Decreased contractile response to endothelin-1 of peripheral microvasculature from diabetic patients

Background. We compared the contractile responses to endothelin-1 (ET-1) with and without the inhibition of ETA receptors and protein kinase C-alpha (PKC-alpha) in the human peripheral microvasculature of diabetic and case-matched, nondiabetic patients. Methods. Chest wall skeletal muscle was harvested from patients with and without diabetics undergoing cardiac surgery. Peripheral arterioles (90-180 mu m in diameter) were dissected from the harvested tissue. Microvascular constriction was assessed by videomicroscopy in response to ET-1 with and without an endothelin-A (ETA) receptor antagonist, an endothelin B (ET-B) antagonist, or a PKC-alpha inhibitor. Results. ET-1 induced a dose-dependent contractile response of skeletal muscle arterioles from diabetic and nondiabetic patients. The contractile response of diabetic arterioles from both prebypass and post by pass to ET-1 (10(-9) mol/L) was decreased compared with those of nondiabetic patients (P <. 05). The contractile responses of microvessels of both diabetics and nondiabetics to ET-1 were inhibited in the presence of either ET-A receptor antagonist BQ123 (10(-7) mol/L) or the PKC-alpha inhibitor safingol (2 x 10(-5) mol/L, P <. 05, respectively). In contrast, the ET-1 induced vasoconstriction was not affected by the administration of the ET-B receptor antagonist BQ788 (10(-7) mol/L). There were no differences in skeletal muscle levels of the ET-A and ET-B receptors between diabetic and nondiabetic groups. Conclusion. Diabetic patients demonstrated a decreased contractile response to ET-1 in human peripheral microvasculature. The contractile response of diabetic vessels to ET-1 occurs via activation of ETA receptors and PKC-alpha. These results provide novel mechanisms of ET-1 induced contraction in vasomotor dysfunction in patients with diabetes. (Surgery 2011;149:247-52.)