The expression and function of Ca(2+)-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes.
OBJECTIVE
The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K(+) channels (IK(Ca)) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes.


METHODS
Pressure myography, western blotting, sharp microelectrode and K(+)-selective electrode recordings were used to investigate the functional expression of the CaR and IK(Ca) in rat mesenteric arteries.


RESULTS
Myocyte hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619-induced vessel contraction elevated the extracellular [K(+)] around the myocytes, and inhibition of this 'K(+) cloud' by iberiotoxin was needed to reveal calindol-induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IK(Ca) expression was also diminished, but IK(Ca)-generated hyperpolarizations mediated by 1-EBIO were unaffected.


CONCLUSIONS
The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IK(Ca) channels. Detection of CaR-mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long-term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.
Weston
A H
AH
Faculty of Life Sciences, The University of Manchester, Manchester, UK.
Absi
M
M
Harno
E
E
Geraghty
A R
AR
Ward
D T
DT
Ruat
M
M
Dodd
R H
RH
Dauban
P
P
Edwards
G
G
D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004594:Electrophysiology; D005786:Gene Expression Regulation; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism* / Q000473:pathology; D008839:Microelectrodes; D032342:Muscle Cells / Q000378:metabolism; D009213:Myography; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology
D024681:Potassium Channels, Calcium-Activated; D044169:Receptors, Calcium-Sensing