Cardiovascular PharmacologyEfficacy of aminaftone in a rat model of monocrotaline-induced pulmonary hypertension
Highlights
► In a validated animal model of pulmonary hypertension we tested chronic treatment with aminaftone, a novel inhibitor of endothelin-1 synthesis. ► Aminaftone increased survival, reduced right ventricular and right atrial hypertrophy. ► Aminaftone reduced plasma concentrations of endothelin-1 and medial wall thickness of pulmonary arteries. ► Aminaftone may represent a novel treatment for pulmonary hypertension, possibly in association with other drugs.
Introduction
Primary pulmonary hypertension is a dreadful clinical condition characterised by sustained elevations of pulmonary artery pressure induced by increased vascular resistances and endothelial remodelling, eventually leading to right heart failure and death (Rubin, 1997). Endothelial disruption and the loss of the natural homeostasis of several cellular pathways and soluble mediators seem to be relevant to the pathogenesis of pulmonary arterial hypertension (PAH). The main mediator of PAH is endothelin-1 (ET-1), since its pulmonary production seems to play a major role in the vascular abnormalities that lead to pulmonary hypertension (Cacoub et al., 1993, Giaid et al., 1993). ET-1 was identified in 1988 (Yanagisawa et al., 1988) as an endothelium-derived peptide with strong vasoconstrictive and pro-fibrotic properties that promote vasospasm, endothelial cell proliferation, smooth muscle hypertrophy in the artery vascular bed (Braun-Moscovici et al., 2004). The development of therapies aimed at decreasing ET-1 detrimental effects on the pulmonary vascular bed via the blockade of ET-1 A and B receptors has dramatically changed the management of pulmonary arterial hypertension, ameliorating the prognosis, the survival and the functional ability of patients (Price and Howard, 2008). Nonetheless, outcome is still bad, not all the patients adequately respond to these therapies and/or the efficacy of treatment may wane during the course of time. Whilst no definitive evidence has been published to explain this individual heterogeneity, it has been postulated that a compensatory rise in ET-1 plasma level following ET-receptor blockade may account for the diminishing efficacy of ET-1 receptor antagonists (Hiramoto et al., 2009). As a consequence, it can be hypothesized that any strategy aimed at reducing ET-1 production may be a valid tool to arrest pulmonary arterial hypertension progression and/or to potentiate the efficacy of ET-1 receptor antagonists in the management of pulmonary arterial hypertension.
We have recently shown that aminaftone (C18-H15-N-O4), a synthetic molecule derived from 4-aminobenzoic acid, down-regulates ET-1 production in vitro by interfering with the transcription of the pre-pro-ET-1 gene (Scorza et al., 2008a). In the present study we assessed whether the inhibition of ET-1 production by aminaftone is a valid strategy to prevent the development of pulmonary hypertension after monocrotaline administration, a well-characterised rodent model of pulmonary arterial hypertension (Kay et al., 1967, Roth and Reindel, 1991).
Section snippets
Animals
Male Wistar rats weighing 300 ± 30 g were purchased from Charles River Laboratories (Calco, Italy). Procedures involving animals and their care conformed to institutional guidelines in compliance with national (4 D.L. N.116, G.U., supplement 40, 18-2-1992) and international (EEC Council Directive 86/609, OJ L 358, 1, 12-12-1987, National Institutes of Health's Guide for the Care and Use of Laboratory Animals, and US National Research Council 1996) law and policies. All rats were housed in
Survival
At the end of the experiment, no rats died in the control and Aminaftone 150 groups, while mortality was 38% in the Monocrotaline group and 13% in the Aminaftone 30 group. Overall, aminaftone-treated rats had a significantly lower mortality compared to rats in the Monocrotaline group (P = 0.044, log-rank test statistic; Fig. 1).
Body weight
Body weight at the beginning of the experiment was similar in the four groups (control: 327 ± 10 g; Monocrotaline: 309 ± 31 g; Aminaftone 30: 309 ± 33 g; Aminaftone 150: 307 ± 32 g; P =
Discussion
Recent in vitro and ex vivo experiments have shown that aminaftone is a compound with relevant endothelial-protective properties (Scorza et al., 2008a, Scorza et al., 2008b). Aminaftone was not initially targeted to endothelial diseases, but its capability to reduce endothelin-1 production in vitro has been demonstrated (Scorza et al., 2008a). Endothelin-1 is expressed by endothelial cells and macrophages (Ehrenreich et al., 1990, MacCumber et al., 1989) and is a potent vasoactive (Yanagisawa
Role of the funding source
The work was entirely supported by internal funds from the Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milano. Animals, reagents and disposables were provided by Laboratori Baldacci SpA (Via S. Michele degli Scalzi, 73, 56124 Pisa, Italy) which had no part in the study design, data analysis, and drafting of the present manuscript.
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The two authors equally contributed to this article.