Are voltage-dependent ion channels involved in the endothelial cell control of vasomotor tone?
In the microcirculation, longitudinal conduction of vasomotor responses provides an essential means of coordinating flow distribution among vessels in a complex network. Spread of current along the vessel axis can display a regenerative component, which leads to propagation of vasomotor signals over many millimeters; the ionic basis for the regenerative response is unknown. We examined the responses to 10 s of focal electrical stimulation (30 Hz, 2 ms, 30 V) of mouse cremaster arterioles to test the hypothesis that voltage-dependent Na(+) (Na(v)) and Ca(2+) channels might be activated in long-distance signaling in microvessels. Electrical stimulation evoked a vasoconstriction at the site of stimulation and a spreading, nondecremental conducted dilation. Endothelial damage (air bubble) blocked conduction of the vasodilation, indicating an involvement of the endothelium. The Na(v) channel blocker bupivacaine also blocked conduction, and TTX attenuated it. The Na(v) channel activator veratridine induced an endothelium-dependent dilation. The Na(v) channel isoforms Na(v)1.2, Na(v)1.6, and Na(v)1.9 were detected in the endothelial cells of cremaster arterioles by immunocytochemistry. These findings are consistent with the involvement of Na(v) channels in the conducted response. BAPTA buffering of endothelial cell Ca(2+) delayed and reduced the conducted dilation, which was almost eliminated by Ni(2+), amiloride, or deletion of alpha(1H) T-type Ca(2+) (Ca(v)3.2) channels. Blockade of endothelial nitric oxide synthase or Ca(2+)-activated K(+) channels also inhibited the conducted vasodilation. Our findings indicate that an electrically induced signal can propagate along the vessel axis via the endothelium and can induce sequential activation of Na(v) and Ca(v)3.2 channels. The resultant Ca(2+) influx activates endothelial nitric oxide synthase and Ca(2+)-activated K(+) channels, triggering vasodilation.
Figueroa
Xavier F
XF
Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Chen
Chien-Chang
CC
Campbell
Kevin P
KP
Damon
David N
DN
Day
Kathleen H
KH
Ramos
Susan
S
Duling
Brian R
BR
D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014666:Vasomotor System / Q000502:physiology*; D014701:Veratridine / Q000494:pharmacology
C504883:Cacna1h protein, mouse; D015220:Calcium Channels; D020747:Calcium Channels, T-Type; D024681:Potassium Channels, Calcium-Activated; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D009569:Nitric Oxide; D014701:Veratridine; D002045:Bupivacaine