The expression and function of Ca²⁺‐sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes

Abstract

Background and purpose: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K þ 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. Experimental approach: Pressure myography, western blotting, sharp microelectrode and K þ -selective electrode recordings were used to investigate the functional expression of the CaR and IK Ca 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 þ ] around the myocytes, and inhibition of this 'K þ 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 Cagenerated 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 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.

Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression

“…A comprehensive analysis of factors involved in the relaxation revealed that this was associated with suppressed EDH-like response and accordingly a reduction in IK Ca channel expression. Interestingly, endothelial dysfunction in Type 2 diabetic rats is also associated with reduced IK Ca expression (10,69), and this expressional change was, at least in part, due to elevated oxidative stress of endothelial cells (72). Whether increased oxidative stress in depression-like state (5,39,45,48) can affect IK Ca is not known.…”

Coordination of Vasomotor Responses by the Endothelium

“…47 On the endothelium, the link between activation of the CaSR and KCa3.1-channels is disrupted in mesenteric arteries from a model of type II diabetes, possibly reflecting decreased expression of CaSRs, although KCa3.1-channel protein, but not hyperpolarization, was also reduced. 48 The CaSR and KCa3.1-channel are colocalized in caveolin-poor regions of the EC membrane in those arteries. 45 KCa2.3-channels localize within the caveolae so abundant in ECs and, inter alia, act as signaling platforms.…”

Endothelium-derived hyperpolarising factors and associated pathways: a synopsis

“…g) K + -selective microelectrode recording from the extracellular space between myocytes in an intact rat mesenteric artery; the thromboxane A 2 receptor agonist U46619 elevated [K + ] o , an effect reversed by iberiotoxin. Data adapted from [19,40,45,112,135,138]; see text for further details subsequent myocyte hyperpolarisation. Instead, endothelial cell hyperpolarisation might simply be conducted via low resistance, gap junctional pathways to the myocyte (see [29,30,63]).…”