Calcium antagonists and evolving myocardial infarction: studies of the effects of nifedipine on tissue ATP, collateral flow and infarct size in the closed chest dog.

In previous studies nifedipine has been shown to limit infarct size during 24 h of regional ischemia in the dog. Using a closed chest embolization procedure, autoradiographic (141-cerium at onset of ischemia) microsphere risk zone analysis and tetrazolium staining, the ability of nifedipine to influence collateral flow, energy metabolism and infarct size over 48 h was assessed in the dog. A second microsphere (46-scandium), which did not interfere with the autoradiography, was given after 48 h of ischemia to allow temporal changes in flow to be assessed. Transmural biopsies, taken after 48 h from non-ischemic tissue, ischemic tissue which had become necrotic and ischemic tissue which had survived (tetrazolium-positive tissue within the risk zone) were assayed for flow, adenosine triphosphate (ATP) and creatine phosphate (CP). The results indicate: nifedipine may still afford some small degree of protection up to 48 h of elapsed ischemia, (infarct size as a percent of risk zone size was 86.1 +/- 3.0 in control vs 70.4 +/- 4.5 in drug group (p less than 0.025 n = 9 in each group), 'salvage' in both the control and the nifedipine-treated groups was predominantly subepicardial and in the transmural plane. The extent and location of salvage and necrosis was determined by the epicardial to endocardial distribution of collateral flow. In tissue which was destined to necrosis (mainly in the subendocardium) collateral flow at the onset of ischemia (7.2 +/- 1.2% relative to surrounding non-ischemic tissue) did not increase over 48 h (8.0 +/- 1.4) whereas in tissue which was 'salvaged' (mainly in the subepicardium) flow was greater (27.4 +/- 3.2%) at onset of ischemia) and increased substantially (to 64.6 +/- 5.9%) over 48 h; nifedipine does not increase the amount of flow per g of tissue in salvaged tissue but rather it may increase the amount of tissue receiving sufficient flow to promote salvage; it follows that in nifedipine-treated animals more flow is delivered to the ischemic zone; tissue ATP and CP parallel flow and the results support the concept of a critical threshold of flow (approx. 25% at onset of ischemia) below which tissue eventually deteriorates to necrosis and above which tissue is likely to amenable to salvage. However, for sustained survival this flow level must eventually increase to above 40-50%. In conclusion, while nifedipine can achieve a substantial delay in the onset of tissue necrosis, for sustained salvage there must be early and substantial reflow to the tissue.