aged↗
PubMed1987

Attenuation of dysfunction in the postischemic 'stunned' myocardium by dimethylthiourea.

The mechanism for the prolonged contractile dysfunction observed in myocardium reperfused after reversible regional ischemia ("stunned" myocardium) is unclear. Recent studies suggest that myocardial stunning may be mediated by oxygen-derived free radicals, but the precise molecular species involved remain unknown. Thus we explored the role of the highly cytotoxic hydroxyl radical in regional postischemic dysfunction by using dimethylthiourea (DMTU), an effective and highly permeable hydroxyl radical scavenger. Open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery followed by 4 hr of reperfusion received either DMTU (0.5 g/kg iv over 45 min starting 30 min before occlusion, n = 14) or saline (n = 15). Control and treated dogs were comparable with respect to variables that may affect postischemic dysfunction, including heart rate, aortic pressure, left atrial pressure, arterial blood gases and hemoglobin concentration, size of the occluded bed (determined by postmortem perfusion), and collateral blood flow (determined by radioactive microspheres). Regional myocardial function was assessed by measuring wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesis during ischemia. After reperfusion, however, wall thickening (expressed as percent of baseline) was considerably greater in treated as compared with control dogs: 53 +/- 9% (mean +/- SEM) vs 9 +/- 14% (p less than .03) at 1 hr, 55 +/- 9% vs 23 +/- 13% (p less than .05) at 2 hr, 60 +/- 9% vs 28 +/- 14% (p less than .05) at 3 hr, and 67 +/- 5% vs 36 +/- 13% (p less than .05) at 4 hr. Thus DMTU produced a significant and sustained improvement in recovery of contractile function. In concentrations greater than the plasma levels attained in vivo, DMTU did not scavenge either hydrogen peroxide or superoxide anion in vitro. These results suggest that the myocardial dysfunction occurring after a brief episode of regional ischemia is mediated in part by the hydroxyl radical.

Animals↗