BKCa and KV channels limit conducted vasomotor responses in rat mesenteric terminal arterioles

Bjørn Olav Hald; Jens Christian Brings Jacobsen; Thomas Hartig Braunstein; Ryuji Inoue; Yuski Ito; Preben Graae Sørensen; Niels-Henrik von Holstein-Rathlou; Lars Jørn Jensen

doi:10.1007/s00424-011-1049-8

BK_Ca and K_V channels limit conducted vasomotor responses in rat mesenteric terminal arterioles

Bjørn Olav Hald, Jens Christian Brings Jacobsen, Thomas Hartig Braunstein, Ryuji Inoue, Yuski Ito, Preben Graae Sørensen, Niels-Henrik von Holstein-Rathlou, Lars Jørn Jensen

25 Citations (Scopus)

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.

Original language	English
Journal	Pflügers Archiv - European Journal of Physiology
Volume	463
Issue number	2
Pages (from-to)	279-295
Number of pages	17
ISSN	0031-6768
DOIs	https://doi.org/10.1007/s00424-011-1049-8
Publication status	Published - Feb 2012

Keywords

Former LIFE faculty

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10.1007/s00424-011-1049-8

Cite this

@article{6f27f5fabcd74d148d8b8346cac0d39c,

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.",

keywords = "Former LIFE faculty, Calcium, Terminal arterioe, Conducted vasoconstriction, Intercellula communication, Electronic conduction, Computer model, Simulation",

author = "Hald, {Bj{\o}rn Olav} and Jacobsen, {Jens Christian Brings} and Braunstein, {Thomas Hartig} and Ryuji Inoue and Yuski Ito and S{\o}rensen, {Preben Graae} and {von Holstein-Rathlou}, Niels-Henrik and Jensen, {Lars J{\o}rn}",

year = "2012",

month = feb,

doi = "10.1007/s00424-011-1049-8",

language = "English",

volume = "463",

pages = "279--295",

journal = "Pfl{\"u}gers Archiv - European Journal of Physiology",

issn = "0031-6768",

publisher = "Springer",

number = "2",

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TY - JOUR

T1 - BKCa and KV channels limit conducted vasomotor responses in rat mesenteric terminal arterioles

AU - Hald, Bjørn Olav

AU - Jacobsen, Jens Christian Brings

AU - Braunstein, Thomas Hartig

AU - Inoue, Ryuji

AU - Ito, Yuski

AU - Sørensen, Preben Graae

AU - von Holstein-Rathlou, Niels-Henrik

AU - Jensen, Lars Jørn

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

KW - Former LIFE faculty

KW - Calcium

KW - Terminal arterioe

KW - Conducted vasoconstriction

KW - Intercellula communication

KW - Electronic conduction

KW - Computer model

KW - Simulation

U2 - 10.1007/s00424-011-1049-8

DO - 10.1007/s00424-011-1049-8

M3 - Journal article

SN - 0031-6768

VL - 463

SP - 279

EP - 295

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

IS - 2

ER -