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Enhanced oxidative stress impairs cAMP-mediated dilation by reducing K_v channel function in small coronary arteries of diabetic rats

¹Department of Medicine and the ²Cardiovascular Center, The Medical College of Wisconsin, Milwaukee, Wisconsin; and ³Heart and Vessel Diseases Center, Beijing Friendship Hospital, Affiliate of Capital University of Medical Sciences, People's Republic of China

Submitted 12 April 2005 ; accepted in final form 31 May 2005

We have shown that short-term exposure of rat small coronary arteries (RSCAs) to high glucose enhances superoxide (O₂^–·) formation and impairs cAMP-mediated dilation by reducing voltage-gated K⁺ (K_v) channel function. However, it is not clear whether the impairment also occurs in diabetes mellitus (DM), where alternate mechanisms could mask or aggravate vasodilator dysfunction. RSCAs were isolated from control and streptozotocin-induced diabetic rats. Reduced constriction to 4-aminopyridine (4-AP) was observed in RSCAs from DM rats, indicating K_v channel impairment. Forskolin increased 4-AP-inhibitable K⁺ channel open-state probability and whole cell K⁺ current density in coronary myocytes from non-DM rats but had little effect on K⁺ current density in cells from DM rats. Diminished dilation to 8-bromo-cAMP, forskolin, or isoproterenol was observed in DM RSCAs. The attenuated dilation to forskolin or isoproterenol in DM RSCAs was partially restored by application of the superoxide dismutase mimetic manganese[III] tetrakis (4-benzoic acid) porphyrin. Histofluorescence studies using hydroethidine revealed a blockage of O₂^–· generation by the NADPH oxidase inhibitor apocynin in DM RSCAs. Sepiapterin, a precursor of tetrahydrobiopterin, had little effect on hyperglycemia-induced O₂^–· formation. Consistent with the findings from the concurrent fluorescence study, apocynin also partially restored the reduced dilator response to forskolin in DM RSCAs. Forskolin-induced cAMP production was unaltered in DM. We conclude that in diabetes, enhanced O₂^–· formation by activation of NADPH oxidase impairs cAMP-medicated dilation in RSCAs by inhibiting K_v channel activity.

hyperglycemia; superoxide; coronary circulation

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