Abstract P122: Downregulation and Inhibition of PKCα Causes Increased Ca 2+ -Sensing Receptor-Mediated Vascular Relaxation in Aged Dahl Salt-Sensitive Rats

Abstract

The G protein-coupled Ca 2+ -Sensing Receptor (CaSR) mediates extracellular calcium (Ca 2+ e ) - induced relaxation of mesenteric arteries under tension and may therefore play a role in blood pressure regulation. This presents CaSR as promising target for therapeutic drug design for cardiovascular pathologies such as hypertension. Protein kinase Cα (PKCα) is an important regulator of CaSR signaling and can phosphorylate the receptor leading to desensitization. In this study, we investigated the effects of CaSR mutation and downregulation of PKCα in CaSR-mediated relaxation of phenylephrine (PE)-contracted mesenteric arteries from aged Dahl salt-sensitive rats, fed a low salt (0.1% NaCl) diet, using automated wire myography. We have observed in our laboratory, that there is significant decrease in relaxation response of PE-contracted mesenteric arteries to Ca 2+ e . as animals get older. The results show minimal relaxation responses of arteries to Ca 2+ e and that downregulation of CaSR expression had no significant effect. PKCα downregulation (siRNA) and inhibition of PKC (Gö 6976) showed greater than 80% increase in maximum Ca 2+ -induced relaxation, with significant decreases in EC 50 values compared to untreated controls. The results indicate that PKCα plays an important role in the regulation of CaSR -mediated relaxation of mesenteric arteries. Therefore, inhibition of PKC may lead to increased CaSR sensitivity to Ca 2+ indicating a possible therapeutic mechanism for intervention in age-related vascular dysfunction.