Effects of an Angiotensin II Receptor Antagonist, CV-11974, on Angiotensin II-Induced Increases in Cytosolic Free Calcium Concentration, Hyperplasia, and Hypertrophy of Cultured Vascular Smooth Muscle Cells

Koh, Eio; Morimoto, Shigeto; Tomita, Jun; Rakugi, Hiromi; Jiang, Bingbing; Inoue, Tatsuo; Nabata, T; Fukuo, Keisuke; Ogihara, Toshio

doi:10.1097/00005344-199411000-00001

Cited by 5 publications

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“…The stimulation of 3 H‐leucine incorporation by Ang II may be mediated by the two receptor subtypes. In order to demonstrate that the augmentation of 3 H‐leucine incorporation was receptor mediated and to determine the involved receptor subtype, the selective AT 1 receptor antagonist candesartan and the AT 2 receptor antagonist PD123319 were used ( Koh et al . 1994 , Hafizi et al .…”

Section: Resultsmentioning

confidence: 99%

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca²⁺‐sensitive PKC‐dependent tyrosine kinase pathway

Hou

Pantev

Möller

et al. 2000

Acta Physiologica Scandinavica

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The aim of the present study was to investigate the proliferative effects of Ang II in human cardiac fibroblasts. The effects of Ang II in human cardiac fibroblasts on the 3H-thymidine incorporation, the cell number, the 3H-leucine incorporation and the total protein content were measured. The expression of receptor mRNA was performed by reverse transcription-polymerase chain reaction (RT-PCR). Ang II increased 3H-leucine incorporation in a concentration-dependent manner but not 3H-thymidine incorporation in primary cultures of human cardiac fibroblasts. The maximum effect (24 +/- 3% over control) was obtained at a concentration of 10 nM. There were no significant alterations of cell number or total protein content, suggesting that Ang II stimulated protein synthesis but did not induce hypertrophy. The accumulation of 3H-leucine was blocked by the AT1 receptor antagonist candesartan but not by the AT2 receptor antagonist PD123319. By using RT-PCR, both AT1 and AT2 receptors mRNA were found to be expressed in human cardiac fibroblasts. The selective MAPKK inhibitor PD098059, the protein kinase C inhibitor K252a or the phospholipase C inhibitor U73122 did not significantly inhibit Ang II augmented 3H-leucine incorporation. However, this was significantly blocked by the Ca2+-dependent protein kinase C inhibitor GO6976, the non-selective protein kinase inhibitor staurosporine and the tyrosine kinase inhibitor tyrphostin 25. The effects of Ang II were unaffected by the Gi-protein blocker pertussis toxin, indicating a Gi-protein-independent pathway. Ang II was synergistic with insulin but showed no significant increase on 3H-leucine incorporation when combined with PDGF or EGF. In summary, Ang II stimulates protein synthesis through AT1 receptors in human cardiac fibroblasts, but has no hypertrophic or hyperplastic effect. The response is mediated by a MAPKK-independent and Ca2+-sensitive PKC-dependent pathway.

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Section: Resultsmentioning

confidence: 99%

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca²⁺‐sensitive PKC‐dependent tyrosine kinase pathway

Hou

Pantev

Möller

et al. 2000

Acta Physiologica Scandinavica

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“…This, in turn, triggers cell growth and constriction (Vincentini & Villereal, 1986). The initial AT 1 receptor-evoked responses can conveniently be measured in primary cell cultures and in cell lines (Dickinson et al, 1994;Koh et al, 1994;Panek et al, 1995;Perlman et al, 1995;Balmforth et al, 1997) and appear to be common to the biological actions of angiotensin II. In addition, it was also observed by Dickinson et al (1994) that angiotensin II increases the rate at which rabbit aortic smooth muscle cells acidify their environment with products of their energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

Vanderheyden¹,

Fierens²,

Backer³

et al. 1999

British J Pharmacology

146

106

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1 CHO-K1 cells that were stably transfected with the gene for the human AT 1 receptor (CHO-AT 1 cells) were used for pharmacological studies of non-peptide AT 1 receptor antagonists. 2 In the presence of 10 mM LiCl, angiotensin II caused a concentration-dependent and long-lasting increase of inositol phosphates accumulation with an EC 50 of 3.4 nM. No angiotensin II responses are seen in wild-type CHO-K1 cells. 5 Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory e ects were halfmaximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 mM losartan indicating a syntopic action of both antagonists. 6 Losartan caused a parallel rightward shift of the angiotensin II concentration-response curves and did not a ect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed-type behavior in both functional and binding studies. 7 Reversal of the inhibitory e ect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT 1 receptor antagonists in functional studies was related to their long-lasting inhibition.

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“…However, Ang I1 is not only a potent vasoconstrictor but also a powerful stimulator of hypertrophy and/or hyperplasia of vascular smooth muscle cells (VSMC) (1,7), and, therefore, is likely to be involved in the pathogenesis of atherosclerosis. Addition of CV-11974, at concentrations of lo-* to M, significantly and dose-dependently suppressed Ang I1 (lo-' M)-induced increases in cytosolic free calcium concentration as well as [3H]thymidine and [3H]leucine incorporation in the cultured VSMC from rat aorta in vitro (10). By oral administration TCV-116, but not hydralazine, significantly reduced hypertrophy of medial smooth muscle cells in one-kidney one-clip hypertensive rats (28).…”

Section: Additional Pharmacologymentioning

confidence: 94%

TCV‐116: A New Angiotensin II Type‐1 Receptor Antagonist

Morimoto

Ogihara

1994

Cardiovascular Drug Reviews

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Key Words: Angiotensin I1 type-1 receptor antagonist--CV-1 1974-hypertension-TCV-1 16The renin-angiotensin system plays an important role in the development and maintenance of hypertension, and in recent years, attempts have been made to treat hypertension by suppressing the renin-angiotensin system (2). Because of their established antihypertensive effect, inhibitors of angiotensin converting enzyme (ACE) are now widely used in patients with hypertension and congestive cardiac failure. However, ACE inhibitors do have some side effects, such as "dry cough" and angioedema, caused by the blocking of bradykinin and substance P degradation (25). The first specific peptidic antagonist of angiotensin I1 (Ang 11), Sar*,Alas-Ang 11, was not suitable for long-term treatment because of the lack of oral bioavailability and inherent agonist activity (21). In the early 1980s, Furukawa and colleagues synthesized some imidazole derivatives that specifically blocked Ang 11-induced vasoconstriction (6,15). Important chemical modification of the initial molecules was then performed, leading to the synthesis of DuP 753 (losartan), an orally active nonpeptide Ang I1 receptor antagonist (3,23,26). DuP 753 is metabolized in vivo to an active compound, EXP3174, to exert Ang I1 receptor antagonistic action.TCV-116 is a newly developed, structurally novel, orally effective, highly potent, and long-acting nonpeptide Ang I1 receptor antagonist with a once-a-day dosing regimen. Like DuP 753, TCV-116 is a prodrug; it is metabolized in vivo to an active compound, CV-1 1974 ( 13,14,20). In various animal models of hypertension TCV-1 16 was demonstrated to exert a more potent and prolonged antihypertensive effect than ACE inhibitors or DuP 753. Its clinical efficacy was, therefore, anticipated (8,11,12). CHEMISTRY TCV-116 was synthesized by Takeda Chemical Industries, Ltd. (Osaka, Japan). The chemical name of TCV-116 is ( + )-1-(cyclohexyloxycarbony1oxy)ethyl 2-ethoxy-l-[[2'-( lH-tetrazo1-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. The corn-

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Effects of an Angiotensin II Receptor Antagonist, CV-11974, on Angiotensin II-Induced Increases in Cytosolic Free Calcium Concentration, Hyperplasia, and Hypertrophy of Cultured Vascular Smooth Muscle Cells

Cited by 5 publications

References 0 publications

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca²⁺‐sensitive PKC‐dependent tyrosine kinase pathway

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca²⁺‐sensitive PKC‐dependent tyrosine kinase pathway

Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors

TCV‐116: A New Angiotensin II Type‐1 Receptor Antagonist

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Effects of an Angiotensin II Receptor Antagonist, CV-11974, on Angiotensin II-Induced Increases in Cytosolic Free Calcium Concentration, Hyperplasia, and Hypertrophy of Cultured Vascular Smooth Muscle Cells

Cited by 5 publications

References 0 publications

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca2+‐sensitive PKC‐dependent tyrosine kinase pathway

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca2+‐sensitive PKC‐dependent tyrosine kinase pathway

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors

TCV‐116: A New Angiotensin II Type‐1 Receptor Antagonist

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Product

Resources

About

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca²⁺‐sensitive PKC‐dependent tyrosine kinase pathway

Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca²⁺‐sensitive PKC‐dependent tyrosine kinase pathway

Distinction between surmountable and insurmountable selective AT₁ receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT₁ receptors