Methylglyoxal-induced enhancement of uridine diphosphate-mediated contraction in rat femoral artery was due to activation of p38 MAPK and Syk tyrosine kinase

Abstract

Although abnormalities of function in femoral artery, including aberrant vascular reactivity to various vasoactive mediators, are common in many chronic disorders including hypertension and diabetes, their inducible and/or progressive factors remain unclear. On the other hand, methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of several chronic disorders. Although our previous studies demonstrated that uridine 5'-diphosphate (UDP)-induced contraction in the femoral artery is increased in hypertensive rat model, the direct relationship between MGO and UDP-mediated contraction is currently unknown in rat femoral artery. We therefore investigated the acute effect of MGO (4.2 × 10−4 M for 60 min) on UDP-induced contraction in the rat femoral artery. MGO amplified the UDP-induced contraction in the Wistar rat femoral artery. This augmented response was not abolished in all conditions, including nitric oxide synthase inhibition by L-NNA (10−4 M), cyclooxygenase inhibition by indomethacin (10−5 M), or endothelial denudation. Moreover, in the endothelium-denuded arteries, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (10−5 M) reduced the UDP-induced contraction in both control and MGO-treated groups, while MGO enhanced the p38 MAPK activation regardless of the UDP presence. Moreover, in the endothelium-denuded arteries, the Syk tyrosine kinase inhibitor piceatannol (10−5 M) reduced the UDP-induced contraction in both control and MGO-treated groups. These results suggest that MGO enhances UDP-induced contraction in rat femoral arteries and that this enhancement may be partly due to increases in the activities of Syk tyrosine kinase and p38 MAPK in femoral arterial smooth muscle.