Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo
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Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo. / Wölfle, Stephanie E; Schmidt, Volker J; Hoyer, Joachim; Köhler, Ralf; de Wit, Cor.
I: Cardiovascular Research, Bind 82, Nr. 3, 01.06.2009, s. 476-83.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo
AU - Wölfle, Stephanie E
AU - Schmidt, Volker J
AU - Hoyer, Joachim
AU - Köhler, Ralf
AU - de Wit, Cor
PY - 2009/6/1
Y1 - 2009/6/1
N2 - AIMS: The activation of endothelial Ca2+-dependent K+-channels, KCa3.1 (IKCa), and KCa2.3 (SKCa) has been proposed to be a prerequisite for endothelial hyperpolarization, which subsequently hyperpolarizes and relaxes smooth muscle [endothelium-derived hyperpolarizing factor (EDHF)-type dilation] and initiates conducted dilations. Although EDHF is the main mediator of acetylcholine (ACh)-induced dilation in the murine skeletal microcirculation, the differential contribution of KCa3.1 and KCa2.3 is not known.METHODS AND RESULTS: We assessed agonist-induced and conducted dilations as well as endothelial hyperpolarization in the cremaster microcirculation of KCa3.1-deficient (KCa3.1-/-) and wild-type mice (wt) in vivo after blockade of NO and prostaglandins. Compared with wt, resting tone was enhanced by approximately 25% in arterioles of KCa3.1-/- mice. ACh-induced dilations in KCa3.1-/- mice were virtually abolished at low and intermediate concentrations and a remaining dilation at 10 micromol/L ACh was abrogated by blockade of KCa2.3 with UCL1684. Sodium nitroprusside- and adenosine-induced dilations were similar in wt and KCa3.1-/-. Focal application of ACh induced dilations at the local site in both genotypes, which conducted along the vessel. However, the amplitude of the dilation decreased with distance only in KCa3.1-/-. Blockade of KCa2.3 in wt did not affect conducted dilations. A KCa3.1 opener induced a conducting dilation in wt but not in KCa3.1-/-. Membrane potential recordings in vivo demonstrated endothelial hyperpolarization in response to ACh in both genotypes; however, the hyperpolarization was severely impaired in KCa3.1-/- (Delta membrane potential: -3 +/- 1 vs. -14 +/- 2 mV).CONCLUSION: We conclude that KCa3.1 is of major importance for endothelial hyperpolarization and EDHF-type responses in skeletal muscle arterioles, and its deficiency is not compensated by KCa2.3. Sole activation of KCa3.1 is capable of initiating conducted responses, and KCa3.1 may contribute to the propagation of the signal, although its presence is not mandatory.
AB - AIMS: The activation of endothelial Ca2+-dependent K+-channels, KCa3.1 (IKCa), and KCa2.3 (SKCa) has been proposed to be a prerequisite for endothelial hyperpolarization, which subsequently hyperpolarizes and relaxes smooth muscle [endothelium-derived hyperpolarizing factor (EDHF)-type dilation] and initiates conducted dilations. Although EDHF is the main mediator of acetylcholine (ACh)-induced dilation in the murine skeletal microcirculation, the differential contribution of KCa3.1 and KCa2.3 is not known.METHODS AND RESULTS: We assessed agonist-induced and conducted dilations as well as endothelial hyperpolarization in the cremaster microcirculation of KCa3.1-deficient (KCa3.1-/-) and wild-type mice (wt) in vivo after blockade of NO and prostaglandins. Compared with wt, resting tone was enhanced by approximately 25% in arterioles of KCa3.1-/- mice. ACh-induced dilations in KCa3.1-/- mice were virtually abolished at low and intermediate concentrations and a remaining dilation at 10 micromol/L ACh was abrogated by blockade of KCa2.3 with UCL1684. Sodium nitroprusside- and adenosine-induced dilations were similar in wt and KCa3.1-/-. Focal application of ACh induced dilations at the local site in both genotypes, which conducted along the vessel. However, the amplitude of the dilation decreased with distance only in KCa3.1-/-. Blockade of KCa2.3 in wt did not affect conducted dilations. A KCa3.1 opener induced a conducting dilation in wt but not in KCa3.1-/-. Membrane potential recordings in vivo demonstrated endothelial hyperpolarization in response to ACh in both genotypes; however, the hyperpolarization was severely impaired in KCa3.1-/- (Delta membrane potential: -3 +/- 1 vs. -14 +/- 2 mV).CONCLUSION: We conclude that KCa3.1 is of major importance for endothelial hyperpolarization and EDHF-type responses in skeletal muscle arterioles, and its deficiency is not compensated by KCa2.3. Sole activation of KCa3.1 is capable of initiating conducted responses, and KCa3.1 may contribute to the propagation of the signal, although its presence is not mandatory.
KW - Acetylcholine
KW - Animals
KW - Arterioles/physiology
KW - Endothelium, Vascular/metabolism
KW - Intermediate-Conductance Calcium-Activated Potassium Channels/genetics
KW - Membrane Potentials
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Microcirculation
KW - Muscle, Skeletal/blood supply
KW - Small-Conductance Calcium-Activated Potassium Channels/metabolism
KW - Vasodilation
U2 - 10.1093/cvr/cvp060
DO - 10.1093/cvr/cvp060
M3 - Journal article
C2 - 19218287
VL - 82
SP - 476
EP - 483
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 3
ER -
ID: 329569724