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Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats

¹Laboratoire de Physiologie Cellulaire Respiratoire, Institut National de la Santé et de la Recherche Médicale (E 356 and Institut Fédératif de Recherche 4), Université Bordeaux 2, 33076 Bordeaux, France; and ²Le Bilarium, Département de Physiologie et Biophysique, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada

Submitted 22 December 2003 ; accepted in final form 18 May 2004

Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca²⁺]_i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10–100 nM) decreased the resting [Ca²⁺]_i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca²⁺]_i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca²⁺]_i response induced by caffeine. Sildenafil (0.1 nM–1 µM) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca²⁺]_i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca²⁺ signaling pathway involved in this model of pulmonary hypertension.

pulmonary hypertension; vascular smooth muscle; phosphodiesterase 5; pulmonary vasodilator

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