Enhanced oxidative stress impairs cAMP-mediated dilation by reducing Kv channel function in small coronary arteries of diabetic rats.
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+ (Kv) 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 Kv 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 Kv channel activity.
Bubolz
Aaron H
AH
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Li
Hongwei
H
Wu
Qingping
Q
Liu
Yanping
Y
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology*; D000242:Cyclic AMP / Q000096:biosynthesis / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D008297:Male; D018715:Microscopy, Video; D009119:Muscle Contraction / Q000187:drug effects; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000975:Antioxidants; D001786:Blood Glucose; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013481:Superoxides; D005576:Colforsin; D015761:4-Aminopyridine; D000242:Cyclic AMP; D019255:NADPH Oxidases