PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension

Ono, Shigehiro; Voelkel, N. F.

doi:10.1152/jappl.1991.71.6.2483

Cited by 43 publications

(35 citation statements)

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“…29 In addition, p-chlorophenylamine, a 5-hydroxytryptamine synthesis inhibitor, has also been shown to inhibit MCT-induced pulmonary hypertension in rats.4' Thus, MCT-induced pulmonary hypertension appears to be caused by several etiologic factors. In the present study, we demonstrated that an ETA receptor antagonist inhibited the development of pulmonary hypertension, suggesting that endogenous ET-1 probably contributes to the progression of cardiopulmonary alterations in MCT rats.…”

Section: Discussionmentioning

confidence: 99%

Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.

Miyauchi

Yorikane

Sakai

et al. 1993

Circulation Research

299

172

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Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. disease, valvular heart disease, and left ventricular failure) and pulmonary diseases (eg, emphysema, lung fibrosis, and obstructive airway disease) are often accompanied by pulmonary hypertension, and the severity of pulmonary hypertension is one determinant of the prognosis of such patients.' Although some researchers believe that pulmonary vasoconstriction plays a role in the pathogenesis of pulmonary hypertension,"2 the mechanism for the progression of pulmonary hypertension is still poorly understood. Received October 26, 1992; accepted July 13, 1993. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, was recently identified.3 This peptide induces proliferation of vascular smooth muscle cells.4 ET-1 has several properties suggestive of a potential pathophysiological role in pulmonary hypertension. First, ET-1 contracts isolated pulmonary vessels5 and increases pulmonary vascular resistance.6'7 Second, ET-1 has a mitogenic effect on vascular smooth muscle cells4'8'9 and fibroblasts,'0"' consistent with a role in vascular remodeling, a prominent finding in pulmonary hypertensive stages. ET-1 has also been reported to be produced by nonvascular tissues such as the heart, kidneys, and central nervous system.'2"3 It has been demonstrated that prepro ET-1 mRNA is expressed in cultured rat cardiomyocytes'4 and that ET-1-like immunoreactivity exists in the renal cortex and medulla of rats.15 In the heart, ET-1 induces myocardial cell hypertrophy'6 and has positive inotropic'7 and chronotropic'8 effects.A single subcutaneous injection of monocrotaline (MCT), a pyrrolizidine alkaloid, causes pulmonary hyby guest on

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Section: Discussionmentioning

confidence: 99%

Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.

Miyauchi

Yorikane

Sakai

et al. 1993

Circulation Research

299

172

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“…Histological analysis of the medial wall thickness of the peripheral pulmonary arteries was performed as described by Ono and Voelkel (1991), with some modifications. In brief, the lungs were immersed in 10% neutral buffered formalin and embedded in paraffin blocks.…”

Section: Assessment Of Pulmonary Arterial Wall Hypertrophymentioning

confidence: 99%

A Long-Acting and Highly Selective Prostacyclin Receptor Agonist Prodrug, 2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), Ameliorates Rat Pulmonary Hypertension with Unique Relaxant Responses of Its Active Form, {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic Acid (MRE-269), on Rat Pulmonary Artery

Kuwano

Hashino²,

Noda³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, longacting nonprostanoid prostacyclin receptor (IP receptor) agonist prodrug. In a rat model of pulmonary hypertension induced by monocrotaline (MCT), NS-304 ameliorated vascular endothelial dysfunction, pulmonary arterial wall hypertrophy, and right ventricular hypertrophy, and it elevated right ventricular systolic pressure and improved survival. {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), the active form of NS-304, is much more selective for the IP receptor than are the prostacyclin analogs beraprost and iloprost, which also have high affinity for the EP 3 receptor. To investigate the effect of receptor selectivity on vasodilation of the pulmonary artery, we assessed the relaxant response to these IP agonists in rats. MRE-269 induced vasodilation equally in large pulmonary arteries (LPA) and small pulmonary arteries (SPA), whereas beraprost and iloprost induced less vasodilation in SPA than in LPA. An EP 3 agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP 3 antagonist attenuated the vasoconstriction. Beraprost showed EP 3 agonism and induced LPA and SPA vasoconstriction, whereas the EP 3 antagonist inhibited this vasoconstriction and enhanced beraprost-and iloprost-induced SPA vasodilation. These findings suggest that the EP 3 agonism of beraprost and iloprost interfered with the SPA vasodilation resulting from their IP receptor agonism. Endothelium removal markedly attenuated the vasodilation induced by beraprost, but not that induced by MRE-269 or iloprost. Moreover, the vasodilation induced by beraprost and iloprost, but not that induced by MRE-269, was more strongly attenuated in LPA from MCT-treated rats than from normal rats. NS-304 is a promising alternative medication for pulmonary arterial hypertension with prospects for good patient compliance.Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance, leading ultimately to right ventricular failure and death (Rich et al., 1987;Farber and Loscalzo, 2004). The pathogenesis of PAH includes at least three processes occurring in small pulmonary arteries (SPA): vasoconstriction, vascular remodeling, and thrombosis (Rubin, 1997;Runo and Loyd, 2003).Prostacyclin (PGI 2 ) is a potent endogenous vasodilator and inhibitor of platelet aggregation that acts at the PGI 2 receptor (IP receptor) (Namba et al., 1994). PGI 2 contributes to the maintenance of homeostasis and has various other physiological effects in many organ systems (Narumiya et al., 1999 ABBREVIATIONS: PAH, pulmonary arterial hypertension; SPA, small pulmonary arteries; PGI 2 , prostacyclin; IP receptor, PGI 2 receptor; PH, pulmonary hypertension; MCT, monocrotaline; NS-304, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide; MRE-269, {4-[(5,6-diphenylpyrazin-2-yl)(isopropy...

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“…Statistical analysis of the medial wall thickness of the pulmonary arteries was performed as described previously. 17 In brief, the external diameter and the medial wall thickness were measured in 30 muscular arteries (ranging in size from 25 to 50 and from 51 to 100 m in external diameter) per lung section. For each artery, the medial wall thickness was expressed as follows: % wall thicknessϭ[(medial thicknessϫ2)/external diameter]ϫ100.…”

Section: Morphometric Analysis Of Pulmonary Arteriesmentioning

confidence: 99%

Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

et al. 2000

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Background-Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Methods and Results-The cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan-liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene-transfected rats compared with controls [mean pulmonary arterial pressure, 31Ϯ1 versus 35Ϯ1 mm Hg (Ϫ12%); total pulmonary resistance, 0.087Ϯ0.01 versus 0.113Ϯ0.01 mm Hg ⅐ mL ⅐ min Ϫ1 ⅐ kg Ϫ1 (Ϫ23%), both PϽ0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF 1␣ , a stable metabolite of prostacyclin, were significantly increased for Ն1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test, PϽ0.01). Conclusions-Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.

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PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension

Cited by 43 publications

References 0 publications

Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.

Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension.

Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

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