Selective modulation of natriuretic peptide-mediated dilatation in the pulmonary vasculature: a novel combination therapy for pulmonary hypertension

Melanie Madhani, Belen Torondel, Raymond J. MacAllister & Adrian J. Hobbs Wolfson Institute for Biomedical Research & Clinical Pharmacology Department, University College London, London WC1E 6AE.

Pulmonary hypertension remains difficult to treat because of the paucity of selective pulmonary vasodilators. Phosphodiesterase (PDE) 5 inhibitors (e.g. sildenafil) are selective pulmonary vasodilators in patients with pulmonary hypertension; however, the mechanism underlying this specificity remains unclear. Herein, we demonstrate both in vitro and in vivo that a combination of atrial natriuretic peptide (ANP) and PDE 5 inhibitor produces dilatation selectively in the pulmonary, but not systemic, vasculature. Such observations give rise to the rationale for a novel, dual therapy for the treatment of pulmonary hypertension.

In vitro : Rat (Sprague-Dawley, male, 200-250g) pulmonary and mesenteric (both 3rd/4th order) small arteries were dissected and mounted in Mulvany-type myographs (Madhani et al. [2003]). The vessels were stretched to 90% of the diameter achieved when under a transmural pressure of 35mmHg (pulmonary) and 100 mmHg (systemic), respectively. Concentration-response curves to the NO-donor spermine-NONOate (SPER-NO; 10nM-10μM) and ANP (1nM-1μM) were constructed in the absence and presence of sildenafil (SIL; 5μM). In vivo:Mice (C57BLK6, male, 20-25g) were anaesthetised continuously with 1.5% isofluorane and ventilated with air. To measure mean arterial blood pressure (MABP), the left common carotid artery was cannulated. To measure right ventricular pressure (RVP), the right jugular vein was isolated and a cannula was introduced into the superior vena cava and then advanced into the right ventricle .The right femoral vein was cannulated for drug administration and dose-response relationships obtained to the NO-donor sodium nitroprusside (SNP; 3 & 10μg/kg) and ANP (10 & 100μg/kg) in the absence and presence of SIL (1mg/kg).

In vitro: SPER-NO and ANP caused concentration-dependent relaxations of pulmonary artery (pEC50 6.27±0.14 and 8.77±0.25, respectively) that were significantly enhanced in the presence of SIL (pEC50 6.94±0.21 * and 9.42±0.16 *, respectively; *P<0.05 vs control). SPER-NO and ANP also caused concentration-dependent relaxations of mesenteric small arteries (pEC 50 5.83±0.17 and 7.25±0.19, respectively). However, only relaxations to SPER-NO were augmented in the presence of SIL (pEC 50 6.50±0.27 * and 7.41±0.30, respectively; *P<0.05 vs control). In vivo: SNP and ANP caused dose-dependent decreases in both MAP and RVP (Table). In the presence of SIL, RVP reductions in response to both SNP and ANP were enhanced, whereas only reductions in MAP in response to SNP were augmented (hypotensive response to ANP remained unchanged; Table).

In conclusion, a combination of ANP and PDE 5 inhibitor produces pulmonary-specific dilatation in vitro and in vivo. This novel dual therapy might represent a significant advance in the treatment of pulmonary hypertension.

Madhani et al. [2003] Br. J. Pharmacol., 139, 1289