Many clinical studies report that (n-3) PUFAs decrease the incidence of sudden death in patients with coronary artery disease after myocardial infarction (MI). However, the mechanisms for the beneficial effects of (n-3) PUFAs are unknown. The objectives of the present study were to confirm the findings from clinical trials using an animal model of MI in which dietary intake could be closely controlled and to utilize the model to investigate molecular mechanisms for the beneficial effects of (n-3) PUFAs. Male rats were subjected to coronary ligation to induce MI and were randomly assigned to diets high in (n-6) (58% of lipid) or (n-3) (28% of lipid) PUFAs for 6 mo. A diet high in (n-3) PUFAs was associated with an improvement in 6-mo survival (89.2% vs. 64.9%, P = 0.013) compared with rats consuming a diet high in (n-6) PUFAs (n = 37/group). In a separate study (n = 5 rats/diet group), the (n-3) PUFA diet decreased the (n-6):(n-3) PUFA ratio in plasma (0.6 +/- 0.1 vs. 7.9 +/- 1.8, P < 0.05) and cardiac tissue (0.9 +/- 0.1 vs. 11.8 +/- 1.6, P < 0.05) of rats fed for 4 wk. The increased survival in the (n-3) diet group was associated with decreased cardiac activities of protein kinase A and calcium calmodulin-dependent kinase II by 33-38% (P < 0.05) and a 28% decrease (P < 0.05) in phosphorylation (activation) of the ryanodine receptor calcium release channel. Based upon our results, we speculate that decreased activities of protein kinases induced by diets high in (n-3) PUFAs are associated with a decrease in sudden death after MI in rats.