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Abstract
Obesity is an established risk factor for hypertension and associated cardiovascular disease. The mechanisms underlying obesity-induced hypertension are unclear, but may involve functional changes in blood vessel reactivity. The large-conductance Ca2+-activated potassium channel (BKCa) in vascular smooth muscle plays a central role in the regulation of vascular tone. The aim of the present study was to examine the effect of dietinduced obesity on BKCa subunit expression and function in skeletal (cremaster) muscle and cerebral arteries.Male Sprague-Dawley rats (7-8 weeks) were fed either a control (standard chow) or a cafeteria-style high fat diet (HFD) for 16-20 weeks. Studies were performed in isolated pressurized first-order arterioles from the cremaster muscle and the main branch of the middle-cerebral artery. BKCa α- and β1-subunit expression was measured by RT-PCR, Western blotting and immunohistochemistry. At the end of the diet period the HFD-fed rats were significantly heavier and had increased fat mass, blood glucose, plasma insulin and leptin. Systolic, diastolic and mean blood pressure were significantly elevated. In cremaster muscle arterioles from obese rats BKCa β1-subunit protein expression and activation by the β1-subunit activator tamoxifen were significantly reduced. Diet-induced obesity also abolished the ability of BKCa to modulate myogenic tone. However, overall myogenic tone and acetylcholine-induced dilation were maintained due to an increased nitric oxide component. In middle-cerebral arteries from obese rats BKCa β1-subunit protein expression and dilation to tamoxifen was significantly increased. Bradykinin-induced endothelium-dependent dilation was impaired in arteries from obese rats. However endothelium-dependent dilation to the PAR2 agonist SLIGRL was not altered by obesity, but there was an increased BKCa component compensating for a decreased nitric oxide component. Obesity did not alter α-subunit protein expression or function as demonstrated with activators NS1619 and pimaric acid in either vessel. The major findings of this study were that diet-induced obesity has contrasting effects on expression and function of BKCa and nitric oxide synthase in different vascular beds. Overall myogenic tone and responses to vasodilator stimuli were maintained in both vascular beds and hence altered BKCa β1-subunit expression and function in the vascular beds studied may make no contribution to obesity-induced hypertension in this model.