Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 154, Issue 3, Pages 652-662Publisher
WILEY-BLACKWELL
DOI: 10.1038/bjp.2008.108
Keywords
calcium-sensing receptor; type II diabetes; ZDF rat; endothelium; K+ cloud; calcium-activated potassium channels; vasodilatation
Categories
Funding
- British Heart Foundation [PG/05/010/18272, FS/06/067] Funding Source: Medline
Ask authors/readers for more resources
Background and purpose: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K+ channels ( IKCa) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes. Experimental approach: Pressure myography, western blotting, sharp microelectrode and K+-selective electrode recordings were used to investigate the functional expression of the CaR and IKCa in rat mesenteric arteries. Key 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; IKCa expression was also diminished, but IKCa-generated hyperpolarizations mediated by 1-EBIO were unaffected. Conclusions and implications: The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IKCa 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available