Role of tyrosine phosphatase in the modulation of pulmonary vascular tone.
In the vascular system, synthesis of the potent vasodilator nitric oxide (NO) is tightly regulated by the constitutively expressed endothelial NO synthase (eNOS). Activity of eNOS is controlled by Ca2+/calmodulin and various seryl/threonyl protein kinases. Less is known about the importance of phosphorylation and dephosphorylation of tyrosyl residues. Therefore the role of tyrosine phosphatase on the modulation of isolated rat pulmonary artery tone has been assessed. Inhibition of tyrosine phosphatase by sodium orthovanadate (SOV, 1x10(-6) M) significantly: 1) increased phenylephrine-induced vasoconstriction and 2) decreased endothelium-dependent relaxation to acetylcholine, but had no effect on endothelium-independent relaxation to the NO donor, sodium nitroprusside. In phenylephrine-precontracted pulmonary arterial rings, SOV (1x10(-7)-1x10(-5) M) had no effect on vascular tone but significantly relaxed rings which were pretreated with the NO-synthase inhibitor, N(omega)-nitro-L-arginine-methyl ester (L-NAME). SOV-induced relaxation in the presence of L-NAME was, however, abolished by glibenclamide. In conclusion, inhibition of tyrosine phosphatase altered pulmonary vascular tone by increasing vasoconstrictor response to phenylephrine and decreasing endothelium-dependent relaxation to acetylcholine. Furthermore, the tyrosine phosphatase inhibitor, sodium orthovanadate, exhibited original vasodilator properties which were only observed when nitric oxide synthesis was inhibited. Thus a new pathway involving the inhibitory effect of nitric oxide on a glibenclamide-sensitive diffusible relaxing factor, that might play an important role in the control of pulmonary vascular tone is described.
Huang
X L
XL
Service de Physiologie-Explorations Fonctionnelles, Centre Hospitalier Universitaire, Cochin Assistance Publique-Hĵpitaux de Paris, Université Paris V, France.
El
Kebir D
KD
De
Buys Roessingh A S
BR
Schneider
J C
JC
Jacob
L
L
Mercier
J C
JC
DallA'va-Santucci
J
J
Dinh-Xuan
A T
AT
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D046508:Culture Techniques; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011336:Probability; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D014638:Vanadates / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D010656:Phenylephrine; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester