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.