Involvement of Endothelium-Derived Factors in Controlling the Active Tone of Smooth Muscle in Aorta from Hypertensive Rats.

Sekiguchi, Fumiko; Matsuda, Kyoko; Shimamura, Keiichi; Takeuchi, Kiyoko; Sunano, Satoru

doi:10.1540/jsmr.34.221

Cited by 8 publications

(6 citation statements)

References 30 publications

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“…Spontaneous tone was not observed until 5 or 6 days of ANG II infusion. In addition, spontaneous tone exists in several hypertensive animal models (7,26,35,44), suggesting that it is more likely a hypertension-related response than a receptormediated response. The results obtained from this study, as well as other studies, suggest that substances that prevent spontaneous tone may be possible therapeutic treatments of hypertension or hypertension-related diseases.…”

Section: Discussionmentioning

confidence: 99%

ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension

Ding¹,

Chapman²,

Boyd³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Arteries from hypertensive animals and humans have increased spontaneous tone. Increased superoxide anion (superoxide) contributes to elevated blood pressure (BP) and spontaneous tone in hypertension. The association between the extracellular signaling-regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK) signaling pathway and generation of superoxide and spontaneous tone in isolated aorta was studied in angiotensin II (ANG II)-infused hypertensive (HT) rats. Systolic BP, phosphorylation of ERK, aortic superoxide formation, and aortic spontaneous tone were compared in sham normotensive and HT rats. Infusion of ANG II (0.5 mg x kg(-1) x day(-1) for 6 days) significantly elevated the systolic BP (P<0.01). The phosphorylation of ERK1/2 vs. total ERK1/2 in thoracic aorta was enhanced, and superoxide was increased in the HT vs. the sham group (P<0.01). Spontaneous tone developed in the HT group, but not in the normotensive group. MAPK/ERK1/2 (MEK1/2)-ERK1/2 signaling pathway inhibitors, PD-98059 (10 micromol/l), and U-0126 (10 micromol/l), significantly reduced the phosphorylation of ERK1/2, superoxide generation (P<0.01), and spontaneous tone (P<0.01) in HT. These findings suggest that ANG II infusion induces the production of superoxide and spontaneous tone and that both are dependent on ERK-MAPK activation. In endothelium-denuded aorta, however, MEK1/2 inhibitors did not inhibit the spontaneous tone, even though they significantly reduced superoxide generation similar to endothelium-intact aorta. These data suggest that inhibition of ERK1/2 signaling pathway, via PD-98059 or U-0126, may regulate spontaneous tone in an endothelium-dependent manner. In conclusion, these findings support the importance of the ERK1/2 signaling pathway in modulating vascular oxidative stress and subsequently mediating spontaneous tone in HT.

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Section: Discussionmentioning

confidence: 99%

ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension

Ding¹,

Chapman²,

Boyd³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Development of spontaneous tone has been studied in blood vessels from several hypertensive animal models including spontaneously hypertensive rats, deoxycorticosterone (DOCA)-salt hypertensive rats and Ang II-induced hypertensive rats (Sekiguchi et al, 1998;Di Wang et al, 1999;Ghosh et al, 2004). Whereas Ca 2ϩ -dependent mechanisms are ascribed for the increased tone of aortae from Ang IIinduced hypertensive rats, the Ca 2ϩ sensitization pathways are yet to be explored.…”

Section: Discussionmentioning

confidence: 99%

Increased RhoA/Rho-Kinase Signaling Mediates Spontaneous Tone in Aorta from Angiotensin II-Induced Hypertensive Rats

Jin

Zhao

Hilgers

et al. 2006

J Pharmacol Exp Ther

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Spontaneous tone in large arteries may contribute to the pathogenesis of hypertension. Reactive oxygen species and Ca 2ϩ influx have been shown to stimulate the development of spontaneous tone in isolated aortic rings in several models of hypertensive rats. The aim of this study was to investigate the role of the RhoA/Rho-kinase signaling pathway in the development of spontaneous tone in angiotensin II-induced hypertension and to explore the underlying mechanisms of RhoA/Rho-kinase activation. Our results showed that spontaneous tone was greatly enhanced in endothelium-denuded aortic rings from angiotensin II-induced hypertensive rats compared with their normotensive counterparts (73 Ϯ 5 versus 7 Ϯ 3% of phenylephrine-induced maximal contraction, respectively). The Rhokinase inhibitor (R)-(ϩ)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) (0.1-10 M) concentration dependently inhibited spontaneous tone in aortic rings from angiotensin II-treated rats. NADPH oxidase inhibitors diphenylene iodonium and apocynin also significantly reduced spontaneous tone. Chronic angiotensin II treatment markedly increased RhoA protein expression (57%) but had no effect on Rho guanine nucleotide exchange factor mRNA or Rho-kinase protein expression levels. In endothelium-denuded rings from normotensive rats, angiotensin II (100 nM) increased RhoA membrane translocation and phosphorylation of the myosin light chain phosphatase target subunit, which were both blocked by the NADPH oxidase inhibitor diphenylene iodonium (10 M). In conclusion, these data suggest that chronic treatment with angiotensin II leads to up-regulation of the RhoA/ Rho-kinase pathway, contributing to spontaneous tone development in rat aorta. Increased NADPH oxidase-dependent reactive oxygen species may be one of the mechanisms mediating the RhoA/Rho-kinase activation.Angiotensin II (Ang II) produced by the renin-angiotensin system is an important hormone in the homeostasis of cardiovascular and renal function. Increased circulating Ang II promotes inflammation and cell growth and increases vascular reactivity (Kagiyama et al., 2002;Seshiah et al., 2002). It is well known that activation of Ang II type I receptor (AT 1 ) increases free intracellular Ca 2ϩ concentration and myosin light chain (MLC) kinase activity, leading to MLC phosphorylation and subsequent smooth muscle contraction. Recent studies suggest that the phosphorylation state of MLC is also modulated by RhoA/Rho-kinase, a Ca 2ϩ sensitization signaling pathway through which smooth muscle is able to contract when the intracellular Ca 2ϩ concentration is low (Somlyo and Somlyo, 2003).The activity of RhoA is regulated by Rho guanine nucleotide exchange factors (RhoGEFs) and Rho GDP disassociation inhibitors (Somlyo and Somlyo, 2003). In its inactive state, RhoA binds with GDP and forms a complex with GDP disassociation inhibitors in the cytosol. When RhoGEF is activated by G protein-coupled receptors such as AT 1 or receptor tyrosine kinase, it facilitates the exchange of ...

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“…Arachidonic acid (AA) is metabolized by the vascular endothelium and smooth muscle cells to a variety of cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CYP450) epoxygenase products, and these metabolites exert influences over vascular tone (Sekiguchi et al, 1998;Roman et al, 2000;Roman, 2002;Fleming, 2001;Miyata and Roman, 2005;Shimamura et al, 2005;Vizoili et al, 2005;Imig, 2006). The identity and potential biological activity of some of the relevant AA metabolites remain poorly characterized (structurally and/or biologically).…”

Section: Introductionmentioning

confidence: 99%

Altered arachidonic acid-mediated responses in the perfused kidney of the streptozotocin-induced diabetic rat

Kamata

Hosokawa

Matsumoto

et al. 2006

J Smooth Muscle Res

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Using perfused kidneys isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we investigated the effects of arachidonic acid (AA) on perfusion pressure in the presence of methoxamine. AA elicited a transient contraction followed by a sustained relaxation in each group. The amplitude of contraction was smaller in the diabetic group than in the control group, whereas the amplitude of the sustained relaxation was greater in the former than in the latter group. In the diabetic group, the AA-induced sustained relaxation was completely inhibited by indomethacin [cyclooxygenase (COX) inhibitor], SKF525A [cytochrome P450 (CYP450) inhibitor], or clotrimazole (epoxygenase inhibitor), but not by furegrelate [thromboxane A2 (TXA2)-synthase inhibitor], SQ29548 (TXA2-receptor antagonist), or baicalein [lipoxygenase (LOX) inhibitor]. In the diabetic kidney, more-or-less additive inhibitions of the AAinduced relaxation were seen when indomethacin was given with either SKF525A or clotrimazole. These results suggest that in the STZ-induced diabetic perfused kidney, vasorelaxant metabolites derived from AA (probably COX and/or CYP450 metabolites) are increased, and may serve to regulate vascular tone.

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Involvement of Endothelium-Derived Factors in Controlling the Active Tone of Smooth Muscle in Aorta from Hypertensive Rats.

Cited by 8 publications

References 30 publications

ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension

ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension

Increased RhoA/Rho-Kinase Signaling Mediates Spontaneous Tone in Aorta from Angiotensin II-Induced Hypertensive Rats

Altered arachidonic acid-mediated responses in the perfused kidney of the streptozotocin-induced diabetic rat

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