title: BKCa and KV channels limit conducted vasomotor responses in rat mesenteric terminal arterioles.
abstract: Intracellular Ca(2+) signals underlying conducted vasoconstriction to local application of a brief depolarizing KCl stimulus was investigated in rat mesenteric terminal arterioles (<40 μm). Using a computer model of an arteriole segment comprised of coupled endothelial cells (EC) and vascular smooth muscle cells (VSMC) simulations of both membrane potential and intracellular [Ca(2+)] were performed. The "characteristic" length constant, λ, was approximated using a modified cable equation in both experiments and simulations. We hypothesized that K(+) conductance in the arteriolar wall limit the electrotonic spread of a local depolarization along arterioles by current dissipation across the VSMC plasma membrane. Thus, we anticipated an increased λ by inhibition of voltage-activated K(+) channels. Application of the BK(Ca) channel blocker iberiotoxin (100 nM) onto mesenteric arterioles in vitro and inhibition of BK(Ca) channel current in silico increased λ by 34% and 32%, respectively. Similarly, inhibition of K(V) channels in vitro (4-aminopyridine, 1 mM) or in silico increased λ by 41% and 21%, respectively. Immunofluorescence microscopy demonstrated expression of BK(Ca), Kv1.5, Kv2.1, but not Kv1.2, in VSMCs of rat mesenteric terminal arterioles. Our results demonstrate that inhibition of voltage-activated K(+) channels enhance vascular-conducted responses to local depolarization in terminal arterioles by increasing the membrane resistance of VSMCs. These data contribute to our understanding of how differential expression patterns of voltage-activated K(+) channels may influence conducted vasoconstriction in small arteriolar networks. This finding is potentially relevant to understanding the compromised microcirculatory blood flow in systemic vascular diseases such as diabetes mellitus and hypertension.
authors: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Bjørn Olav
authors: BO
authors: Hald
authors: Jens Christian Brings
authors: JC
authors: Jacobsen
authors: Thomas Hartig
authors: TH
authors: Braunstein
authors: Ryuji
authors: R
authors: Inoue
authors: Yushi
authors: Y
authors: Ito
authors: Preben Graae
authors: PG
authors: Sørensen
authors: Niels-Henrik
authors: NH
authors: Holstein-Rathlou
authors: Lars Jørn
authors: LJ
authors: Jensen
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D051666:Kv1.5 Potassium Channel / Q000502:physiology*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008638:Mesenteric Arteries / Q000502:physiology*; D023421:Models, Animal; D008962:Models, Theoretical; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000502:physiology*; D014666:Vasomotor System / Q000502:physiology*
chemical_list: C494842:Kcnma1 protein, rat; D051666:Kv1.5 Potassium Channel; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015221:Potassium Channels; D051669:Shab Potassium Channels; D002118:Calcium