Involvement of epidermal growth factor receptor-protein tyrosine kinase transactivation in endothelin-1-induced vascular contraction.
OBJECTIVE
Endothelin-1 (ET-1) is one of the major inducers of vasospasm following subarachnoid hemorrhage (SAH). It is generally accepted that extracellular signal-regulated kinase 1 and 2 (ERK1/2) are involved in ET-1-induced vascular contraction. In addition, ET-1 transactivates epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK), which leads to ERK1/2 stimulation. Therefore, the authors examined whether EGFR-PTK transactivation contributes to ET-1-induced vascular contraction in this study.


METHODS
Mitogen-activated protein kinase inhibitor, PD98059, inhibited ET-1-induced ERK1/2 stimulation in rabbit basilar artery (BA) vascular smooth-muscle cells (VSMCs). Moreover, PD98059 inhibited ET-1-induced contraction of rabbit BA rings. A specific inhibitor of EGFR PTK, AG1478, inhibited ET-1-induced EGFR-PTK transactivation, ERK1/2 stimulation, and contraction of BA rings in a concentration-dependent manner. The concentration of AG1478 required for 50% inhibition of the ET-1-induced contraction of BA rings was similar to that for ET-1-induced EGFR-PTK transactivation. Furthermore, AG1478 also inhibited ET-1-induced BA vasospasm in vivo.


CONCLUSIONS
The results indicate that EGFR-PTK transactivation pathway plays an important role in ET-1-induced vascular contraction.
Kawanabe
Yoshifumi
Y
Department of Neurosurgery and Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan. kawanabe@takatsuki.jrc.or.jp
Masaki
Tomoh
T
Hashimoto
Nobuo
N
D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology*; D011817:Rabbits; D015398:Signal Transduction; D013345:Subarachnoid Hemorrhage / Q000150:complications; D015533:Transcriptional Activation; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000503:physiopathology*
D019332:Endothelin-1; D066246:ErbB Receptors