Midazolam stimulates vascular endothelial growth factor release in aortic smooth muscle cells: role of the mitogen-activated protein kinase superfamily.
BACKGROUND
Intravenous anesthetics used during perioperative periods affect the vascular signaling molecules and the vascular reactivity. Vascular endothelial growth factor (VEGF), an angiogenesis factor produced in and secreted from aortic smooth muscle cells, is a specific mitogen for vascular endothelial cells. This study investigated the effects of various intravenous anesthetics on VEGF release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells.


METHODS
Intravenous anesthetics (midazolam and propofol) were continuously administered to rats by infusion. Cultured A10 cells were stimulated by intravenous anesthetics (midazolam, propofol, and ketamine). VEGF was evaluated by immunoassay. The phosphorylation of mitogen-activated protein (MAP) kinases was evaluated by Western blotting.


RESULTS
Continuous infusion of midazolam, but not propofol, increased the VEGF concentration in rat plasma. In cultured cells, midazolam stimulated VEGF release, but propofol and ketamine did not. Midazolam induced phosphorylation of p44/p42 MAP kinase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), without affecting p38 MAP kinase. PD98059 and U0126, specific inhibitors of MAP kinase kinase, significantly reduced the midazolam-stimulated release of VEGF. SP600125, a specific inhibitor of SAPK/JNK, significantly reduced midazolam-stimulated VEGF release. Applied together, PD98059 and SP600125 produced an additive reduction in midazolam-stimulated VEGF release. Moreover, a bolus injection of PD98059 truly inhibited the midazolam-increased VEGF concentration in rat plasma in vivo.


CONCLUSIONS
Midazolam, but not propofol or ketamine, stimulates VEGF release in aortic smooth muscle cells. Its effect is mediated at least in part via activation of p44/p42 MAP kinase and SAPK/JNK.
Tanabe
Kumiko
K
Department of Anesthesiology and Critical Care Medicine, Gifu University Hospital, Gifu, Japan.
Dohi
Shuji
S
Matsuno
Hiroyuki
H
Hirade
Kouseki
K
Kozawa
Osamu
O
D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000097:blood / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D007700:Kinetics; D008222:Lymphokines / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008874:Midazolam / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000759:Adjuvants, Anesthesia; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D008874:Midazolam; D015742:Propofol