Serelaxin Elicits Bronchodilation and Enhances β-Adrenoceptor-Mediated Airway Relaxation.

Maggie Lam,Chrishan S Samuel,Simon G Royce,Laura J Parry,Maria Jelinic,Jane E Bourke,Chantal Donovan

doi:10.3389/fphar.2016.00406

Abstract

Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250–350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via epithelial-dependent and -independent mechanisms, likely via RXFP1 activation and generation of NO, prostaglandins and cAMP/cGMP. rhRLX also enhanced responsiveness to other dilators, suggesting its potential as an alternative or add-on therapy for severe asthma.

Highlights

Asthma is a chronic inflammatory disease of the airways, affecting 300 million world-wide (Masoli et al, 2004)
While treatment with the β2-adrenoceptor agonist salbutamol (SAL) generally reverses asthma symptoms, dilator responses in many patients may be limited by factors such as frequent use and/or viral infection leading to tolerance and receptor desensitization (Duechs et al, 2014; Spina, 2014). β2adrenoceptor agonists have been shown to have relatively lower efficacy in small airways in the distal lung, where increased inflammation and airway hyperresponsiveness (AHR) contributes to asthma severity (Donovan et al, 2013; Bourke et al, 2014)
This study provides the first evidence that Recombinant human serelaxin (rhRLX) is an effective bronchodilator and bronchoprotective agent in rat and guinea pig airways

Summary

Introduction

Asthma is a chronic inflammatory disease of the airways, affecting 300 million world-wide (Masoli et al, 2004). Recruitment of inflammatory cells and stimulation of resident structural cells in asthma promotes epithelial damage, goblet cell metaplasia, fibrosis and the accumulation of airway smooth muscle (ASM) (Mauad et al, 2007) These inflammatory and structural changes contribute to the development of airway hyperresponsiveness (AHR), characterized by excessive bronchoconstriction to allergic and non-allergic stimuli (Yeganeh et al, 2013). RhRLX is generally associated with vascular changes in pregnancy and childbirth, its recent clinical assessment for acute heart failure was associated with beneficial effects on hemodynamics and reduced mortality (Teerlink et al, 2013) These findings were consistent with rhRLX-enhanced vasorelaxation in isolated rodent small renal and mesenteric arteries (McGuane et al, 2011; Leo et al, 2014) and human gluteal and subcutaneous resistance arteries (Fisher et al, 2002; McGuane et al, 2011). These findings were consistent with rhRLX-enhanced vasorelaxation in isolated rodent small renal and mesenteric arteries (McGuane et al, 2011; Leo et al, 2014) and human gluteal and subcutaneous resistance arteries (Fisher et al, 2002; McGuane et al, 2011). rhRLX has been shown to influence gastrointestinal motility in mice via the generation of nitric oxide (NO) from an intact epithelial layer (Baccari et al, 2013)

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