Tyrosine Kinase Inhibitors Suppress Agonist-Induced Contraction in Smooth Muscle

DiSalvo, Joseph; Steusloff, Annette; Semenchuk, Lori A.; Satoh, Shoji; Kolquist, K.; Pfitzer, Gabriele

doi:10.1006/bbrc.1993.1144

Cited by 159 publications

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“…In the present study, genistein and tyrphostin 23 showed a differential inhibitory effect on the acidic pH , PE-, and KCl-induced contractions, that is, the drugs inhibited the acidic pH and PE-induced contractions markedly compared with that induced by KCl. Similar relaxant effects of tyrosine kinase inhibitors, including tyrphostin 23 and genistein, on a variety of agonists-induced contractions in vascular tissues have been reported through inhibition of tyrosine kinases (Di Salvo et al, 1993;Jin et al, 1996;Watts et al, 1996;Yang et al, 2000b;Carmines et al, 2001). …”

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confidence: 62%

“…Tyrosine kinase-mediated pathways have also been shown to cause agonist-stimulated VSM contractile processes (Khalil et al, 1995;Banes et al, 1999). Consistently, tyrosine kinase inhibitors have been shown to attenuate vasoconstriction caused by a number of agents, including noradrenaline and angiotensin II in intact arteries (Di Salvo et al, 1993Laniyonu et al, 1994;Carmines et al, 2001). Recent studies have shown that the voltage-dependent Ca 2ϩ channels (VDCCs), activated by many vasoactive agents, are inhibited by tyrosine kinase inhibitors via tyrosine kinases (Wijetunge et al, 1992;Wijetunge et al, 1998;Lagaud et al, 1999).…”

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confidence: 93%

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Stimulated Tyrosine Phosphorylation of Phosphatidylinositol 3-Kinase Causes Acidic pH-Induced Contraction in Spontaneously Hypertensive Rat Aorta

Rohra

Yamakuni²,

Furukawa³

et al. 2002

J Pharmacol Exp Ther

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Acidic pH induced a contraction (APIC) in isolated aortas from spontaneously hypertensive (SHR) and Wistar Kyoto rats, but failed to produce any response in age-matched Wistar rat aorta. This study was conducted to test the hypothesis that tyrosine phosphorylation of proteins is a molecular mechanism underlying the APIC. Tyrosine kinase inhibitors, genistein and tyrphostin 23 inhibited the APIC in a concentration-dependent manner. APIC was inhibited by phosphatidylinositol 3-kinase (PI3-kinase) inhibitors, LY-294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride] and wortmannin. Consistent with the results from tension measurement experiments, Western blot analysis showed that acidic pH induced an appreciable increment of tyrosine phosphorylation of 85-kDa protein (p85) in SHR aorta, which was completely inhibited by tyrphostin 23, whereas in Wistar rat aorta, the protein tyrosine phosphorylation was not observed. Further investigations using immunoprecipitation followed by Western blotting confirmed an increase in the tyrosine phosphorylation of p85. Analysis by SDS-polyacrylamide gel electrophoresis followed by silver staining of the gel revealed that amounts of multiple proteins with molecular sizes of 120, 130, 210, and 225 kDa were increased at acidic pH, which were immunoprecipitated with anti-phosphotyrosine antibody. Western blotting using a specific anti-PI3-kinase antibody identified the p85 as the regulatory subunit of PI3-kinase, whereas 120-, 130-, and 225-kDa proteins were identified by mass spectrometry as pro-␣2 (I) collagen, collagen ␣1 (I) chain, and fibernectin I, respectively. As assayed by Western blotting using anti-myosin light chain (MLC) antibody, acidic pH induced a stimulation of MLC phosphorylation, and the stimulated MLC phosphorylation was abolished by tyrphostin 23 and LY-294002. These results suggest that acidic pH induces an increase in tyrosine phosphorylation of PI3-kinase, resulting in the MLC phosphorylation-dependent contraction of SHR aorta.

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confidence: 62%

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confidence: 93%

Stimulated Tyrosine Phosphorylation of Phosphatidylinositol 3-Kinase Causes Acidic pH-Induced Contraction in Spontaneously Hypertensive Rat Aorta

Rohra

Yamakuni²,

Furukawa³

et al. 2002

J Pharmacol Exp Ther

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“…This observation is consistent with the fact that phosphorylation of tyrosyl residues by tyrosine kinase is implicated in the mechanisms leading to constriction of vascular smooth muscle [18][19][20][21][22]. Vasoconstriction occurs as a result of activation of myosin light chain kinase (MLCK) that, in turn, phosphorylates myosin light chain, thereby enabling formation of actin-myosin cross bridges resulting in vascular smooth muscle contraction [23].…”

Section: Discussionsupporting

confidence: 78%

Role of tyrosine phosphatase in the modulation of pulmonary vascular tone

Huang¹,

Kebir²,

Roessingh³

et al. 2002

European Respiratory Journal

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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 Ca 2z /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, 1610 -6 M) significantly: 1) increased phenylephrine-induced vasoconstriction and 2) decreased endotheliumdependent relaxation to acetylcholine, but had no effect on endothelium-independent relaxation to the NO donor, sodium nitroprusside. In phenylephrine-precontracted pulmonary arterial rings, SOV (1610 -7 -1610 -5 M) had no effect on vascular tone but significantly relaxed rings which were pretreated with the NO-synthase inhibitor, N v -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 endotheliumdependent 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. Pulmonary vascular tone is modulated by a variety of endothelium-derived relaxing factors including prostacyclin, nitric oxide (NO) [1,2], and the endothelium-derived hyperpolarizing factors (EDHF) [2,3]. NO is one of the most potent vasodilators known to date. Its synthesis is tightly regulated by intracellular free Ca 2z and the Ca 2z / calmodulin complex that, in turn, stimulate the constitutive isoform of endothelial NO synthase (eNOS). Alternatively, phosphorylation on seryl and threonyl residues by various seryl/threonyl kinases is also thought to modulate eNOS activity [4,5].Shear stress is the major physiological factor modulating pulmonary vascular tone in health and disease. The underlying mechanism most likely involves synthesis and release of NO from pulmonary endothelial cells. Recent evidence suggests that endothelial production of NO is increased in response to shear stress through tyrosine phosphorylation via a calcium-independent pathway in the systemic circulation [4,6]. Contradictory studies alternatively suggest that tyrosine phosphorylation of eNOS might also reduce its activity [7]. Whether or not alteration of phosphorylation and/or dephosphorylation of tyrosyl residues of eNOS affects its activity in the pulmonary artery has yet to be investigated.In various vascular beds, EDHF causes relaxatio...

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“…However, studies with platelets (30,31,34), fibroblasts (20), and colonic smooth muscle (10,13) have suggested that depletion of intracellular calcium stores induces calcium influx across the plasma membrane via a PTK-dependent mechanism. Moreover, inhibitors of PTKs have been shown to inhibit contractions of isolated bronchioles of the rat (9).…”

Section: Discussionmentioning

confidence: 99%

Refilling of caffeine-sensitive intracellular calcium stores in bovine airway smooth muscle cells

Madison

Ethier

Yamaguchi

1998

American Journal of Physiology-Lung Cellular and Molecular Phys

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Yamaguchi. Refilling of caffeine-sensitive intracellular calcium stores in bovine airway smooth muscle cells. Am. J. Physiol. 275 (Lung Cell. Mol. Physiol. 19): L852-L860, 1998.-The goal of this study was to assess the mechanisms by which the caffeine-sensitive calcium stores of airway smooth muscle cells are refilled. Bovine trachealis cells were loaded with fura 2-AM (0.5 µM) for imaging of cytosolic calcium concentrations ([Ca 2ϩ ] i ) in the inner cytosol. After a first stimulation (S1) with caffeine, the response to a second stimulation (S2) depended on the presence of extracellular calcium during an intervening 80-s-long refilling phase. The S2-to-S1 ratio (S2/S1) was 0.11 Ϯ 0.05 (n ϭ 13 cells) during calcium-free refilling but 0.72 Ϯ 0.04 (n ϭ 36 cells) within 80 s of exposure to extracellular calcium. Maximum mean [Ca 2ϩ ] i during the 80 s of refilling was not different for calcium-free (116 Ϯ 19 nM; n ϭ 13 cells) versus extracellular calcium plus nickel (2 mM) (121 Ϯ 12 nM; n ϭ 21 cells); despite this, significantly greater refilling (S2/S1 0.58 Ϯ 0.06; n ϭ 24 cells) occurred in the presence of extracellular calcium plus nickel. The protein tyrosine kinase inhibitors genistein (100 µM) and ST-638 (50 µM) significantly decreased refilling over 80 s (S2/S1 0.35 Ϯ 0.06, n ϭ 14 cells and 0.51 Ϯ 0.07, n ϭ 14 cells, respectively). Daidzein (100 µM) had no effect on S2/S1. We concluded that [Ca 2ϩ ] i of the inner cytosol during refilling correlated poorly with S2/S1 values and that, therefore, additional compartments not well detected by fura 2 contribute to refilling. The findings suggest that calcium influx for refilling is segregated from the inner cytosol of the cell, relatively insensitive to nickel, and regulated or modulated by protein tyrosine kinase activity.tracheal smooth muscle; fura 2; capacitative calcium entry; sarcoplasmic reticulum; protein tyrosine kinase EVIDENCE FROM MANY CELL TYPES, including smooth muscle (7, 23), supports the essential feature of the capacitative calcium entry model (3,26). In that model of intracellular calcium store refilling, the calcium content of intracellular calcium stores regulates or modulates calcium influx across the plasma membrane. How a decrease in the calcium content of intracellular stores stimulates the calcium influx that refills intracellular calcium stores is not known, but possibilities have included signaling by direct protein-protein interactions (15), guanyl nucleotide binding proteins (11), diffusible messengers (28), and protein tyrosine kinase (PTK) phosphorylations (13,20,30,34).Among different cell types, there may be differences in the extent to which cytosolic calcium concentration ([Ca 2ϩ ] i ) is the determinant of intracellular store refilling. In most nonexcitable cells such as parotid acinar cells (27, 32), pancreatic acini (25), and human leukemia cells (24), it was shown that an increase in [Ca 2ϩ ] i was necessary for refilling of intracellular stores. However, in human fibroblasts, intracellular calcium stores refilled witho...

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Tyrosine Kinase Inhibitors Suppress Agonist-Induced Contraction in Smooth Muscle

Cited by 159 publications

References 0 publications

Stimulated Tyrosine Phosphorylation of Phosphatidylinositol 3-Kinase Causes Acidic pH-Induced Contraction in Spontaneously Hypertensive Rat Aorta

Stimulated Tyrosine Phosphorylation of Phosphatidylinositol 3-Kinase Causes Acidic pH-Induced Contraction in Spontaneously Hypertensive Rat Aorta

Role of tyrosine phosphatase in the modulation of pulmonary vascular tone

Refilling of caffeine-sensitive intracellular calcium stores in bovine airway smooth muscle cells

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