Effects of TCV-116 on Endothelin-1 and PDGF A-Chain Expression in Angiotensin II-Induced Hypertensive Rats.

Hara, Kazuyoshi; Kobayashi, Naohiko; Nakano, Shigefumi; Mori, Yoshihide; Tsubokou, Yusuke; Matsuoka, Hiroaki

doi:10.1291/hypres.24.55

Cited by 12 publications

(9 citation statements)

References 54 publications

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“…In addition, we have reported that up-regulated preproET-1, endothelin A receptor, and platelet-derived growth factor (PDGF) A-chain mRNA expression in Ang II-induced hypertensive rats were significantly decreased by a subdepressor dose of candesartan (1 mg/kg/day). Moreover, after 2 weeks of treatment, candesartan effectively improved left ventricular hypertrophy and cardiovascular structural changes, and decreased type I collagen mRNA expression, possibly due to a decrease in preproET-1, endothelin A receptor, and PDGF A-chain mRNA expression in the LV (Hara et al, 2001). Therefore, in the present study, these results suggested that cardiovascular remodeling in Ang II-induced hypertensive rats was significantly ameliorated by a subdepressor dose of candesartan, which may be in part mediated by an increase in eNOS expression and a decrease in ET-1 and PDGF A-chain expression in the LV.…”

Section: Discussionmentioning

confidence: 94%

Involvement of Rho-Kinase Pathway for Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Gene Expression and Cardiovascular Remodeling in Hypertensive Rats

Kobayashi¹,

Nakano²,

Mita³

et al. 2002

J Pharmacol Exp Ther

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Angiotensin II (Ang II) is a potent stimulator of plasminogen activator inhibitor-1 (PAI-1) expression, which is an important regulator of pathogenesis of atherosclerosis. Rho-kinase, a downstream target protein of small GTP-binding protein Rho, plays a key role for various cellular functions. We evaluated the cardioprotective effects of a specific Rho-kinase inhibitor, (R)-(ϩ)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), and an Ang II type 1 receptor antagonist, candesartan, on PAI-1 gene expression and cardiovascular remodeling in Ang II-induced hypertensive rats. Rats given Ang II alone (200 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) were compared with rats also receiving Ang II plus Y-27632 or Ang II plus candesartan. Ang II-induced PAI-1 mRNA up-regulation in the left ventricle was inhibited by Y-27632 and candesartan. In addition, increased RhoA protein, Rho-kinase, and c-fos gene expression, and myosin light chain phosphorylation were suppressed by Y-27632 and candesartan. In contrast, Y-27632 had no effect on Ang II-stimulated phospho-p42/p44 extracellular signalregulated kinases (ERK) and phospho-p70S6 kinase activities, which are reported to be involved in Ang II-induced protein synthesis. Moreover, activated Ang II-induced phosphorylation of ERK and p70S6 kinase were blocked by candesartan. Y-27632 or candesartan administration resulted in significant improvements in the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These results suggested that differential activation of Rho-kinase and ERK pathways may play a critical role in Ang II-induce PAI-1 gene expression, and upregulation of Rho-kinase plays a key role in the pathogenesis of Ang II-induced hypertensive rats. Thus, inhibition of the Rhokinase pathway may be at least a useful therapeutic strategy for treating cardiovascular remodeling.Left ventricular hypertrophy is the primary mechanism by which the heart compensates for a sustained increase in hemodynamic loading. Previous studies have shown that increased load itself is directly linked to hypertrophic growth in terms of both a quantitative increase in cardiac mass and qualitative changes in the cardiac phenotype (Cooper, 1987). However, the signaling mechanisms of hypertrophic cardiac growth are largely unknown. Activation of cell proliferation by hormones and growth factors has been shown to correlate with the intracellular activation of several interacting protein cascades. One of the kinases activated by all mitogens is p70S6 kinase, which leads to phosphorylation of the ribosomal S6 protein and increases the rate of translation of mRNAs containing a polypyrimidine tract. Previous studies have demonstrated P70S6 kinase activation in several cell types after either mitogenic stimulation, mechanical stretch, or integrin receptor engagement. Therefore, p70S6 kinase could play a key role in the load-induced hypertrophic growth process (Laser et al., 1998). Furthermore, the mitogen-activated protein kinases are a superfamily of proline-directed serine/threonin...

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Section: Discussionmentioning

confidence: 94%

Involvement of Rho-Kinase Pathway for Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Gene Expression and Cardiovascular Remodeling in Hypertensive Rats

Kobayashi¹,

Nakano²,

Mita³

et al. 2002

J Pharmacol Exp Ther

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“…Candesartan cilexetil as well as other angiotensin II antagonists have shown a considerable benefit controlling VSM growth and modulating extracellular protein synthesis in different tissues. [40][41][42][43] It is worth mentioning that many characteristics of the CSM are similar to those of VSM; therefore potential pathophysiologic projections, particularly for the use of selective angiotensin II blocking agents, have gained importance.…”

Section: Discussionmentioning

confidence: 99%

Candesartan cilexetil protects cavernous tissue in spontaneously hypertensive rats

Toblli

Stella²,

Mazza

et al. 2004

Int J Impot Res

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In previous experiments, our group demonstrated morphological changes in erectile tissue from male spontaneously hypertensive rats (SHR). The present study was performed to determine whether an angiotensin II receptor blocker could protect cavernous tissue (CT) from these structural alterations in SHR. Male SHR and Wistar-Kyoto (WKY) rats were studied during 4 months. Rats were divided into three groups: SHR (n ¼ 10), SHR with candesartan cilexetil (n ¼ 10) and WKY rats (n ¼ 10). Candesartan cilexetil 7.5 mg/kg/day was administered orally throughout the study. CT was processed for pathology studies. The amount of (1) cavernous smooth muscle (CSM), (2) vascular smooth muscle (VSM), (3) collagen type III, and the rat endothelial cell antibody (RECA-1)/tunica media ratio in cavernous arteries were evaluated. SHR with candesartan cilexetil showed a lower blood pressure, a lower percentage of CSM, smaller VSM area, with a higher RECA-1/media ratio, and a lower percentage of collagen type III, when compared to untreated SHR. In addition, SHR showed a positive correlation between systolic blood pressure (SBP) and CSM amount (r ¼ 0.91; Po0.01), and SBP and the percentage of collagen type III (r ¼ 0.88; Po0.01); these correlations were not observed either in SHR treated with candesartan cilexetil or in WKY rats. We conclude that candesartan cilexetil provides a significant protective role against morphologic changes in vessels as well as in cavernous spaces of the erectile tissue, caused by high blood pressure, in SHR.

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“…23 The beneficial effect of trandolapril and candesartan cilexetil on urinary ET-1 levels may be, in part, due to reduced intraglomerular pressure. Hara et al 24 reported that myocardial remodeling in angiotensin IIinduced hypertension in rats was significantly ameliorated by candesartan cilexetil and this may have been due to a decrease in ET-1 expression in the left ventricle. Angiotensin II was reported to enhance ET-1 synthesis in cultured endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy of trandolapril and candesartan cilexetil reduces microalbuminuria and urinary endothelin-1 excretion in patients with type 2 diabetes

et al. 2002

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Background. Angiotensin (AT)-converting enzyme inhibitors (ACEIs) and AT1-receptor blockers (ARBs) are widely used to reduce urinary albumin excretion (UAE) and slow the progression of diabetic nephropathy. The aim of the present study was to determine whether treatment with trandolapril (an ACEI) and candesartan cilexetil (an ARB) in combination has more effect on UAE and urinary endothelin (ET)-1 excretion than treatment with trandolapril or candesartan cilexetil alone in patients with type 2 diabetes. Methods. Sixty normotensive type 2 diabetes patients with microalbuminuria were randomly assigned to four treatment groups: (A) treatreatment with trandolapril at 2 mg/day (n = 15), (B) treatment with candesartan cilexetil at 8 mg/day (n = 15), (C) treatment with trandolapril at 2 mg/day and candesartan cilexetil at 8 mg/day (n = 15), and (D) treatment with placebo (n = 15). The study period was 18 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in the patients before treatment and after 12 and 18 months of treatment. Results. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little between the four groups. Trandolapril and candesartan cilexetil administered alone reduced UAE and urinary ET-1 excretion to a similar extent (12 months; P < 0.05 and 18 months; P < 0.01). When trandolapril and candesartan cilexetil were coadministered, UAE and urinary ET-1 excretion decreased to a significantly greater extent at 12 and 18 months (P < 0.05) than with trandolapril or candesartan cilexetil alone. However, plasma ET-1 and systemic blood pressure levels were not affected. Conclusions. The data suggest that combination therapy with trandolapril and candesartan cilexetil has an additive effect on the reduction of microalbuminuria in microalbuminuric normotensive type 2 diabetes patients.

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Effects of TCV-116 on Endothelin-1 and PDGF A-Chain Expression in Angiotensin II-Induced Hypertensive Rats.

Cited by 12 publications

References 54 publications

Involvement of Rho-Kinase Pathway for Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Gene Expression and Cardiovascular Remodeling in Hypertensive Rats

Involvement of Rho-Kinase Pathway for Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Gene Expression and Cardiovascular Remodeling in Hypertensive Rats

Candesartan cilexetil protects cavernous tissue in spontaneously hypertensive rats

Combination therapy of trandolapril and candesartan cilexetil reduces microalbuminuria and urinary endothelin-1 excretion in patients with type 2 diabetes

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