Treatment of reperfusion injury with intracoronary calcium channel antagonists and reduced coronary free calcium concentration in regionally ischemic, reperfused porcine hearts

Abstract

The effect of intracoronary diltiazem, EGTA (ethylene-bis-(beta-aminomethylether)-N,N'-tetraacetic acid), nifedipine, verapamil and isotonic saline solution as placebo on reperfusion injury was investigated in regionally ischemic, reperfused porcine hearts. The left anterior descending coronary artery was distally occluded for 45 min and was reperfused for 3 days. Intracoronary infusion was started immediately before reperfusion and continued during 45 min of reperfusion. Infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). Regional systolic shortening was assessed by sonomicrometry. Apart from left ventricular end-diastolic pressure before ischemia and during 45 min of reperfusion, global hemodynamic values in the five treatment groups did not differ; in particular, calculated left ventricular oxygen consumption before and during ischemia was equally low. Intracoronary EGTA decreased coronary venous free calcium concentration to about 70% of baseline value. Infarct size was reduced from 76 +/- 10% (control group, n = 8) to 60 +/- 10% (p less than 0.01) by intracoronary diltiazem (n = 8) and to 55 +/- 15% (p less than 0.01) by intracoronary EGTA (n = 8). Insignificant reductions in infarct size were found after treatment with intracoronary verapamil (63 +/- 18%, n = 8) and intracoronary nifedipine (68 +/- 9%, n = 7). Regional systolic shortening of the risk region, which did not differ among the groups before occlusion and during ischemia, recovered to the greatest extent in the EGTA-treated pigs (p less than 0.01 compared with values in the control group). Treatment with intracoronary calcium antagonists resulted in only marginal improvement of systolic shortening.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural evaluation of postischemic cell death (lethal reperfusion injury) in porcine hearts

“…Anesthesia, medication, and general surgical procedures have been described in detail in previous studies [3,10]. Twelve male and female farm pigs (Department of Agriculture, University of GSttingen, FRG), weighing 38-47 kg, were used.…”

“…Indirect evidence for the existence of postischemic cell death has come from studies that demonstrated that the administration of different agents at the time of reperfusion aimed to scavenge oxygen free radicals [1], improve perfusion [2], lower coronary free calcium [3], or inhibit the contractile apparatus [4] were able to reduce infarct size in different species by 28-75%. However, many of the positive studies have been questioned by negative findings [reviewed in [5][6][7].…”

Reperfusion Damage ― A Story of Success, Failure, and Hope ―

“…28 When tested in larger animal preparations, calcium antagonists decreased infarct size. 29 Despite this evidence, the results of the corresponding clinical trials have been unequivocally negative, irrespective of whether the calcium antagonists were administered before, during or after ischemia. 30, 31 Another possibility of reducing calcium overload is to inhibit the sodium-hydrogen exchange.…”

Detection of apoptosis in patients with coronary artery disease : Assessment of temporal patterns and potential sources

“…At the time of myocardial reperfusion, there is an abrupt increase in intracellular Ca 2+, secondary to sarcolemmal membrane damage and oxidative stress-induced dysfunction of the sarcoplasmic reticulum. These two forms of injury overwhelm the normal mechanisms that regulate Ca 2+ in the cardiomyocyte, a phenomenon termed the calcium paradox [127]. The result is intracellular and mitochondrial Ca 2+ overload, inducing cardiomyocyte death by causing hypercontracture of the heart cells.…”