Miles P Maxwell

Sustained limitation of myocardial necrosis 24 hours after coronary artery occlusion: Verapamil infusion in dogs with small myocardial infarcts

Studies were undertaken to ascertain whether verapamil infusion affords a sustained limitation of myocardial injury in the dog after a 24-hour period of coronary artery occlusion. Regional myocardial ischemia was induced by an embolization procedure which did not involve thoracotomy. Immediately after embolization radioactive microspheres were administered intraventricularly to define any area of myocardial underperfusion (zone at risk of infarction). Verapamil (0.005 mg/kg/min) was then administered and maintained for 24 hours during which time the dogs were allowed to recover from anesthesia. The control group received a corresponding infusion of saline solution. After 24 hours the dogs were killed and transverse myocardial sections (3 mm) were prepared. The resulting area of necrosis was visualized by tetrazolium staining, and risk zones were visualized by autoradiography. In the control heart, 62 +/- 7% of the zone at risk deteriorated to necrotic tissue, whereas in the verapamil-treated group only 18 +/- 4% of the tissue in the zone at risk became necrotic. Verapamil appeared to exert a significant (p less than 0.001) tissue-sparing effect that was sustained for at least 24 hours after the onset of ischemia.

Inability of desferrioxamine to limit tissue injury in the ischaemic and reperfused rabbit heart.

The role of iron-catalysed hydroxyl radical production in development of myocardial injury was examined in an in vivo rabbit heart with regional ischaemia (45 min) and reperfusion (3 h). Open-chest anaesthetised rabbits were assigned to control (saline) or desferrioxamine-treated [30 mg/kg subcutaneously (s.c.) plus 1, 10, 20, or 100 mg/kg/h intravenously (i.v.) starting 15 min before ischaemia] groups. Haemodynamics and ECG were monitored throughout. Following reperfusion, hearts were excised and perfused in vitro with buffer. The artery was religated, and fluorescent particles were injected to delineate the ischaemic zone. Tetrazolium staining was used to define necrosis. Planimetry was performed on photographed heart slices for calculation of the size of the hearts and of the ischaemic and infarcted zones. Infarct size (as a percentage of ischaemic zone size) in control hearts was 51.2 +/- 5.8% (n = 10) and in the groups treated with desferrioxamine 1, 10, 20, and 100 mg/kg/h it was 53.1 +/- 11.7% (n = 8), 45.3 +/- 6.3% (n = 9), 65.1 +/- 10.1% (n = 6), and 52.5 +/- 9.4% (n = 7), respectively (p = NS vs. control in each instance). In addition, no antiarrhythmic effects were observed at any dose. Thus, iron-catalysed hydroxyl radical damage may not play a role in the pathogenesis of tissue injury under these conditions.

Inability of Metoprolol to Achieve a Sustained Limitation of Infarct Size 24 h After Coronary Artery Embolization in the Closed Chest Dog

Studies were undertaken to ascertain whether metoprolol, a beta 1-selective adrenergic blocking agent, could offer a limitation of myocardial injury throughout a 24-h period of coronary embolization in the dog. Regional myocardial ischaemia was induced through the use of a bead embolization technique which did not require thoracotomy. In order to delineate the zone at risk of infarction (hypoperfused area), radioactive microspheres (141Ce) were administered intraventricularly immediately after embolization. In the drug-treated group (n = 8) metoprolol administration was initiated by an intravenous bolus injection (0.3 mg X kg-1). This was followed by a continuous infusion (0.003 mg X kg-1 X min-1) during the 24-h experimental period. In the control group (n = 8) saline was administered throughout the 24-h period. Electrocardiographic activity was monitored throughout the experiment and this confirmed the negative chronotropic and antiarrhythmic properties of metoprolol. After 24 h, the hearts were excised and transverse myocardial sections (3 mm) prepared. Areas of necrosis were visualized by tetrazolium staining and risk zones were defined by microsphere autoradiography. In the control and metoprolol-treated groups, 73.3 +/- 7.7% and 68.2 +/- 6.1% of the risk zone became necrotic, respectively. There was no significant difference between these groups.

Selective 5-lipoxygenase inhibitor BW A4C does not influence progression of tissue injury in a canine model of regional myocardial ischaemia and reperfusion

The effects of BW A4C, a selective arachidonate 5-lipoxygenase (5-LO) inhibitor, on the progression of myocardial tissue injury were examined in anaesthetised, open-chest beagle dogs subjected to 90-min occlusion of the left anterior descending coronary artery (LAD)) followed by 120-min repertusion. Regional myocardial blood flow (RMBE, microspheres), segment shortening (sonomicrometry, and infaret size (tetrazolium stain) as an index of tissue injury were measured. Control animals (group I. n - 11) received an infusion of vehicle [50 vol vol glveofurol and distilled water, 47 ml at 12 mlh, intravenously (i.v)] beginning 15 min before ischaemia and continuing until the end of reperfusion. Treated animals received either 10 (group 2.n - 11 or 50 μg kg ‘min’ (group 3.n) BW A4C iv, in the same period. The infaret risk zone ratio (IR) in group I (24.1 ± 6.0 ±) was not significantly different from that of group 2(28.0 ± 8.4± or group 3 (46.1 ± 6.7). The close inverse relationship ohserved in controls between 1 R ratio and collateral flow was not altered by either dose of BW A4C. Segment shortening during ischaemia 0.2 ± 2.7. 2.4 ± 1.7, and 1.5 ± 1.7) and reperfusion (4.9 + 2.8. 1.0 + 1.8. and 1.0 + 1.9 and during an isoprenaline infusion to unmask stunned myocardium (14.7 ± 3.0, 14.7 + 2.6, and 7.4 + 1.7) were not significantly different between groups 1.2. and 3. Plasma levels of BW A4C reached steady state by 45 min of ischaemia at both doses and in both group 2 (0.52–0.72 μg ml) and group 3 (1.55–2.13 μg ml were above the IC50 value for 5 LOs inhibition. Thus. a selective inhibitor of 5 LO. BW A4C, did not influence progression of myocardial tissue injury in this experimental model although plasma levels were above the IC3p value for 5-LO inhibition. These results cast doubt on the role of the products of 5-LO in propagation of myocardial necrosis after ischaemia.

Verapamil and nifedipine limit infarct size in the dog

We studied the ability of two calcium antagonists, nifedipine and verapamil, to limit infarct size in the closed-chest, coronary-embolized dog. Immediately after embolization, 141Ce-labeled microspheres were administered into the left ventricle. Myocardium not receiving microspheres was considered to be the region at risk. The nifedipine group received 16 micrograms/kg, i.v., over 8 min as a loading dose, followed by continuous infusion (0.04 mg/kg per 24 hr) within 10 min after embolization. The verapamil group received a 0.2 mg/kg bolus over 2 min, followed by a continuous infusion of 8 mg/kg per 24 hr. Again, the drug was started within 10 min of embolization. The control groups received an equal volume of saline. At 24 hr after embolization, the dogs were sacrificed, the hearts were sectioned into 3-mm slices, and the slices were stained with tetrazolium to reveal the infarct. The region at risk was determined by autoradiography of the microspheres in the heart slices. Infarct and risk-zone volume were determined by planimetric methods. Infarct size was normalized by expressing it as a percentage of the region at risk. Nifedipine significantly reduced this percentage when compared to matched controls (38.7 +/- 4.7 vs. 79.5 +/- 4.3%, p less than 0.001). Similarly, verapamil also reduced infarct size (18.0 +/- 4.4 vs. 62.0 +/- 7.4%, p less than 0.001). We conclude that both these drugs appear to offer protection in the presence of permanent coronary occlusion.