01 March 2017 by Jocelyn Dupuis

Sildenafil improves right ventricular function but does not ameliorate the reduced biologically active lung vasculature in pulmonary hypertension induced by hypoxia/sugen in rats

Introduction

Sildenafil is approved for the therapy of pulmonary arterial hypertension (PAH). Studies suggest that its benefit may preferentially derive from its effect on right ventricular (RV) function while its effects on pulmonary vascular disease is unclear. We developed pulmobind (PB), a novel biomarker of the metabolically active pulmonary vascular endothelium. PB is used to image the pulmonary circulation by binding to the specific adrenomedullin (AM) receptors densely expressed in the pulmonary vascular endothelium.

  1. Severe PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist Sugen and hypoxia. 3 weeks thereafter, rats were randomized to receive sildenafil (25 and 100 mg/kg/day) for 4 weeks. Lung 99mTc-PB uptake kinetics were assessed by SPECT analyses and quantified from the activity-time curve integral. RV function and PA pressure were evaluated by echocardiography.
  2. Sildenafil at low and high doses significantly decreased RV hypertrophy (0.52 ± 0.06; p<0.01,0.45 ± 0.02; p<0.0001, respectively) compared to PAH (0.82 ± 0.18). Treatments also mildly significantly increased pulmonary artery acceleration time (20.88 msec ± 0.91; p<0.01, 21.26 msec ± 1.41; p<0.01, respectively) compared to PAH (17.23 msec ± 0.84) and significantly increased tricuspid annulus plane systolic excursion (2.61 mm ± 0.14; p<0.001, 3.06 mm ± 0.13; p<0.0001, respectively) compared to PAH (1.94 mm ± 0.13). However, pulmonary activity-time integral of 99mTc-PB was reduced in PAH rats (508.3 ± 37.14, p<0.05) compared to controls (629.5 ± 29.81) but unchanged by Sildenafil at low and high doses (459.9 ± 27.82, 475.2 ± 28.48, respectively).

Conclusion

Sildenafil dose-dependently improves the function of the RV, but does not modify impaired pulmonary vascular endothelium function assessed by the AM receptor ligand PB.

Key Contributors

Nassiba Merabet, Quang Trinh Nguyen, Natacha Duquette, Sophie Marcil, Yan Fen Shi, Jean-Claude Tardif, François Harel, Jocelyn Dupuis. Research Center, Montreal Heart Institute, University of Montreal, Quebec, Canada


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