Characterization of vanadyl sulfate effect on vascular contraction: roles of calcium and tyrosine phosphorylation.
In order to explore the mechanism of action of vanadyl sulfate (VOSO4), previously described as an antidiabetic and antihypertensive agent, we have investigated the role of calcium and tyrosine phosphorylation in the contractile responses of rat aorta or skinned rabbit mesenteric artery rings. VOSO4 induced a concentration-dependent contraction of aorta (pD2 = 3.2), which was potentiated by endothelium removal (pD2 = 4.2). After a first exposure to VOSO4, no change in responsiveness was observed even though high vanadium concentrations had accumulated in the aortic tissue (approximately 4 x 10(-3) M). VOSO4 induced, in calcium-free medium, a significant response that, relative to contractions measured in Krebs-Henseleit buffer, was higher (36%) than norepinephrine (16%)-, arginine-vasopressin (8%)- or KCI (5%)-induced responses. 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), an intracellular calcium release inhibitor, did not modify VOSO4-induced response either in the presence or in the absence of ambient calcium. On skinned preparations, VOSO4 antagonized Ca++-induced contraction. The tyrosine kinase inhibitors tyrphostin 23 (T23) and tyrphostin 47 (T47) potentiated by 4- and 14-fold, respectively, the activity of VOSO4, in contrast to the lack of effect of T47 on pervanadate-induced contraction. When phosphotyrosine content was revealed by Western blotting, VOSO4 had no effect alone, but in the presence of T47, it dramatically increased the phosphotyrosine content. This result contrasts again with PV-induced tyrosine phosphorylation, which was blocked by T47. These data suggest that the signaling events involved in vascular effects of VOSO4, although they depend little on calcium mobilization, are related to tyrosine phosphorylation, likewise through a pathway different from that of pervanadate.
Cadène
A
A
Laboratoire de Pharmacologie, Faculté de Pharmacie, Montpellier, France.
Grigorescu
F
F
Serrano
J J
JJ
Cros
G
G
D000818:Animals; D002118:Calcium / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000378:metabolism*; D017968:Vanadium Compounds / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D017968:Vanadium Compounds; D014443:Tyrosine; C034028:vanadyl sulfate; D010739:Phospholipase D; D002118:Calcium