We previously reported that pressure loading of the vascular wall can activate mitogen-activated protein kinases (MAPKs), enzymes believed to be involved in the pathway for cell proliferation, partly via the vascular angiotensin system in isolated perfused rat aorta. In this study, we examined whether cyclic stretching of vascular smooth muscle cells (VSMC) also produces activation of p42 and p44 MAPKs in cultured rat VSMC and whether stretch-induced MAPK activation is mediated via angiotensin and endothelin systems in VSMC. Cyclic stretching of VSMC produced an elongation-dependent and frequency-dependent increase in p42 and p44 MAPK activity. The stretch-induced p42 and p44 MAPK activation was inhibited by the angiotensin receptor antagonist losartan and by the angiotensin-converting enzyme inhibitor, captopril. The MAPK activation was also inhibited by the endothelin receptor antagonist cyclo(D-α-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl) (BQ123) and by the endothelin-converting enzyme inhibitor phosphoramidon. Replacement of medium with culture medium of stretched cells caused MAPK activation, which was inhibited by losartan and BQ123. The results of the present study suggest that cyclic stretching of VSMC can activate p42 and p44 MAPKs and that the MAPK activation is mediated via angiotensin and endothelin systems in VSMC.