Impaired function of coronary BK_Cachannels in metabolic syndrome

Abstract

The role of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in regulation of coronary microvascular function is widely appreciated, but molecular and functional changes underlying the deleterious influence of metabolic syndrome (MetS) have not been determined. Male Ossabaw miniature swine consumed for 3-6 mo a normal diet (11% kcal from fat) or an excess-calorie atherogenic diet that induces MetS (45% kcal from fat, 2% cholesterol, 20% kcal from fructose). MetS significantly impaired coronary vasodilation to the BK(Ca) opener NS-1619 in vivo (30-100 microg) and reduced the contribution of these channels to adenosine-induced microvascular vasodilation in vitro (1-100 microM). MetS reduced whole cell penitrem A (1 microM)-sensitive K(+) current and NS-1619-activated (10 microM) current in isolated coronary vascular smooth muscle cells. MetS increased the concentration of free intracellular Ca(2+) and augmented coronary vasoconstriction to the L-type Ca(2+) channel agonist BAY K 8644 (10 pM-10 nM). BK(Ca) channel alpha and beta(1) protein expression was increased in coronary arteries from MetS swine. Coronary vascular dysfunction in MetS is related to impaired BK(Ca) channel function and is accompanied by significant increases in L-type Ca(2+) channel-mediated coronary vasoconstriction.

Microglial Ca2+-Activated K+Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

“…The differential consequences on the pain hypersensitivity of NS1619 with different two concentrations might be due to the differential sensitivities of neuronal and microglial BK channels. The effective dose of NS1619 in vivo was ϳ30 g (Borbouse et al, 2009). Thus, 0.072 g of NS1619 might induce microglial hyperactivation and allodynia-like behavior without affecting the neuronal excitability.…”

Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca2+-sensitive K+ current in miniature swine with LV hypertrophy

“…Reduced currents and altered expression of coronary smooth muscle cell K Ca channels have been observed in animal models of LV hypertrophy, aging, and metabolic syndrome (1,3,28). K Ca channels are ubiquitously expressed in smooth muscle cells and are sensitive to both membrane potential and Ca 2ϩ influx (37,41).…”

“…Considerable evidence exists indicating that profound modulation of both cardiomyocyte and smooth muscle cell electrophysiological phenotype are involved in cardiovascular disease (36, 47, 51). Calcium-activated K ϩ (K Ca ) channels play an important role in the regulation of arterial tone and vascular resistance and have been implicated in vascular dysfunction observed during the pathogenesis of left ventricular (LV) hypertrophy, hypertension, diabetes, and metabolic syndrome (3,13,28,31,41). Together, these studies suggest altered regulation of these channels may underlie impairments in coronary vascular function commonly observed in HF.…”

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

“…However, few studies have examined BK Ca function in a diet-induced obesity model that reflects the etiology of primary human diet-related obesity. Furthermore, the mechanism by which BK Ca function was inhibited in these studies is unclear, with reactive oxygen species (6,20,23) or altered BK Ca subunit expression (4, 44, 45) suggested to underlie changes in vascular function. Some recent studies have suggested metabolic disease may selectively reduce vascular BK Ca ␤ 1 -subunit function, reducing the channel sensitivity to changes in membrane potential or intracellular [Ca 2ϩ ].…”