Abstract
Inhibition of type-5 phosphodiesterase by sildenafil decreases capacitative Ca2+ entry mediated by transient receptor potential proteins (TRPs) in the pulmonary artery. These families of channels, especially the canonical TRP (TRPC) subfamily, may be involved in the development of bronchial hyperresponsiveness, a hallmark of asthma. In the present study, we evaluated i) the effects of sildenafil on tracheal rings of rats subjected to antigen challenge, ii) whether the extent of TRPC gene expression may be modified by antigen challenge, and iii) whether inhibition of type-5 phosphodiesterase (PDE5) may alter TRPC gene expression after antigen challenge. Sildenafil (0.1 µM to 0.6 mM) fully relaxed carbachol-induced contractions in isolated tracheal rings prepared from naive male Wistar rats (250-300 g) by activating the NO-cGMP-K+ channel pathway. Rats sensitized to antigen by intraperitoneal injections of ovalbumin were subjected to antigen challenge by ovalbumin inhalation, and their tracheal rings were used to study the effects of sildenafil, which more effectively inhibited contractions induced by either carbachol (10 µM) or extracellular Ca2+ restoration after thapsigargin (1 µM) treatment. Antigen challenge increased the expression of the TRPC1 and TRPC4 genes but not the expression of the TRPC5 and TRPC6 genes. Applied before the antigen challenge, sildenafil increased the gene expression, which was evaluated by RT-PCR, of TRPC1 and TRPC6, decreased TRPC5 expression, and was inert against TRPC4. Thus, we conclude that PDE5 inhibition is involved in the development of an airway hyperresponsive phenotype in rats after antigen challenge by altering TRPC gene expression.
Highlights
Sildenafil (Viagra®) is a selective inhibitor of the cyclic guanosine monophosphate-specific type-5 phosphodiesterase (PDE5) and is useful in the treatment of erectile dysfunction and pulmonary arterial hypertension [1,2]
Our data showed that antigen challenge modified the gene expression of several members of the TRPC subfamily in the rat trachea, a phenomenon modifiable by PDE5 inhibition caused by sildenafil pretreatment
The beneficial effects of sildenafil in the treatment of male erectile dysfunction and pulmonary hypertension are attributable to its ability to potentiate the vasorelaxant effect of NO on vascular smooth muscle cells, which are relaxed by sildenafil-induced cyclic guanosine monophosphate (cGMP) accumulation in response to generated NO [1,2]
Summary
Sildenafil (Viagra®) is a selective inhibitor of the cyclic guanosine monophosphate (cGMP)-specific type-5 phosphodiesterase (PDE5) and is useful in the treatment of erectile dysfunction and pulmonary arterial hypertension [1,2]. Research has concentrated on proteins of the canonical TRP (TRPC) subfamily, and much evidence suggests that they are a part of store-operated Ca2+ channels in many cells [6,7,8]. Such channels are regulated by the filling status of intracellular Ca2+ stores and, once depleted by either Ca2+ release from the sarcoplasmic reticulum or inhibition of adenosine triphosphate-driven sarcoplasmic/endoplasmic reticulum Ca2+ (SERCA) pumps, subsequent Ca2+ entry from extracellular compartments may be promoted [9].
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