Reperfusion injury after temporary coronary occlusion.

In 24 anesthetized open-chest dogs, we examined the time course of changes in contractile function, diastolic muscle stiffness (sonomicrometry), tissue water content, and ultrastructure after 1 hour of occlusion of the left anterior descending coronary artery and after 2 hours of unmodified reperfusion. One hour of occlusion of the left anterior descending artery replaced active shortening with passive bulging (21.4% +/- 2.9% versus -5.9% +/- 0.9%, p less than 0.05) in the involved segment. There was no increase in either subendocardial water content (78.6% +/- 0.1% versus 79.7% +/- 0.7%) or operative muscle stiffness (2.80 +/- 0.72 versus 2.36 +/- 0.42 mm Hg/mm) after the occlusion period. There were only mild to moderate ultrastructural alterations suggestive of reversible injury. In sharp contrast, reperfusion was associated with a 2.48% increase in subendocardial water content (p less than 0.05), a 42% increase in diastolic muscle stiffness (3.34 +/- 0.42 mm Hg/mm, p less than 0.05), and greater ultrastructural damage. We conclude that myocardial injury is significantly extended with unmodified blood reperfusion after temporary coronary occlusion.

Surgical revascularization of acute evolving myocardial infarction without blood cardioplegia fails to restore postischemic function in the involved segment.

This study determines the additional protection provided by multidose hypothermic potassium blood cardioplegia over cardiopulmonary bypass alone following one hour of coronary occlusion. In 19 anesthetized dogs having an open-chest procedure, the left anterior descending coronary artery (LAD) was occluded for one hour, and this resulted in loss of active shortening in the affected zone (sonomicrometry). Cardiopulmonary bypass was established, and the dogs were divided into two groups based on the mode of reperfusion. In 10 dogs, hearts were arrested for one hour with amino acid-enhanced multi-dose blood cardioplegia; the ligatures were removed prior to the second infusion. In the 9 remaining dogs, the ligatures were removed and reperfusion was initiated with unmodified blood on total vented bypass. Both groups were reperfused for one additional hour. Postischemic levels of adenosine triphosphate (ATP) were comparable in the blood cardioplegia and bypass groups, and subendocardial levels averaged 42.8% and 45.8% of controls, respectively. Levels of creatine phosphate returned to control values. Subendocardial water content was significantly less in the blood cardioplegia hearts than the bypass hearts (79.4 +/- 0.5% vs. 81.5 +/- 0.5%; p less than .05); subendocardial water content in the blood cardioplegia group was not different from controls (78.6 +/- 0.1%). Blood cardioplegia restored significantly more fractional shortening than total vented bypass alone (39.3 +/- 9.8% vs. 6.3 +/- 9.1% of control), despite similarities in postischemic levels of ATP. We conclude that blood cardioplegia allows better myocardial salvage in the setting of evolving infarction. Therefore, attention must be directed to both the conditions (bypass, delivery pressure) and composition (cardioplegia) of reperfusion.

Myocardial protection with blood cardioplegia in ischemically injured hearts: reduction of reoxygenation injury with allopurinol.

Myocellular injury mediated by oxygen radicals potentially limits myocardial protection in ischemically damaged hearts. This damage may be greater with oxygen-carrying blood cardioplegic solutions. A major mechanism of oxygen radical production is the conversion of hypoxanthine to uric acid by xanthine oxidase. In 16 anesthetized dogs, we studied whether adding allopurinol, a xanthine oxidase inhibitor, to blood cardioplegia would improve recovery of left ventricular (LV) performance and oxygen consumption. Millar transducer-tipped catheters and minor axis ultrasonic crystals were placed to assess LV performance by the slope of the end-systolic pressure-minor axis diameter relationships (Emax). Following total vented bypass, the hearts underwent 30 minutes of normothermic ischemia and then hypothermic blood cardioplegia with 1 mM allopurinol (N = 8) or without allopurinol (N = 8). Postischemic LV performance was significantly better with allopurinol than without (49.5 +/- 8.0 versus 17.4 +/- 4.1% of preischemic Emax; p less than 0.004). Postischemic LV oxygen consumption in the beating working state, calculated from LV blood flow (15 microm microspheres) and oxygen extraction, was comparable to preischemic values with and without allopurinol (10.2 +/- 1.2 versus 8.6 +/- 1.2 ml O2/100 gm/min). We conclude that allopurinol enhancement of blood cardioplegia increases myocardial protection in severely ischemic ventricles.

Oxygen-derived free radical scavengers and skeletal muscle ischemic/reperfusion injury.

Total injury in ischemic skeletal muscle is a function of ischemic damage and reperfusion injury. In an attempt to decrease reperfusion injury, we gave the oxygen-derived free radical scavengers allopurinol, superoxide dismutase, or mannitol during reperfusion of canine gracilis muscle made ischemic for 4 hours. We measured muscle O2 consumption (MVO2), and tissue calcium, water, and adenosine triphosphatase (ATP) before ischemia, after ischemia, and at 5 minutes and 60 minutes of reperfusion. The results at 60 minutes showed no improvement in MVO2 or ATP. In fact, ATP was significantly depressed with allopurinol and superoxide dismutase treatment, and tissue edema did not decrease in any of the groups. We conclude that the simple addition of oxygen-derived free radical scavengers during the initial reperfusion of totally ischemic skeletal muscle does not attenuate reperfusion injury.

Antigen-induced B cell apoptosis is independent of complement C4.

Deficiencies in early complement components are associated with the development of systemic lupus erythematosus (SLE) and therefore early complement components have been proposed to influence B lymphocyte activation and tolerance induction. A defect in apoptosis is a potential mechanism for breaking of peripheral B cell tolerance, and we hypothesized that the lack of the early complement component C4 could initiate autoimmunity through a defect in peripheral B lymphocyte apoptosis. Previous studies have shown that injection of a high dose of soluble antigen, during an established primary immune response, induces massive apoptotic death in germinal centre B cells. Here, we tested if the antigen-induced apoptosis within germinal centres is influenced by early complement components by comparing complement C4-deficient mice with C57BL/6 wild-type mice. We demonstrate that after the application of a high dose of soluble antigen in wild-type mice, antibody levels declined temporarily but were restored almost completely after a week. However, after antigen-induced apoptosis, B cell memory was severely limited. Interestingly, no difference was observed between wild-type and complement C4-deficient animals in the number of apoptotic cells, restoration of antibody levels and memory response.

Assessment of accuracy of intraesophageal pH probe in a dog model.

We performed an experiment in dogs in order to assess the accuracy of an intraesophageal pH probe and to examine possible mechanisms for any lack of accuracy. Two pH probes were placed in the esophagus of supine anesthetized dogs and acid was infused in small serial volumes from an infusion tube placed at the gastroesophageal junction. Two general patterns of pH probe responses were seen: (1) neither probe recorded a fall in pH with acid infusion, and (2) both probes recorded a fall in pH, but in a nonsynchronous manner. Changing the relationship of the tips of the probes with respect to the adjacent mucosa caused a fall in the pH recorded by each probe to the pH of the intraesophageal infusate. This and other evidence seen in the pH tracings suggest that mucosal abutment of the probe tips causes a falsely negative pH recording and raises the question of whether such a phenomenon occurs in human studies.

Ticlopidine versus aspirin and dipyridamole: influence on platelet deposition and three-month patency of polytetrafluoroethylene grafts.

In an attempt to establish a specific drug regimen that would retard neointimal fibrous thickening (NFT) and promote patency of small arterial grafts, we studied acute platelet accumulation and 3-month patency of 4 mm polytetrafluoroethylene (PTFE) grafts in dogs treated with oral aspirin (2 mg/kg/day) in combination with dipyridamole (5 mg/kg/day) (ASA/D) or ticlopidine (25 mg/kg/day) (T). After 3 days of treatment, 15 dogs were given indium 111-labeled autologous platelets and then had bilateral femoral artery grafts placed (control, 10 grafts; each drug group, 10 grafts). The calculated graft radioactivity expressed as average counts per 10 minutes +/- standard error of the mean (SEM) was as follows: control = 542,003 +/- 63,991; ASA/D = 135,163 +/- 14,443 (p less than 0.001, Student's t test); T = 104,650 +/- 14,004 (p less than 0.001). Bilateral femoral artery and carotid artery grafts were placed in 15 other dogs (control, 20 grafts; each drug group, 20 grafts). Three months later the 60 grafts were excised and their patency recorded: control = 20% (4 of 20 grafts); ASA/D = 70% (12 of 17 grafts) (p less than 0.01, chi-square analysis); T = 30% (6 of 20 grafts) (p greater than 0.05). Mean anastomotic NFT +/- SEM of each graft was measured with an ocular micrometer: control = 1.6 +/- 0.2 mm; ASA/D = 0.7 +/- 0.2 mm (p less than 0.001, Student's t test); T = 1.3 +/- 0.2 mm (p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)