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Enhanced oxidative stress impairs cAMP-mediated dilation by reducing Kv channel function in small coronary arteries of diabetic rats.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2005 Nov; Vol. 289 (5), pp. H1873-80. Date of Electronic Publication: 2005 Jun 03. - Publication Year :
- 2005
-
Abstract
- 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.
- Subjects :
- 4-Aminopyridine pharmacology
Animals
Antioxidants pharmacology
Blood Glucose metabolism
Body Weight physiology
Colforsin pharmacology
Coronary Vessels drug effects
Cyclic AMP biosynthesis
Male
Microscopy, Video
Muscle Contraction drug effects
NADPH Oxidases antagonists & inhibitors
Oxidative Stress drug effects
Patch-Clamp Techniques
Potassium Channel Blockers pharmacology
Potassium Channels drug effects
Rats
Rats, Sprague-Dawley
Spectrometry, Fluorescence
Superoxides metabolism
Vasodilation drug effects
Coronary Vessels physiopathology
Cyclic AMP physiology
Diabetes Mellitus, Experimental physiopathology
Oxidative Stress physiology
Potassium Channels physiology
Vasodilation physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 289
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 15937095
- Full Text :
- https://doi.org/10.1152/ajpheart.00357.2005