Evolving myocardial infarction in the rat in vivo: an inappropriate model for the investigation of drug-induced infarct size limitation during sustained regional ischaemia.

Despite the rat heart having very low collateral flow, there are many reports of pharmacological limitation of infarct size in rats with permanent coronary occlusion. Investigating possible artefacts, cardiac function was measured in isolated rat hearts (n = 12/group) 1, 2, 4, 6, 12, 18, 24, or 48 h after permanent coronary occlusion. In sham operated controls, cardiac output was 63.8 +/- 3.8 ml/min; in rats with occlusion this fell to 37.7 +/- 3.3 ml/min after 1 h of occlusion and did not increase during the 48 h of study. Lumen areas, areas of underperfusion, and minimum wall thickness were unchanged after 4 h of occlusion. Between 4 and 12 h, substantial wall thinning occurred (midinfarct wall thickness decreased from 3.69 +/- 0.24 mm to 2.01 +/- 0.16 mm). After 12 h of occlusion, wall thinning and expansion of the infarct increased lumen volume by three- to fourfold. Wall thinning resulted in a progressive decrease in the volume of the zone of underperfusion (which decreased by almost 30% over 48 h). Tetrazolium negative tissue was not evident in the first 4 h of occlusion but by 12 h, 85.0 +/- 2.6% of the underperfused tissue was necrotic. Gross examination of sections often indicated apparently tetrazolium positive tissue within the zone of underperfusion. Microscopic examination of histological sections revealed this tissue to be necrotic but, in contrast to the tetrazolium negative tissue within the zone of underperfusion, not yet subject to white cell infiltration. "Apparent" infarct size limitation in the rat heart might be due to: (1) incorrect designation of tissue as tetrazolium positive within the severely ischaemic zone of underperfusion; (2) inappropriately equating the zone of underperfusion (measured at the end of ischaemia) to the risk zone (measured at the onset of ischaemia); (3) the possibility that some drugs might affect white cell infiltration, tetrazolium staining characteristics, wall thinning, and tissue remodelling.