Regulation of vascular and gastric smooth muscle contractility by pervanadate

Abstract

1 The contractile actions of vanadate (VO4) and pervanadate (PV, peroxide(s) of vanadate) were studied in rat gastric longitudinal muscle strips and in aortic rings. The roles of extracellular sodium and calcium were evaluated and the potential effects of nerve-released agonists were considered. The possibility that these responses were due to the potentiation of tyrosine kinase activity, as a result of PV-mediated tyrosine phosphatase inhibition was explored with the use of tyrosine kinase inhibitors (genistein, tyrphostin) and by Western blot analysis of phosphotyrosyl proteins in PV-treated tissues. The ability of PV to mimic the action of the tyrosine kinase receptor-associated agonist, epidermal growth factor-urogastrone (EGF-Uro), in the gastric preparation was also studied. 2 PV caused concentration-dependent contractions in both gastric and aorta-derived tissues, with a potency that was 1 to 2 orders of magnitude greater than that of VO4. 3 Although repeated exposure of gastric and aortic tissues to a fixed concentration of V04 caused reproducible contractions in both tissues, repeated exposure of gastric tissue to PV caused an increased contractile response plateauing after 3 exposures. In contrast, a single exposure of aortic tissue to PV (20 JM) caused a prolonged desensitization of the tissue to the subsequent contractile actions of PV or other agonists. 4 The contractile responses to PV were unaffected in both preparations by tetrodotoxin, atropine, yohimbine and phenoxybenzamine; and in the aortic preparation, the responses to V04 and PV were the same in the presence or absence of a functional endothelium. 5 PV-induced contractions in both tissues were observed in the absence of extracellular sodium but required extracellular calcium and were attenuated by 1 JAM nifedipine. 6 In the gastric preparation, the characteristics of the contractile actions of PV paralleled those of EGF-Uro in terms of (1) inhibition by genistein, (2) inhibition by indomethacin and (3) a requirement for extracellular calcium. These response characteristics differed from those of other contractile agonists such as carbachol. 7 In both the gastric and aortic preparations genistein was able to inhibit PV-induced contractions selectively without causing comparable inhibition of KCI-induced contractions. Tyrphostin (AG18) also selectively blocked PV-induced contractions in the gastric, but not in the aortic preparation. 8 In both the gastric and aortic tissue, in step with an increased contractile response, PV caused increases in tissue phosphotyrosyl protein content, as detected by Western blot analysis using a monoclonal antiphosphotyrosine antibody; the increases in phosphotyrosyl protein content were reduced when tissues were treated with PV at the same time as a tyrosine kinase inhibitor. 9 PV, at sub-contractile concentrations, potentiated the contractile action of angiotensin II in both the gastric and aorta tissue.10 We conclude that the growth factor-mimetic agent, PV, is a much more potent contractile agonist than V...

Effects of flavonoids on rat aortic smooth muscle contractility: Structure-activity relationships

“…These results imply that position 2 or 3 of the phenyl ring is not essential for the vasodilatory activity. Tyrosine kinase inhibitors, such as genistein (Akiyama et al, 1987) selectively inhibit pervanadate-induced contractions, in both gastric and aortic preparations, without causing comparable inhibition of KCl-induced contraction (Laniyonu et al, 1994). Because pervanadate mimics the action of the tyrosine kinase receptor-associated agonist epidermal growth factor, the inhibition of contractions evoked by the agonist tested in this study, is independent of the tyrosine kinase pathway.…”

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

“…On the other hand, vanadate was found to augment free intracellular Ca 2+ in smooth muscle cells, thereby promoting increased vascular tone and contractility (99). The increased level of tyrosine phosphorylation, typically described in the mechanism of the insulinomimetic effects of vanadium derivates (13,100), was also found to be associated with the smooth muscle contractile activities by vanadium compounds (101,102). Carr et al (103) demonstrated that protein tyrosine phosphatase (PTPase) inhibition by BMOV enhances the endothelial receptor tyrosine kinase (RTK) activity and improves collateral blood flow.…”

Orthovanadate-Induced Vasoconstriction of Rat Mesenteric Arteries Is Mediated by Rho Kinase-Dependent Inhibition of Myosin Light Chain Phosphatase

“…23) Several studies show that vanadium compounds stimulate smooth muscle constriction, which is mediated by activation of Rho kinase in several tissue types. [9][10][11][12][13][14][24][25][26] Mori and Tsushima showed that Rho kinase played a role in OVA-induced smooth muscle constriction using guinea pig ileal longitudinal smooth muscle; Rho kinase inhibitor Y-27632 blocked OVA-induced constriction and MLC phosphorylation. 15) Our study in rat thoracic aorta tissue also showed that OVA-induced constriction was abolished by a Rho kinase inhibitor.…”

“…7,8) Vanadium compounds exert contractile effects on vascular and non-vascular smooth muscle, such as the guinea pig taenia coli, trachea, and gallbladder smooth muscle. [9][10][11] The contractile effects of vanadates have been considered to be due to inhibition of PTPase, 9,11,12) but not ATPase, 13,14) because genistein, a protein tyrosine kinase inhibitor, attenuates vanadateinduced constriction. Vanadate-induced muscle constriction was regulated by activation of Rho kinase-dependent signaling in ileal longitudinal smooth muscle in guinea pigs, resulting in increased phosphorylation of the myosin light chain (MLC).…”