Orally Active Endothelin Receptor Antagonist BMS-182874 Suppresses Neointimal Development in Balloon-Injured Rat Carotid Arteries

Ferrer, Patricia; Valentine, Maria; Jenkins-West, Tonya; Weber, Helen; Goller, N. L.; Durham, Stephen K.; Molloy, Christopher J.; Moreland, Suzanne

doi:10.1097/00005344-199512000-00009

Cited by 49 publications

(22 citation statements)

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“…Accordingly, enhanced apoptosis of the neointimal SMCs is likely to be involved in the mechanisms of prevention of neointima formation by Y27632. It is noteworthy that Y27632 enhanced SMC apoptosis in the injured artery without any effect on cell replication; in contrast, SMC replication is prevented by most other inhibitors of neointima formation, including endothelin receptor antagonist, 19 cilostazol, 20 and tranilast. 21 The precise molecular mechanisms whereby Y27632 enhanced neointimal SMC apoptosis remain to be determined.…”

Section: Discussionmentioning

confidence: 95%

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

et al. 2001

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Background —The Rho/Rho-associated kinase (Rho-kinase) system is implicated in various cellular functions, including migration, proliferation, and apoptosis. Because a possible role of the system is suggested in neointima formation after vascular injury, we sought to examine whether a new specific Rho-kinase inhibitor, Y27632, prevents neointima formation of the balloon-injured rat carotid artery, and if so, to investigate the effects of Y27632 on migration, proliferation, and apoptosis of smooth muscle cells (SMCs) in the injured artery. Methods and Results —Y27632 was administered intraperitoneally from 1 day before to 14 days after vascular injury. Treatment with Y27632 inhibited phenylephrine-induced Rho-kinase activation in the carotid artery on the basis of immunoblotting against the phosphorylated myosin-binding subunit of myosin phosphatase. Y27632 markedly prevented neointima formation at days 7 and 14. In controls, BrdU + proliferating and TUNEL + apoptotic SMCs were transiently and coincidentally increased in the neointima, with a peak at day 7. Y27632 significantly increased the neointimal TUNEL + SMCs at days 7 and 14, but not BrdU + SMCs. Y27642 significantly decreased the number of intimal SMCs at day 4, while not affecting the number of BrdU + or TUNEL + SMCs. Reendothelialization after balloon injury was not significantly affected by Y27632 at days 7 and 14. Conclusions —Y27632 inhibited neointima formation by enhancing SMC apoptosis and probably by suppressing early SMC migration. Therefore, a role of Rho-kinase is suggested in neointima formation after vascular injury.

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Section: Discussionmentioning

confidence: 95%

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

et al. 2001

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“…Normotensive male Sprague Dawley rats (Taconic Farms Inc., Germantown, NY), 11-12 wk of age (350-400 g) at the time of surgery, were handled in accordance with the guidelines of the Bristol-Myers Squibb Animal Care and Use Committee. On the day of surgery, rats were anesthetized intraperitoneally with ketamine hydrochloride (70-80 mg/kg) and xylazine hydrochloride (8-10 mg/kg) and the neck was prepared for aseptic surgery as described previously (32). Briefly, the bifurcation of the common carotid artery was exposed and a 2F Fogarty arterial balloon catheter was inserted into the left external carotid artery, passed through the common carotid artery, and advanced into the aortic arch.…”

Section: Methodsmentioning

confidence: 99%

Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

Pawlowski

Taylor²,

Valentine³

et al. 1997

J. Clin. Invest.

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“…In parallel experiments, the aryl sulphonamide, selective non-peptidic orally active ET A receptor antagonist BMS-182874 (60 mg kg 71 per day; Bristol Myers Squibb, Canada) was added to rat chow 1 week following ovariectomy and continued for 2 weeks (Battistini & Dussault, 1998). BMS-182874 has a &1000 fold higher a nity for ET A versus ET B and doses of 40 to 100 mg kg 71 per day have been used to examine the role of the ET A receptor in hypertension, and vascular remodelling (Park & Schi rin, 2001;Rossi et al, 2000;Battistini & Dussault, 1998;Ferrer et al, 1995). In a second series of experiments, oestradiol (E 2 ; 0.1 mg kg day 71 ) was injected IP immediately following ovariectomy, and continued for 3 weeks.…”

Section: Ovariectomymentioning

confidence: 99%

Elevated mean arterial pressure in the ovariectomized rat was normalized by ET_A receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

Mercier

Pham-Dang

Clement

et al. 2002

British J Pharmacology

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1 The in¯uence of menopause on ventricular function and remodelling remains unde®ned. The following study examined the e ect of ovariectomy on ventricular contractility, cardiac hypertrophy and extracellular matrix protein expression. 2 Elevated circulating levels of the vasoconstrictor endothelin-1 have been reported in postmenopausal women. Moreover, endothelin-1 has been shown to in¯uence blood pressure, ventricular function and cardiac remodelling. In this regard, the potential pathophysiological role of endothelin-1 in the ovariectomized rat was assessed via the administration of the selective endothelin A receptor (ET A ) antagonist BMS-182874.3 In 3 and 6 week ovariectomized female Sprague ± Dawley rats, uterus atrophy was associated with a signi®cant increase in mean arterial pressure, and left ventricular systolic pressure, as compared to sham. By contrast, right ventricular contractile indices were normal in the ovariectomized rat. Despite increased systolic load, left ventricular hypertrophy was not evident, prepro-atrial natriuretic peptide (prepro-ANP) mRNA levels and collagen protein content were similar to sham. 4 The treatment of ovariectomized rats with BMS-182874 (60 mg kg 71 per day) did not reverse uterus atrophy. However, BMS-182874 normalized mean arterial pressure, and left ventricular systolic pressure in the ovariectomized rat. 5 Thus, despite elevated blood pressure, ovariectomized rats were not associated with either cardiac hypertrophy or ®brosis. Lastly, endothelin-1, acting via the stimulation of the ET A receptor represents an integral mechanism implicated in the increase of mean arterial pressure following ovariectomy.

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Orally Active Endothelin Receptor Antagonist BMS-182874 Suppresses Neointimal Development in Balloon-Injured Rat Carotid Arteries

Cited by 49 publications

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Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

Elevated mean arterial pressure in the ovariectomized rat was normalized by ET_A receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

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Orally Active Endothelin Receptor Antagonist BMS-182874 Suppresses Neointimal Development in Balloon-Injured Rat Carotid Arteries

Cited by 49 publications

References 0 publications

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury

Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo.

Elevated mean arterial pressure in the ovariectomized rat was normalized by ETA receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

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Elevated mean arterial pressure in the ovariectomized rat was normalized by ET_A receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis