Comparative Investigations Using a Type II Diabetes Model to Examine the Expression and Functionality of Ca²⁺ Sensing Receptors in Rat Mesenteric Arteries

Myocyte hyperpolarization is indirectly caused by the activation of endothelial intermediate-conductance, calcium-sensitive K+ channels (IKCa) by the extracellular Calcium-sensing Receptor (CaR) in vascular endothelial cells. We investigated whether a rat model of type II diabetes affected the expression and function of CaR. The functional expression of the CaR and IKCa in rat mesenteric arteries was examined using pressure myography, Western blotting, sharp microelectrode, and K+ selective electrode recordings. Calhex 231 reduced myocyte hyperpolarization to the CaR activator calindol. The extracellular (K+) surrounding the myocytes was increased by U46619-induced vascular contraction; iberiotoxin-induced suppression of this "K+ cloud" was required to disclose calindol-induced vasodilatations. These were considerably smaller in Zucker Diabetic Fatty rat (ZDF) vessels than in Zucker Lean (ZL) controls, and they were triggered by Calhex 231. Hyperpolarizations of myocytes ZDF arteries had lower responses to calindol than ZL arteries did. ZDF arteries showed decreased expression of CaR protein in endothelial cells and decreased expression of IKCa; nevertheless, the hyperpolarizations caused by IKCa and mediated by 1-EBIO remained unaltered. Reduced CaR expression rather than a change in IKCa channels is the cause of the decreased CaR mediated hyperpolarizing and vasodilator responses in ZDF arteries. Iberiotoxin was needed to detect CaR-mediated vasodilatation, indicating that CaR contributes to vascular diameter, which is negatively correlated with the degree of vasoconstriction. A disruption in the CaR pathway could potentially lead to the long-term elevation of basal vascular tone and vascular problems linked to type II diabetes.