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.
Subject(s)
Animals , Male , Rats , Calcium Channels/drug effects , Carbachol/pharmacology , Piperazines/pharmacology , Sulfones/pharmacology , TRPC Cation Channels/drug effects , Trachea/drug effects , Vasodilator Agents/pharmacology , Calcium Channels/metabolism , Carbachol/antagonists & inhibitors , Gene Expression , Lactones/pharmacology , Muscle Contraction/drug effects , Muscle Contraction/physiology , Nitric Oxide/metabolism , Ovalbumin/pharmacology , Purines/pharmacology , Rats, Wistar , Sesquiterpenes/pharmacology , TRPC Cation Channels/genetics , TRPC Cation Channels/metabolism , Trachea/metabolism , Trachea/physiopathologyABSTRACT
The effect of atropine injection into the medial septal area (MSA) or medial preoptic area (MPOA) on carbachol-induced drinking was evaluated in conscious unrestrained rats during a food-associated drinking test reinforced by 14 h of food deprivation. Atropine did not alter food intake when injected into either area, nor did it affect drinking after its injection into the MPOA. However, atropine markedly reduced water intake after its injection into the MSA. These results suggest that the central cholinergic system in the MSA can participate in the regulation of food-associated drinking