Proteinase‐activated receptor 2‐mediated vasodilation is preserved in diabetes

Proteinase activated receptor‐2 (PAR‐2) is a novel G‐protein coupled receptor activated by proteolytic cleavage of the extracellular N‐terminus. We propose that activation of endothelial small (SK Ca ) and intermediate conductance (IK Ca ) Ca 2+ ‐activated K + channels is central to PAR‐2 mediated vasodilation of rat mesenteric resistance arteries and that activation this pathway may be beneficial for endothelial dysfunction in diabetes. PAR‐2 mediated endothelium‐dependent dilation of rat mesenteric resistance arteries was unaffected by inhibition of endothelial nitric oxide, potentiated by block of cyclooxygenase and abolished by blockade of SK Ca and IK Ca channels or by exposure to a PAR‐2‐selective antibody. In arteries from streptozocin‐treated diabetic rats, PAR‐2 mediated relaxations were maintained but endothelium‐dependent relaxations to acetylcholine were attenuated. Furthermore, prior exposure to PAR‐2 activators significantly enhanced responses to acetylcholine in these vessels. These data indicate that endothelial SK Ca and IK Ca channels are central to PAR2‐mediated vasodilation and that PAR‐2 and/or endothelial K Ca channels may represent potential therapeutic targets for endothelial dysfunction. Supported by HSFC.