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Metabolic Syndrome

Impaired endothelin-induced vasoconstriction in coronary arteries of Zucker obese rats is associated with uncoupling of [Ca²⁺]_i signaling

Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina

Submitted 7 June 2005 ; accepted in final form 27 September 2005

Although insulin resistance (IR) is a major risk factor for coronary artery disease, little is known about the regulation of coronary vascular tone in IR by endothelin-1 (ET-1). We examined ET-1 and PGF₂-induced vasoconstriction in isolated small coronary arteries (SCAs; 250 µM) of Zucker obese (ZO) rats and control Zucker lean (ZL) rats. ET-1 response was assessed in the absence and presence of endothelin type A (ET_A; BQ-123), type B (ET_B; BQ-788), or both receptor inhibitors. ZO arteries displayed reduced contraction to ET-1 compared with ZL arteries. In contrast, PGF₂ elicited similar vasoconstriction in both groups. ET_A inhibition diminished the ET-1 response in both groups. ET_B inhibition alone or in combination with ET_A blockade, however, restored the ET-1 response in ZO arteries to the level of ZL arteries. Similarly, inhibition of endothelial nitric oxide (NO) synthase with N-nitro-L-arginine methyl ester (L-NAME) enhanced the contraction to ET-1 and abolished the difference between ZO and ZL arteries. In vascular smooth muscle cells from ZO, ET-1-induced elevation of myoplasmic intracellular free calcium concentration ([Ca²⁺]_i) (measured by fluo-4 AM fluorescence), and maximal contractions were diminished compared with ZL, both in the presence and absence of L-NAME. However, increases in [Ca²⁺]_i elicited similar contractions of the vascular smooth muscle cells in both groups. Analysis of protein and total RNA from SCA of ZO and ZL revealed equal expression of ET-1 and the ET_A and ET_B receptors. Thus coronary arteries from ZO rats exhibit reduced ET-1-induced vasoconstriction resulting from increased ET_B-mediated generation of NO and diminished elevation of myoplasmic [Ca²⁺]_i.

insulin resistance; endothelial nitric oxide synthase

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