PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension

Abstract

Endothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99m Technetium ( 99m Tc)-labelled PB binds to adrenomedullin receptors (AM 1 ) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM 1 receptors activity using 99m Tc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99m Tc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99m Tc-PB was reduced in PAH (508% · min ± 37, p < 0.05) compared to controls (630% · min ± 30), but unchanged by sildenafil at low and high doses. Lung tissue expressions of the AM 1 receptor components were reduced in PAH and also unaffected by sildenafil. In experimental angio-proliferative PAH, sildenafil improves RV dysfunction and remodeling, but does not modify pulmonary vascular endothelium dysfunction assessed by the adrenomedullin receptor ligand 99m Tc-PB.

Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure

“…Ramp2 mRNA is higher than Ramp3 mRNA in the lungs [ 37 ] and kidneys [ 38 ] of rats. AM derivative PulmoBind is a molecular SPECT imaging agent distributed in the human lung and is a specific ligand for AM receptor composed of CLR and RAMP2 [ 39 ]. In RD-Ag rats, Calcrl expression showed a downward trend in the lungs and was significantly reduced in the kidneys.…”

Effects of the FGF receptor‐1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension

“…# P < .05, significantly different from PAH-SAL; Kruskal-Wallis test followed by Dunn's multiple comparisons test vitro, and ultimately reduced RVSP with minimal effects on pulmonary vascular remodelling. Previous experimental studies (Merabet et al, 2019;Schermuly et al, 2004;Zhang et al, 2019) have shown positive effects of sildenafil on vascular remodelling in PAH models. However, these studies used higher sildenafil doses (30 and 25 mgÁkg −1 , respectively) than that used in the present study (20 mgÁkg −1 ).…”

Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases

“…AM receptors are abundantly expressed in the lungs, especially in the endothelium of alveolar capillaries [ 117 , 118 ], and the lung functions as a primary site for AM clearance [ 119 , 120 ]. Additionally, the expression of AM receptors is altered under pathological conditions, such as pulmonary hypertension [ 121 ]. An interesting approach for imaging the human pulmonary vascular endothelium is by using AM receptor ligands, such as 125 I-rAM (1-50) and 99m Tc-PulmoBind, for PET and SPECT imaging [ 122 – 124 ].…”