BKCa and KV channels limit conducted vasomotor responses in rat mesenteric terminal arterioles
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Intracellular Ca2+ 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 [Ca2+] 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 BKCa channel blocker iberiotoxin (100 nM) onto mesenteric arterioles in vitro and inhibition of BKCa channel current in silico increased λ by 34% and 32%, respectively. Similarly, inhibition of KV channels in vitro (4-aminopyridine, 1 mM) or in silico increased λ by 41% and 21%, respectively. Immunofluorescence microscopy demonstrated expression of BKCa, 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.
KeywordsCalcium Terminal arteriole Conducted vasoconstriction Intercellular communication Electrotonic conduction KV channel BKCa channel Computer model Simulation
Vascular smooth muscle cell
LJJ was the recipient of a postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS), and a part of his work was carried out at the Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. BOH was a recipient of a Ph.D. fellowship from the Faculty of Health Sciences, University of Copenhagen. The study received grants-in-aid from JSPS, The Danish Medical Research Council, The Lundbeck Foundation, The Danish Heart Foundation, The Novo Nordisk Foundation, and Fonden til Lægevidenskabens Fremme.
- 24.Inoue R, Jensen LJ, Jian Z, Shi J, Hai L, Lurie AI, Henriksen FH, Salomonsson M, Morita H, Kawarabayashi Y, Mori M et al (2009) Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/omega-hydroxylase/20-HETE pathways. Circ Res 104:1399–1409PubMedCrossRefGoogle Scholar
- 33.Knudsen OS (1995) Stoftransport, membranpotentialer og elektriske impulser over biologiske membraner. Akademisk Forlag, CopenhagenGoogle Scholar