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Manipulating the natriuretic peptide system for the treatment of pulmonary hypertension

Background

We have recently reported that the combination of a neutral endopeptidase inhibitor (NEPI; prevents the breakdown of natriuretic peptides) and a phosphodiesterase 5 inhibitor (PDE5-I; prevents the hydrolysis of cyclic GMP), synergistically prevents pathogenesis in a hypoxia-induced model of pulmonary hypertension (PH; [1]). Herein, we have assessed the efficacy of this novel combination therapy to reverse disease severity in (a) established PH and (b) bleomycin-induced pulmonary fibrosis.

Methods and results

(a) Reversal of existing PH

In this study, the combination therapy (NEPI: ecadotril 60 mg/kg/day; PDE5I: sildenafil 30 mg/kg/day) was initiated after rats had been exposed to 3 weeks of chronic hypoxia (10% O2) to induce PH. This intervention resulted in a less pronounced elevation in right ventricular pressure (Control: 21.57 ± 3.432 mmHg, Hypoxia: 34.32 ± 3.882 mmHg, Hypoxia + combination therapy: 29.17 ± 1.965 mmHg) and reduced right ventricular hypertrophy (RV/LV+S ratio; Control: 0.2839 ± 0.01874, Hypoxia: 0.3411 ± 0.03317, Hypoxia + combination therapy: 0.3063 ± 0.01412) compared to untreated animals.

(b) Bleomycin-induced pulmonary fibrosis

Pulmonary hypertension often complicates interstitial lung disease, where it is associated with higher mortality. Bleomycin, a peptide antibiotic, causes oxidant-mediated DNA scission leading to fibrogenic cytokine release and is a commonly used mouse model of pulmonary fibrosis. Our data suggest that the NEPI/PDE5-I combination is effective in ameliorating the rise in right ventricular systolic pressure (RSVP) in response to bleomycin (1 U/kg; Control: 21.14 ± 4.028 mmHg, bleomycin: 33.84 ± 2.397 mmHg, bleomycin + combination therapy: 25.18 ± 1.902 mmHg; Figure 1).

Figure 1
figure1

RSVP in control animals (n = 6) and bleomycin-treated animals (n = 6) in the absence and presence of sildenafil (SILD, n = 7), ecadotril (NEPI, n = 8) and combination treatment (SILD+NEPI, n = 9). *P < 0.05.

Conclusion

These data demonstrate that the NEPI/PDE5I combination is effective in ameliorating disease severity in two models of PH with disparate aetiologies. First, the combination is valuable in reversing established (hypoxia-induced) PH and, second, the dual therapy is capable of reversing the pulmonary haemodynamic dysfunction in bleomycin-induced pulmonary fibrosis. Thus, this work substantiates the therapeutic potential of this novel combination therapy in PH.

References

  1. 1.

    Baliga RS, Zhao L, Madhani M, Lopez-Torondel B, Visintin C, Selwood D, Wilkins MR, MacAllister RJ, Hobbs AJ: Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008, 178: 861-869. 10.1164/rccm.200801-121OC.

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Correspondence to Reshma S Baliga.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Baliga, R.S., Trinder, S., Scotton, C.J. et al. Manipulating the natriuretic peptide system for the treatment of pulmonary hypertension. BMC Pharmacol 9, P2 (2009). https://doi.org/10.1186/1471-2210-9-S1-P2

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Keywords

  • Pulmonary Hypertension
  • Natriuretic Peptide
  • Pulmonary Fibrosis
  • Bleomycin
  • Interstitial Lung Disease