Factors that determine the wide variation in the severity of isoproterenol-induced myocardial necrosis (ISO-MN) are numerous and poorly defined. We have investigated the role of age, body weight, food intake, and genetic strain differences on vulnerability to ISO-MN in rats. The proportion of apical myocardium that became necrotic after administration of toxic doses of isoproterenol was used as the index of ISO-MN. Sprague-Dawley (SD) rats of 8 to 10 and 16 to 18 weeks of age had 3.4 and 3.3 fold more severe apical myocardial lesions respectively than 5- to 6-week-old rats. Among Zucker rats of 8 to 9 weeks of age there was 5.2 times more necrosis in obese than in lean animals. Fifty percent food restriction for one week, or 24 hours of fasting in 8- to 10-week-old SD rats led to a 50% reduction in the area of necrosis compared to ad lib fed controls. Under similar conditions 16- to 18-week-old rats showed a similar reduction with 24-hour fasting, but 50% food restriction had no effect. Similarly, food restriction had no effect in 5- to 6-week-old SD or obese Zucker rats. Feeding of diets containing lard, or olive, corn, or fish oils for one week had no significant effect on ISO-MN in SD rats. These results suggests that age, obesity, and food intake alter vulnerability to ISO-MN.