Pentoxifylline attenuates edema formation in proteolytic enzyme-induced lung injury.

Ex vivo canine lung lobes were exposed to a pancreatic proteolytic enzyme (chymotrypsin) alone or chymotrypsin after pretreatment with a continuous infusion with pentoxifylline. The lobes exposed to chymotrypsin gained 133 g, while the pentoxifylline-treated lobes gained only 65 g (p less than .05) over the 3-h experimental period. These results suggest that pentoxifylline significantly attenuates the lung weight gain associated with chymotrypsin.

Early phosphorus 31 nuclear magnetic resonance bioenergetic changes potentially predict rejection in heterotopic cardiac allografts.

The development of a noninvasive screening test for the detection of cardiac allograft rejection would improve the potential for management of heart transplant recipients. To assess the possibility that changes in myocardial high-energy phosphate metabolism precede frank rejection, 17 beagles received cervical cardiac allografts. Recipients underwent serial phosphorus 31 nuclear magnetic resonance spectroscopy, endocardial biopsy (blindly graded, 0 to 8), and left ventricular pressure measurements starting on the day of surgery. The first (less than 24 hours) spectrum was considered the baseline for all additional studies. The phosphocreatine to inorganic phosphate ratio (PCr/Pi), an index of myocardial bioenergetic supply/demand balance, was determined and expressed as a percentage of baseline of initial and all subsequent spectra. To evaluate the predictive utility of the PCr/Pi ratio, a 50% decrease from baseline was designated as a positive test and was correlated with biopsy-proved rejection (score greater than 3). When PCr/Pi values were compared with the subsequent day's biopsy score, we observed a 91% sensitivity, 90% specificity, and a predictive value of 92%. We conclude that the PCr/Pi ratio is sensitive in predicting heterotopic allograft rejection in its earliest stages. Thus phosphorus 31 nuclear magnetic resonance holds promise for clinical use in the noninvasive diagnosis and monitoring of cardiac rejection.

Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury.

To determine the importance of reperfusion injury and the ability of the free-radical scavenger recombinant human superoxide dismutase (h-SOD) to prevent it, open-chest dogs underwent 90 min of proximal circumflex coronary artery occlusion, and only at the moment of reperfusion received either h-SOD (400,000 IU bolus into the left atrium followed by a 300,000 IU iv infusion over 1 hr) or saline. After 48 hr the surviving animals were killed and measurements were made of the risk region (by postmortem angiography) and infarct size (by gross pathology). All measurements were made by investigators blinded to treatment given, and the code was broken only at the end of the study. Hemodynamic variables and collateral flow during ischemia were similar in the two groups. Infarct size in control animals (n = 8) averaged 22.4 +/- 3.1% of the left ventricle and 52.2 +/- 7.1% of the risk region, compared with 13.3 +/- 0.8% of the left ventricle and 33.6 +/- 2.1% of the risk region in h-SOD-treated dogs (n = 8) (p less than .05). Infarcts in treated animals were not only smaller, but also exhibited a distinctive "patchiness," suggesting protection along vascular distributions. Furthermore, analysis of the relationship between infarct size and collateral flow measured during ischemia in the two groups indicated that protection by h-SOD was greatest in animals with the lowest collateral flows. This study supports the concept that reperfusion of ischemic myocardium results in a separate component of cell damage, presumably linked to the generation of oxygen free radicals on reflow. Since the h-SOD preventable reperfusion component of injury was most pronounced in hearts with the most severe ischemia, scavenging of oxygen radicals at the time of reflow may offer a novel and particularly promising therapeutic approach for the protection of ischemic myocardium.

Protective effect of early and late treatment with nifedipine during myocardial infarction in the conscious dog.

The effect of early and late nifedipine treatment on collateral blood flow and myocardial infarct size was investigated in 24 previously instrumented conscious dogs. Nifedipine was infused intravenously for 5 hr beginning 15 min (n = 9) and 3 hr (n = 6) after permanent occlusion of the midcircumflex coronary artery and compared with early and delayed vehicle treatment (controls; n = 9). Doses of nifedipine (90 to 168 micrograms/hr) were titrated to reduce mean arterial pressure by 5% to 10%. After animals died or were killed 2 to 7 days later, the anatomic risk region, or occluded coronary bed, was defined by postmortem coronary arteriography. The masses of infarct and risk region were measured by planimetry of weighed transverse sections of the left ventricle. Infarct size was smaller (p less than .05) with early and late nifedipine treatment compared with control, both as percent of left ventricle (15.6% and 14.6% vs 21.6%) and as percent of risk region (46.7% and 41.6% vs 65.7%). Collateral blood flow, measured with radioactive microspheres, increased 31% to 50% during 5 hr of nifedipine treatment, but the mean increase was not statistically greater than that seen in controls. Myocardial protection by nifedipine occurred consistently when epicardial collateral flow exceeded 0.40 ml/min/g and the increase after the drug was at least 0.1 ml/min/g. When flows were less than these amounts, however, only about half of the animals demonstrated reduced infarct size. The results suggest that an increase in collateral flow accounts for part of the beneficial effect of nifedipine but that direct mechanisms not mediated by flow may also contribute.