Potassium Channel Dysfunction in Cerebral Arteries of Insulin-Resistant Rats Is Mediated by Reactive Oxygen Species

Abstract

Background and Purpose-Insulin resistance (IR) increases the risk of stroke in humans. One possible underlying factor is cerebrovascular dysfunction resulting from altered K ϩ channel function. Thus, the goal of this study was to examine K ϩ channel-mediated relaxation in IR cerebral arteries. Methods-Experiments were performed on pressurized isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats. Results-Dilator responses to iloprost, which are BK Ca channel mediated, were reduced in the IR compared with control arteries (19Ϯ2% versus 33Ϯ2% at 10 Ϫ6 mol/L). Similarly, relaxation to the K ATP opener pinacidil was diminished in the IR MCAs (17Ϯ2%) compared with controls (38Ϯ2% at 10 Ϫ5 mol/L). IR also reduced the K ATP channel-dependent component in calcitonin gene-related peptide-induced dilation; however, the magnitude of the relaxation remained unchanged in IR because of a nonspecified K ϩ channel-mediated compensatory mechanism. In contrast, K ir channel-mediated relaxation elicited by increases in extracellular [K ϩ ] (4 to 12 mmol/L) was similar in the control and IR arteries. Blockade of the K ir and K v channels with Ba 2ϩ and 4-aminopyridine, respectively, constricted the MCAs in both experimental groups with no significant difference. Pretreatment of arteries with superoxide dismutase (200 U/mL) plus catalase (150 U/mL) restored the dilatory responses to iloprost and pinacidil in the IR arteries. Immunoblots showed that the expressions of the pore-forming subunits of the examined K ϩ channels are not altered by IR. Conclusions-IR

Dietary obesity increases NO and inhibits BKCa-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

“…In keeping with observations that NOS activity may be enhanced in the early, developing stages of diabetes but decreased with longer duration of the disease (52), it is quite possible that the duration of this well-characterized dietary model of obesity and observations reported in the study represent an intermediate or partial adaptive state in the response of the cremaster muscle artery to diet-induced obesity. A longer duration of the dietary period (i.e., Ͼ20 wk) may lead to the development of further systemic inflammation, oxidative stress, microvascular rarefaction, worsened hypertension, and other adaptations causing more obvious vascular dysfunction, typically observed in models such as the Zucker rat (17,18,23,25,26,66,69,73,76).…”

“…In smaller arteries and arterioles, however, particularly those in skeletal muscle (43), NO generally makes a relatively minor contribution to endothelium-dependent vasodilation, with EDH having a more significant role (31,56). Relatively few studies have examined the effect of diet-induced obesity on EDHmediated vasodilation, and most of these have utilized genetic models of obesity (6,7,17,18,39) as opposed to dietary interventions that may be more representative of the human condition. Furthermore, the association between the vascular adaptations to obesity and expression of caveolae and caveolins has been little explored.…”

Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats

“…32,33 Antioxidant treatment restores impaired BK channel function. 31,33,34 NO increases BK channel activity in VSMC 35 and cslo (canine BK channel ␣-subunit) transfected HEK-293 cells. 36 This response is mediated by cGMP-dependent channel phosphorylation.…”

“…31 Direct application of peroxynitrite to skeletal muscle resistance and human coronary arteries inhibits BK channel activity and causes vasoconstriction. 32,33 Antioxidant treatment restores impaired BK channel function.…”

Oxidative Stress Inhibits Vascular KATP Channels by S-Glutathionylation

“…In diabetic patients, in whom oxidative stress is evident, K ATP channel function is disrupted, leading to impaired vasodilation responses (12). In insulin-resistant rats, the K ATP channel-dependent vasodilation is also impaired, which is likely to be mediated by ROS (13). Although the dysfunction of K ATP channels in oxidative stress has been documented, the mechanism underlying channel modulation remains unknown (9,14).…”