Impaired Vascular K_ATP Function Attenuates Exercise Capacity in Obese Zucker Rats

Abstract

Objective Obese subjects exhibit decreased exercise capacity (VO2max). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function. Methods VO2max was measured in LZR and OZR by treadmill running before and following treatment with the KATP blocker glibenclamide i.p. One week later the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application. In additional animals, LZR and OZR were treated with apocynin for 5 weeks. VO2max and arteriolar dilation experiments were repeated. Results OZR exhibited decreased VO2max, functional and cromakalim-induced vasodilation as compared to LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR but reduced in apocynin-treated OZR. Apocynin increased the VO2max, functional and cromakalim-induced vasodilation in OZR with no effect in LZR. Conclusion Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…Dilation of middle cerebral arteries mediated by K ATP channels also is impaired in this model of insulin resistance (384, 385). Similarly, K ATP channel-mediated arteriolar vasodilation is impaired in obese Zucker rats (608, 910). In this model, exercise capacity is reduced, an effect that can be reproduced by inhibition of K ATP channels in lean control animals.…”

“…The reduced function of K ATP channels in fructose-fed rats appears to be mediated by ROS (385). Also, obesity-induced decreases in K ATP channel function in Obese Zucker rats are associated with increased vascular levels of ROS (910). Inhibition of NADPH oxidase with apocynin reduces ROS and improves K ATP channel function in this model (910).…”

“…Also, obesity-induced decreases in K ATP channel function in Obese Zucker rats are associated with increased vascular levels of ROS (910). Inhibition of NADPH oxidase with apocynin reduces ROS and improves K ATP channel function in this model (910). Thus the down-regulation of K ATP channel expression and function may be induced by an increase in ROS production in obesity and the metabolic syndrome.…”

Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth

“…The function of VSM K ATP channels appears to be decreased in obesity (Erdos, Miller, & Busija, 2002; Erdos, Simandle, Snipes, Miller, & Busija, 2004; Hodnett, Xiang, Dearman, Carter, & Hester, 2008; Irat, Aslamaci, Karasu, & Ari, 2006; Lu et al, 2013; Miller, Tulbert, Puskar, & Busija, 2002; Spallarossa et al, 2001) and diabetes (Bouchard, Dumont, & Lamontagne, 1999; Kamata, Miyata, & Kasuya, 1989; Kinoshita et al, 2006; S. S. Li et al, 2015; Mayhan, 1994; Mayhan & Faraci, 1993; Miura et al, 2003).…”

Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats

“…Stemming from this, the OZR becomes progressively insulinresistant, dyslipidemic (moderate hypercholesterolemia and severe hypertriglyceridemia), and moderately hypertensive (1,15,20,49). Although considerable evidence has been presented by our laboratory (5,27) and by numerous others (18,30,32,35,36,47,53) regarding the correlation between indexes of vascular dysfunction with characteristics of the metabolic syndrome in these animals at specific ages, minimal evidence has been produced regarding the temporal development of the vascular impairments in these animals, and how these correlate with the evolution of the metabolic syndrome, and other putative markers of dysfunction (e.g., markers of inflammation).…”