TY - JOUR
T1 - Stimulation of the calcium-sensing receptor induces relaxations of rat mesenteric arteries by endothelium-dependent and -independent pathways via BKCa and KATP channels
AU - Carlton-Carew, Simonette R. E.
AU - Greenberg, Harry Z. E.
AU - Connor, Eleanor J.
AU - Zadeh, Pooneh
AU - Greenwood, Iain A.
AU - Albert, Anthony P.
N1 - Funding Information:
This work was supported by a British Heart Foundation PhD Studentships for H. Z. E. Greenberg (FS/13/10/30021 to A.P.A) and S.R.E.C‐C (FS/17/40/32942 to A.P.A) and by the Biotechnology and Biological Sciences Research Council (BB/J007226/1 to A.P.A).
Publisher Copyright:
© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
PY - 2024/1
Y1 - 2024/1
N2 - Stimulation of the calcium-sensing receptor (CaSR) induces both vasoconstrictions and vasorelaxations but underlying cellular processes remain unclear. This study investigates expression and effect of stimulating the CaSR by increasing external Ca2+ concentration ([Ca2+]o) on contractility of rat mesenteric arteries. Immunofluorescence studies showed expression of the CaSR in perivascular nerves, vascular smooth muscle cells (VSMCs), and vascular endothelium cells. Using wire myography, increasing [Ca2+]o from 1 to 10 mM induced vasorelaxations which were inhibited by the calcilytic Calhex-231 and partially dependent on a functional endothelium. [Ca2+]o-induced vasorelaxations were reduced by endothelial NO synthase (eNOS, L-NAME) and large conductance Ca2+-activated K+ channels (BKCa, iberiotoxin), with their inhibitory action requiring a functional endothelium. [Ca2+]o-induced vasorelaxations were also markedly inhibited by an ATP-dependent K+ channel (KATP) blocker (PNU37883), which did not require a functional endothelium to produce its inhibitory action. Inhibitor studies also suggested contributory roles for inward rectifying K+ channels (Kir), Kv7 channels, and small conductance Ca2+-activated K+ channels (SKCa) on [Ca2+]o-induced vasorelaxations. These findings indicate that stimulation of the CaSR mediates vasorelaxations involving multiple pathways, including an endothelium-dependent pathway involving NO production and activation of BKCa channels and an endothelium-independent pathway involving stimulation of KATP channels.
AB - Stimulation of the calcium-sensing receptor (CaSR) induces both vasoconstrictions and vasorelaxations but underlying cellular processes remain unclear. This study investigates expression and effect of stimulating the CaSR by increasing external Ca2+ concentration ([Ca2+]o) on contractility of rat mesenteric arteries. Immunofluorescence studies showed expression of the CaSR in perivascular nerves, vascular smooth muscle cells (VSMCs), and vascular endothelium cells. Using wire myography, increasing [Ca2+]o from 1 to 10 mM induced vasorelaxations which were inhibited by the calcilytic Calhex-231 and partially dependent on a functional endothelium. [Ca2+]o-induced vasorelaxations were reduced by endothelial NO synthase (eNOS, L-NAME) and large conductance Ca2+-activated K+ channels (BKCa, iberiotoxin), with their inhibitory action requiring a functional endothelium. [Ca2+]o-induced vasorelaxations were also markedly inhibited by an ATP-dependent K+ channel (KATP) blocker (PNU37883), which did not require a functional endothelium to produce its inhibitory action. Inhibitor studies also suggested contributory roles for inward rectifying K+ channels (Kir), Kv7 channels, and small conductance Ca2+-activated K+ channels (SKCa) on [Ca2+]o-induced vasorelaxations. These findings indicate that stimulation of the CaSR mediates vasorelaxations involving multiple pathways, including an endothelium-dependent pathway involving NO production and activation of BKCa channels and an endothelium-independent pathway involving stimulation of KATP channels.
KW - BK channels
KW - calcium-sensing receptor
KW - endothelial cells
KW - K channels
KW - nitric oxide
KW - perivascular nerves
KW - vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=85183753430&partnerID=8YFLogxK
U2 - 10.14814/phy2.15926
DO - 10.14814/phy2.15926
M3 - Article
C2 - 38281732
AN - SCOPUS:85183753430
VL - 12
JO - Physiological Reports
JF - Physiological Reports
SN - 2051-817X
IS - 2
M1 - e15926
ER -