Impaired function of coronary BKCa channels in metabolic syndrome
obesity; Physiology; Cardiovascular System & Cardiology; channels; smooth-muscle-cells; circulation; cardiovascular-disease; Ion channels; beta-1 subunit; activated potassium; arteriolar dilation; blood flow; ca2+-activated k+ channels; currents; diabetic fatty rats; induced relaxation; large-conductance; outward
Borbouse L, Dick GM, Asano S, Bender SB, Dincer UD, Payne GA, Neeb ZP, Bratz IN, Sturek M, Tune JD. Impaired function of coronary BKCa channels in metabolic syndrome. Am J Physiol Heart Circ Physiol 297: H1629-H1637, 2009. First published September 11, 2009; doi:10.1152/ajpheart.00466.2009.-The role of large-conductance Ca2+-activated K+ (BKCa) 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 BKCa opener NS-1619 in vivo (30-100 mu g) and reduced the contribution of these channels to adenosine-induced microvascular vasodilation in vitro (1-100 mu M). MetS reduced whole cell penitrem A (1 mu M)-sensitive K+ current and NS-1619-activated (10 mu M) current in isolated coronary vascular smooth muscle cells. MetS increased the concentration of free intracellular Ca2+ and augmented coronary vasoconstriction to the L-type Ca2+ channel agonist BAY K 8644 (10 pM-10 nM). BKCa channel alpha and beta(1) protein expression was increased in coronary arteries from MetS swine. Coronary vascular dysfunction in MetS is related to impaired BKCa channel function and is accompanied by significant increases in L-type Ca2+ channel-mediated coronary vasoconstriction.
Borbouse L; Dick G M; Asano S; Bender S B; Dincer U D; Payne G A; Neeb Z P; Bratz I N; Sturek M; Tune J D
American Journal of Physiology-Heart and Circulatory Physiology
2009
2009-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajpheart.00466.2009" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00466.2009</a>
Penitrem A as a Tool for Understanding the Role of Large Conductance Ca2+/Voltage-Sensitive K+ Channels in Vascular Function
metabolic syndrome; Pharmacology & Pharmacy; expression; calcium; smooth-muscle; coronary vasodilation; ca2+; activated potassium channel; beta-1 subunit; bkca channels; elevated blood-pressure; sparks
Large conductance, Ca2+/voltage-sensitive K+ channels (BK channels) are well characterized, but their physiological roles, often determined through pharmacological manipulation, are less clear. Iberiotoxin is considered the "gold standard" antagonist, but cost and membrane-impermeability limit its usefulness. Economical and membrane-permeable alternatives could facilitate the study of BK channels. Thus, we characterized the effect of penitrem A, a tremorigenic mycotoxin, on BK channels and demonstrate its utility for studying vascular function in vitro and in vivo. Whole-cell currents from human embryonic kidney 293 cells transfected with hSlo alpha or alpha + beta 1 were blocked >95% by penitrem A (IC50 6.4 versus 64.4 nM; p < 0.05). Furthermore, penitrem A inhibited BK channels in inside-out and cell-attached patches, whereas iberiotoxin could not. Inhibitory effects of penitrem A on whole-cell K+ currents were equivalent to iberiotoxin in canine coronary smooth muscle cells. As for specificity, penitrem A had no effect on native delayed rectifier K+ currents, cloned voltage-dependent Kv1.5 channels, or native ATP-dependent K-ATP current. Penitrem A enhanced the sensitivity to K+-induced contraction in canine coronary arteries by 23 +/- 5% (p < 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 +/- 11% ( p < 0.05). Our data indicate that penitrem A is a useful tool for studying the role of BK channels in vascular function and is practical for cell and tissue (in vitro)
Asano S; Bratz I N; Berwick Z C; Fancher I S; Tune J D; Dick G M
Journal of Pharmacology and Experimental Therapeutics
2012
2012-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1124/jpet.111.191072" target="_blank" rel="noreferrer noopener">10.1124/jpet.111.191072</a>