Prostanoid TP receptor-mediated impairment of cyclic AMP-dependent vasorelaxation is reversed by phosphodiesterase inhibitors.
Activation of the thromboxane prostanoid (TP) receptor produces potent vasoconstriction, which contributes to the increased vascular tone and blood pressure. The present study was designed to examine the hypothesis that stimulation of prostanoid TP receptors impairs endothelium-independent relaxations to cyclic AMP-elevating agents via increasing the activity of phosphodiesterases (PDEs). Rat carotid arteries without endothelium were isolated and suspended in myograph for the measurement of changes in isometric tension; the tissue content of cyclic AMP was assayed by enzyme immunoassay kit; and prostanoid TP receptor was detected in vascular wall by immunohistochemistry and Western blot. In phenylephrine-contracted rings without endothelium, relaxations induced by isoprenaline (receptor-mediated) and forskolin (receptor-independent) were markedly reduced by the presence of a prostanoid TP receptor agonist, U46619; the attenuated relaxations were prevented by acute treatment with S18886, the selective prostanoid TP receptor antagonist, but not by protein kinase C inhibitors. The reduced relaxations were partially restored by IBMX (non-selective PDE inhibitor), cilostazol (PDE3 inhibitor), rolipram (PDE4 inhibitor) or by Y27632 (Rho kinase inhibitor), but not by T0156 (PDE5 inhibitor). U46619 diminished isoprenaline- or forskolin-stimulated rise in cyclic AMP and this effect was inhibited by cilostazol, rolipram or Y27632. The present results suggest that activation of prostanoid TP receptors impairs cyclic AMP-dependent vasorelaxations partly via PDE- and RhoA/Rho kinase-dependent mechanisms. Inhibitors of PDEs and Rho kinase may be useful in the treatment of cardiovascular complications.
Liu
Cui Qing
CQ
Department of Physiology, Hangzhou Normal University, China.
Wong
Siu Ling
SL
Leung
Fung Ping
FP
Tian
Xiao Yu
XY
Lau
Chi Wai
CW
Lu
Limin
L
Yao
Xiaoqiang
X
Chen
Zhen Yu
ZY
Yao
Tai
T
Huang
Yu
Y
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D010726:Phosphodiesterase Inhibitors; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D000242:Cyclic AMP; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine