O'Neill, Mark, Claire E. Sears, and David J. Paterson. Interactive effects of K⁺, acid, norepinephrine, and ischemia on the heart: implications for exercise. J. Appl. Physiol. 82(4): 1046-1052, 1997.We tested the hypothesis that cardiac ischemia uncouples the beneficial interaction among hyperkalemia, acidosis, and raised plasma catecholamines when these chemicals are changed to mimic their exercise levels. Potassium chloride, lactic acid, and norepinephrine (NE) were infused intravenously for 2 min into anesthetized, artificially ventilated, thoracotomized rabbits during either occlusion of the left circumflex artery (3 min; n = 10) or after a period of prolonged ischemia (20 min; n = 7) that led to a small infarction. NE (1 µg · kg¹ · min¹ iv) offset the negative cardiac effects of hyperkalemia (up to 8.7 ± 0.7 mM) and acidosis (arterial pH 7.09 ± 0.03) in normal hearts. Cardiac performance was not significantly depressed by either acute or chronic ischemia before any infusions. However, the protective effect of NE during acute ischemia or after prolonged ischemia with hyperkalemia and acidosis was substantially reduced. These results show that cardiac ischemia attenuates the protective action of NE and increases the depressive effects of hyperkalemia and acidosis. Whether myocardial ischemia amplifies the cardiotoxic effects of hyperkalemia and acidosis during vigorous exercise by attenuating the beneficial effect of catecholamines remains to be determined.