Role of 5-hydroxytryptamine in the progression of monocrotaline induced pulmonary hypertension in rats

Kanai, Yae; Hori, Shingo; Tanaka, Tsuyoshi; Yasuoka, Megumi; Watanabe, Kazuo; Aikawa, Naoki; Hosoda, Yasuhiro

doi:10.1093/cvr/27.9.1619

Cited by 47 publications

(31 citation statements)

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“…Platelet activation is enhanced in patients with primary pulmonary hypertension (Farber and Loscalzo, 1999), and intravascular thrombosis has also been observed both in patients and in model systems. Moreover, experimentally induced thrombocytopenia reduces the development of pulmonary hypertension (Kanai et al, 1993). In this study, staining for thrombocytes (␣IIb␤3) and fibrinogen showed platelet deposition and thrombosis in the pulmonary vasculature of wild-type hypoxic mice.…”

Section: Cox-gene Disruption and Pulmonary Hypertension 55supporting

confidence: 55%

Cyclooxygenase-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis

Cathcart

Tamošiūnienė²,

Chen³

et al. 2008

J Pharmacol Exp Ther

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Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n ϭ 8), and hematocrit (n ϭ 3), was induced by 3 weeks of hypobarichypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 Ϯ 1.4 versus 13.8 Ϯ 1.9 mm Hg; n ϭ 8; p Ͻ 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 Ϯ 2.7 mm Hg; p Ͻ 0.05). Urinary thromboxane (TX)B 2 excretion increased following hypoxia (44.6 Ϯ 11.1 versus 14.7 Ϯ 1.8 ng/ml; n ϭ 6; p Ͻ 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 Ϯ 10.8 ng/ml; n ϭ 6). In contrast, the increase in 6-keto-prostacyclin 1␣ excretion following hypoxia was reduced by COX-2 gene disruption (29 Ϯ 3 versus 52 Ϯ 4.6 ng/ml; p Ͻ 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA 2 / endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA 2 , and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia.Pulmonary hypertension (PH) is characterized by an elevation in pulmonary vascular tone and a striking degree of pulmonary vascular remodeling. As a consequence, there is increased pulmonary vascular resistance and right ventricular hypertrophy that ultimately leads to right ventricular failure and death (Blumberg et al., 2002). Prostaglandins have been implicated in the pathogenesis of at least some forms of PH (Christman et al., 1992). These bioactive products are generated by the enzyme cyclooxygenase (COX

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Section: Cox-gene Disruption and Pulmonary Hypertension 55supporting

confidence: 55%

Cyclooxygenase-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis

Cathcart

Tamošiūnienė²,

Chen³

et al. 2008

J Pharmacol Exp Ther

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“…Plasma levels of 5-HT were significantly increased in PAH patients and rodent models. 9,20,46 We also showed that circulating 5-HT level was elevated in MCT-induced PAH rats ( Figure S1, available in the online-only Data Supplement). It remains unclear that, in PAH models and patients, the elevation in circulating 5-HT and the upregulation of 5-HT2BR which comes first.…”

Section: -Ht2brmentioning

confidence: 64%

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

Liu

Tian²,

Mao³

et al. 2012

Hypertension

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“…A previous pathophysiological review identified several lines of evidence to suggest a relationship between thrombotic arteriopathy and PAH [1]. Abnormalities of the activated clotting system [17][18][19], impaired fibrinolysis [20,21], abnormal platelet function [22,23] and histological evidence of microvascular thrombosis [24,25] have been associated with animal models and patients with IPAH. Thus, there is a biologically plausible rationale for anticoagulation therapy in these patients, with the goals of preventing progression of disease, decreasing Ppa, and improving symptoms and prognosis [1].…”

Section: Discussionmentioning

confidence: 99%

Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review

Johnson¹,

Mehta²,

Granton³

2006

European Respiratory Journal

120

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Thrombotic arteriopathy has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, the role of anticoagulants in the treatment of PAH is uncertain. Through a qualitative systematic review of epidemiological studies, the effectiveness of anticoagulation therapy with warfarin on survival was evaluated in patients with PAH.MEDLINE (1966( to November 2005, EMBASE (1966 to November 2005, bibliographies of included studies and published reviews were searched without language restriction. Epidemiological studies evaluating the effectiveness of warfarin in PAH were included. Studies had to report mortality as an outcome.Seven observational studies evaluating the effectiveness of warfarin comprising 488 patients were identified. Five studies support the effectiveness of anticoagulation therapy, whereas two do not.Data from observational studies suggest that anticoagulation therapy may be an effective intervention in pulmonary arterial hypertension. However, given the methodological limitations and the small number of existing observational studies, a randomised controlled trial is needed in order to definitively address this important clinical issue.

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Role of 5-hydroxytryptamine in the progression of monocrotaline induced pulmonary hypertension in rats

Abstract: The present study suggests that 5-HT released from platelets contributes to the initiation and progression of monocrotaline induced pulmonary hypertension.

Cited by 47 publications

References 0 publications

Cyclooxygenase-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis

Cyclooxygenase-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review

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