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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1921.)
© 2001 American Heart Association, Inc.

Vascular Biology

Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

Jacqueline Ohanian; Pamela Cunliffe; Enrico Ceppi; Angela Alder; Egidius Heerkens; Vasken Ohanian

From the Department of Medicine, University of Manchester, Manchester Royal Infirmary, Manchester, UK.

Correspondence to Dr Jacqueline Ohanian, Department of Medicine, University of Manchester, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. E-mail johanian{at}man.ac.uk

Small-artery responses to vasoconstrictor agonists are important for vascular function. To investigate the signaling pathways involved in contraction, we studied the activation and regulation of p38 mitogen-activated protein kinases (p38MAPKs) and heat shock protein (HSP) kinase by endothelin and noradrenaline in rat mesenteric arteries. Both vasoconstrictors activated p38 and/or p38ß but not p38 or p38, leading to increased HSP kinase activity. p38MAPK activation by noradrenaline was maximum between 2 and 10 minutes and was wholly dependent on calcium influx but insensitive to the tyrosine kinase inhibitor herbimycin A. In contrast, endothelin induced a biphasic response, with activation at 2 and 10 minutes. The early activity was wholly dependent on calcium influx and inhibited by herbimycin A. The later activity was only 50% calcium dependent, was insensitive to herbimycin A, but was 50% inhibited by genistein, a nonselective tyrosine kinase inhibitor. With both agonists, p38MAPK activity returned to basal by 30 minutes. SB203580, a p38MAPK inhibitor, blocked agonist-induced HSP kinase activity, and herbimycin A inhibited activation by endothelin but not by noradrenaline. In addition, SB203580 inhibited noradrenaline-induced contraction but had little effect on contraction to endothelin. These data show that vasoconstrictors use different upstream activators of p38MAPK in vascular tissue and that the p38MAPK pathway is selectively implicated in the contractile response to noradrenaline in small arteries.

Key Words: vasoconstrictors • vascular smooth muscle • heat shock proteins • signal transduction