Difference in signal transduction mechanisms involved in 5-hydroxytryptamine- and U46619-induced vasoconstrictions.
In order to elucidate the signal transduction pathways of vascular smooth muscle contractions induced by stimulation of receptors for 5-hydroxytryptamine (5-HT) and thromboxane A2 (TXA2), both of which are released from activated platelets, we examined whether protein kinases, such as tyrosine kinase, p38 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC), are involved in the contraction produced by either 5-HT or U46619 (an analog of TXA2) in the rat aorta. Both 5-HT and U46619 induced sustained contractions, which were markedly reduced in the absence of extracellular Ca2+. Verapamil (a L-type Ca2+ channel blocker) markedly inhibited the contractile response to 5-HT, while the U46619-induced contraction was only slightly inhibited by verapamil. Both contractile responses to 5-HT and U46619 were significantly inhibited by calphostin C (a PKC inhibitor). On the other hand, both genistein (5 microM, a tyrosine kinase inhibitor) and SB203580 (a p38 MAPK inhibitor) significantly inhibited 5-HT-induced contractions but had little effects on the contractions induced by U46619. These results suggest that the signal transduction mechanisms involved in the contractions mediated via 5-HT and TXA2 receptors are different as follows. Both the tyrosine kinase and p38 MAPK pathways are involved in 5-HT contraction but not in TXA2 contraction, while both contractions are strongly dependent on transplasmalemmal Ca2+ entry. The contractile responses to both 5-HT and TXA2 involve voltage-dependent Ca2+ channels and PKC.
Tasaki
Katsunari
K
Department of Hygiene & Preventive Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Hori
Masatoshi
M
Ozaki
Hiroshi
H
Karaki
Hideaki
H
Wakabayashi
Ichiro
I
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D011725:Pyridines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D012701:Serotonin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D014700:Verapamil; D019833:Genistein; C058819:calphostin C; C093642:SB 203580; D002118:Calcium