Isoproterenol (ISO), a drug which causes an increased strength of myocardial contraction when administered to animals in mug/kg doses, causes myocardial necrosis when given mg/kg doses. Previous studies suggested that necrosis might be due to flooding of the heart muscle cells by calcium. To determine if this is true, and to distinguish between flooding due to release of Ca from sequestered intramyocardial compartments and increased influx from the blood, we have measured total myocardial calcium ([Ca](m)) after ISO administration. The concentration of myocardial calcium, measured by atomic absorption spectroscopy after dry ashing, increased within 10 minutes of the intraperitoneal injection of ISO in rats. After 10 minutes the [Ca](m) remained constant at its new level for at least 50 minutes if the dose of ISO was 10(2) mug/kg or less but continued to rise at a slower rate than noted during the first 10 minutes if the ISO dose was 10(3) mug/kg or more. As measured 1 hour after ISO administration, the increase in [Ca](m), was proportional to the dose, up to 10(2) mug/kg. At higher doses there was no further increase until the dose exceeded 2 x 10(3) mug ISO/kg. Since the amount of necrosis is proportional to dose from about 10(2) to 10(5) mug/kg, while the changes in [Ca](m) are not proportional to dose over this entire range, it is concluded that ISO-induced myocardial necrosis is not mediated exclusively by flooding of heart muscle with plasma-derived calcium, although this is undoubtedly an important factor. This conclusion was further supported by experiments showing that propranolol, at doses which completely suppressed the increase in [Ca](m) due to ISO, did not completely prevent necrosis.