Differential effects of diet-induced obesity on BK_Ca β₁-subunit expression and function in rat skeletal muscle arterioles and small cerebral arteries

Abstract

Howitt L, Sandow SL, Grayson TH, Ellis ZE, Morris MJ, Murphy TV. Differential effects of diet-induced obesity on BK Ca ␤1-subunit expression and function in rat skeletal muscle arterioles and small cerebral arteries. Am J Physiol Heart Circ Physiol 301: H29-H40, 2011. First published May 2, 2011; doi:10.1152/ajpheart.00134.2011.-Mechanisms underlying obesity-related vascular dysfunction are unclear. This study examined the effect of diet-induced obesity on expression and function of large conductance Ca 2ϩ -activated potassium channel (BKCa) in rat pressurized small resistance vessels with myogenic tone. Male Sprague-Dawley rats fed a cafeteria-style high fat diet (HFD; ϳ30% energy from fat) for 16 -20 wk were ϳ30% heavier than controls fed standard chow (ϳ13% fat). Obesity did not alter BKCa ␣-subunit function or ␣-subunit protein or mRNA expression in vessels isolated from the cremaster muscle or middle-cerebral circulations. In contrast, BKCa ␤1-subunit protein expression and function were significantly reduced in cremaster muscle arterioles but increased in middle-cerebral arteries from obese animals. Immunohistochemistry showed ␣-and ␤ 1-subunits were present exclusively in the smooth muscle of both vessels. Cremaster muscle arterioles from obese animals showed significantly increased medial thickness, and media-to-lumen ratio and pressurized arterioles showed increased myogenic tone at 30 mmHg, but not at 50 -120 mmHg. Myogenic tone was not affected by obesity in middle-cerebral arteries. The BKCa antagonist iberiotoxin constricted both cremaster muscle and middlecerebral arterioles from control rats; this effect of iberiotoxin was abolished in cremaster muscle arteries only from obese rats. Dietinduced obesity has contrasting effects on BKCa function in different vascular beds, through differential effects on ␤1-subunit expression. However, these alterations in BKCa function had little effect on overall myogenic tone, suggesting that the mechanisms controlling myogenic tone can be altered and compensate for altered BKCa expression and function. arteriolar remodeling; large conductance calcium-activated potassium channel; myogenic tone OBESITY IS AN INDEPENDENT risk factor for cardiovascular disease, atherosclerosis, dyslipidemia, and stroke (58), with increased peripheral vascular resistance being a common and consistent feature (31, 50). Increased vascular resistance in obesity may result, in part, from decreased function of the large conductance Ca 2ϩ -activated potassium channel (BK Ca ) in vascular smooth muscle. This channel plays a central role in the regulation of vascular tone, both as a regulator of vasoconstriction and a target of vasodilator agents (35, 43). BK Ca have a high conductance of ϳ240 pS (35), and hence a relatively low level of BK Ca activity can exert a profound hyperpolarizing effect on muscle cell membrane potential, and thus excitability, reducing Ca 2ϩ entry through voltage-sensitive mechanisms and causing relaxation. BK Ca are composed of four pore-forming ␣-subunits and four ...

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

“…other investigations concur with respect to the effect of HFD (23,24); however, hyperglycemia in type 1 diabetes models, which do not incorporate obesity, is associated with perturbed myogenic responsiveness (25)(26)(27). These type 1 diabetes models, however, typically induce more severe hyperglycemia than in the current study (i.e., 2.0-to 4.0-fold above baseline), which is a possible explanation for the discrepancy.…”

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

“…A recent study (32) in diet-induced obese rats showed that the expression of BK Ca ␤ 1 -subunit and BK Ca function was reduced in cremaster muscle arterioles, a vessel where BK Ca plays a critical role in endothelium-mediated vasodilation (43). The hypothesis underlying the present study was that reduced BK Ca ␤ 1 -subunit activity, as a consequence of dietary obesity, reduced BK Ca -mediated endothelium-dependent vasodilation of rat cremaster muscle arterioles.…”

“…Tissue preparation for electron microscopy was as described previously (32,57). In brief, first order cremaster muscle arterioles from control and obese rats (n ϭ 10, each from a different animal) were dissected from perfusion fixed rats (1% paraformaldehyde, 3% glutaraldehyde in 0.1 mmol/l sodium cacodylate buffer, with 10 mmol/l betaine, pH 7.4), embedded, sectioned, and imaged at ϫ10 -40k on a Phillips 7100 transmission electron microscope at 16 megapixel resolution (camera from Scientific Instruments and Applications, Duluth, MN).…”

“…The large-conductance, Ca 2ϩ -activated K ϩ channel (BK Ca ) plays an important role in many vascular beds (21,41,43), along with SK Ca and IK Ca , which are primarily expressed in endothelial cells and mediate EDH. BK Ca are expressed in the smooth muscle of arteries (32,34,58), including the rat cremaster muscle arteriole (32), and may be activated by endothelium-derived substances such as epoxyeicosatrienoic acid (EETs; Ref. 8), NO and PGI 2 (51), and H 2 O 2 (70).…”

Expression and alteration of BKCa channels in the sphincter of Oddi's from rabbits with hypercholesterolemia

“…It has been found that the a-and b 1 -subunits of the BK Ca channels are differentially expressed in different arteries of rats with diet-induced obesity. 27 In addition, there are aging-associated regional differences in the expression and function of BK Ca channel. 28 In this study, we found that HC did not alter the total expression of BK Ca a-and b 1 -subunits, but significantly downregulated the Tyr-phosphorylation of BK Ca a-subunit, suggesting that the Tyr-phosphorylation of BK Ca a-subunit may be important for the regulation of SO muscle tone.…”