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

Abstract

Howitt L, Grayson TH, Morris MJ, Sandow SL, Murphy TV. Dietary obesity increases NO and inhibits BK Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae. Am J Physiol Heart Circ Physiol 302: H2464 -H2476, 2012. First published April 6, 2012 doi:10.1152/ajpheart.00965.2011.-Obesity is a risk factor for hypertension and other vascular disease. The aim of this study was to examine the effect of diet-induced obesity on endothelium-dependent dilation of rat cremaster muscle arterioles. Male Sprague-Dawley rats (213 Ϯ 1 g) were fed a cafeteria-style high-fat or control diet for 16 -20 wk. Control rats weighed 558 Ϯ 7 g compared with obese rats 762 Ϯ 12 g (n ϭ 52-56; P Ͻ 0.05). Diet-induced obesity had no effect on acetylcholine (ACh)-induced dilation of isolated, pressurized (70 mmHg) arterioles, but sodium nitroprusside (SNP)-induced vasodilation was enhanced. ACh-induced dilation of arterioles from control rats was abolished by a combination of the KCa blockers apamin, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), and iberiotoxin (IBTX; all 0.1 mol/l), with no apparent role for nitric oxide (NO). In arterioles from obese rats, however, IBTX had no effect on responses to ACh while the NO synthase (NOS)/guanylate cyclase inhibitors N -nitro-L-arginine methyl ester (L-NAME; 100 mol/l)/1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 mol/l) partially inhibited ACh-induced dilation. Furthermore, NOS activity (but not endothelial NOS expression) was increased in arteries from obese rats. L-NAME/ODQ alone or removal of the endothelium constricted arterioles from obese but not control rats. Expression of caveolin-1 and -2 oligomers (but not monomers or caveolin-3) was increased in arterioles from obese rats. The number of caveolae was reduced in the endothelium of arteries, and caveolae density was increased at the ends of smooth muscle cells from obese rats. Dietinduced obesity abolished the contribution of large-conductance Ca 2ϩ -activated K ϩ channel to ACh-mediated endothelium-dependent dilation of rat cremaster muscle arterioles, while increasing NOS activity and inducing an NO-dependent component. (72). Many of these enzymes and channels are localized within caveolae, as cholesterol-rich invaginations of the plasma membrane (10). Caveolins, the structural proteins of caveolae, have an established role in modulating vascular signaling mechanisms including NO synthase (NOS) and BK Ca activity (1,13,20).Studies on the impact of obesity on endothelium-dependent vasodilation have focused on impaired NO-mediated responses and, in particular, the altered endothelial NOS (eNOS) activity and NO bioavailability associated with inflammatory mediators and oxidative stress (24, 53). Decreased NO-dependent vasodilation, as an apparent consequence of oxidative stress, has been observed in animal models of obesity (16,18,25,26). In smaller arteries and arterioles, however, particularly those in skeletal muscle (43), NO generally makes a relatively minor...

BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice

“…Several studies in animal models of hypertension provide evidence that both supports and minimizes a role for BK channel dysfunction in hypertension. [6,7, 10-12,17-19] Studies in C57BL/6J BK β1-knockout mice do not support an association of vascular BK channel dysfunction with hypertension, as these mice are not hypertensive under normal conditions. [10-12] More recent work in high-fat fed rats and mice indicated that impaired BK channel function contributes to elevated BP through increased tone in resistance arteries, and that reduced BK β1-subunit expression plays a major role in obesity associated vascular dysfunction.…”

“…[13] Animal models of metabolic disorders such as insulin resistance[14], diabetes[15], and genetic[16]or high-fat diet-induced obesity[17-19] also show vascular BK channel dysfunction. Reduced expression[17-19] or increased degradation of BK β1-subunit protein caused by oxidative signaling[14,15] appears responsible for vascular BK channel dysfunction, as α-subunit protein expression is unchanged. BK channel deficiency contributes to increased vascular tone and blood pressure regulation in these animal models of metabolic disease.…”

“…[21] Thus maintenance of BK channel activity may protect against vascular dysfunction and hypertension, and reduced BK β1-subunit expression/function may be responsible for impaired vascular BK channel function in obesity. [17-19] We hypothesized that preexisting SMC BK channel deficiency would promote vascular dysfunction and hypertension in mice fed a high-fat diet. As there is no specific BK β1-subunit inhibitor, we used high-fat-fed BK β1-knockout mice to model human high-fat diet-induced obesity[22], and by utilizing mice with SMC specific knockout of BK β1-subunit, we minimized interference of BK channel function in other tissues.…”

“…As there is no specific BK β1-subunit inhibitor, we used high-fat-fed BK β1-knockout mice to model human high-fat diet-induced obesity[22], and by utilizing mice with SMC specific knockout of BK β1-subunit, we minimized interference of BK channel function in other tissues. The high-fat diet fed rodent models have been used extensively in studies on the pathophysiology of obesity-associated metabolic disorders, and are presumed to mimic the etiology of primary human diet-induced obesity[17-19, 22]. BK β1-knockout mice have been used by others to mimic the SMC BK channel deficiency known to occur in hypertension[10,12], septic shock[11], and metabolic disorder.…”

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

“…Obesity is associated with increased circulating levels of cholesterol and leptin 34 . Cholesterol levels are higher in caveoli 35 , the location of hERG a-and b-subunit insertions 36 . Direct interaction may occur between membrane lipids and amino acids in membrane-traversing domains of ion channel proteins 37 , and hERG channel kinetics are sensitive to the cholesterol content of the plasma membrane 36 .…”