Previously, we showed that development of myocardial necrotic lesions is associated with impaired endothelium-dependent coronary artery relaxation in young cardiomyopathic hamsters. Since active necrosis declines with aging, this study was designed to determine whether coronary artery endothelium-dependent relaxation to ACh is restored and to identify the mechanisms mediating this effect. Intraluminal diameter was recorded in coronary arteries (150-250 µm) from control (C, 297 ± 5 days old) and cardiomyopathic (M, 296 ± 4 days old) hamsters. Relaxation to ACh (10⁹-3 × 10⁵ M) was similar in vessels from C and M hamsters. However, mechanisms mediating relaxation to ACh were altered. Inhibition of nitric oxide synthase (NOS) activity with N-nitro-L-arginine (1 mM) had a greater inhibitory effect in vessels from C hamsters, indicating a reduction in NOS-dependent relaxation in vessels from M hamsters. Conversely, inhibition of large Ca²⁺-dependent K⁺ (BK_Ca) channels with charybdotoxin (CTX, 0.1 µM) had a greater inhibitory effect in vessels from M hamsters. In the presence of both N-nitro-L-arginine and CTX, relaxation to ACh was abolished in both groups. CTX (0.1 µM) produced a 50 ± 4 and 30 ± 3% contraction of vessels from M and C hamsters, respectively, indicating an enhanced role for BK_Ca channels in regulation of coronary artery tone in M hamsters. Finally, vasodilatory cyclooxygenase products contributed to ACh-induced relaxation in vessels from M, but not C, hamsters. In conclusion, NOS-dependent relaxation of coronary small arteries is reduced in the late stage of cardiomyopathy. An increase in relaxation mediated by BK_Ca channels and vasodilatory cyclooxygenase products compensates for this effect.