title: Effects of selective inhibition of PDE4 and PDE7 on airway reactivity and cough in healthy and ovalbumin-sensitized guinea pigs.
abstract: Phosphodiesterases (PDEs) are enzymes responsible for degradation of cAMP and cGMP in cells. Thus, PDE inhibitors may have significant clinical benefit in respiratory diseases associated with inflammation. The aim of the present study was to evaluate the effects of selective PDE4 (rolipram, ROL) and PDE7 inhibitors (BRL50481, BRL) on citric acid-induced cough, in vivo and in vitro airway smooth muscle reactivity in both healthy and ovalbumin sensitized guinea pigs. The drugs tested were administered intraperitoneally to male guinea pigs once daily for 7 days - ROL 1 mg/kg, BRL 1 mg/kg, and ROL+BRL 0.5 mg/kg. Double chamber whole body plethysmography was used for the evaluation of citric acid (0.6 M)-induced cough and specific airway resistance. An organ bath method was used for the measurement of tracheal and lung tissue strip contractions evoked by cumulative doses (10(-8)-10(-3) mol/L) of acetylcholine (ACH) and histamine (HIS). In healthy guinea pigs, the only significant relaxation was observed after ROL in ACH-induced contractions in vitro and the effect on cough was negligible. In ovalbumin-sensitized animals, more pronounced in vitro relaxing effects of BRL in HIS-induced contractions and of combination (ROL+BRL) in ACH-induced contractions were observed, with similar results in vivo, and no significant change in the number of cough efforts was observed in any of the groups tested. The results suggest that PDE4 and PDE7 inhibitors have stronger anti-inflammatory effects compared with direct effects on smooth muscle and cough, with a potential benefit of their concomitant administration.
authors: Department of Pharmacology, Comenius University, Martin, Slovakia. mokry@jfmed.uniba.sk
authors: Juraj
authors: J
authors: Mokry
authors: Marta
authors: M
authors: Joskova
authors: Daniela
authors: D
authors: Mokra
authors: Ingrid
authors: I
authors: Christensen
authors: Gabriela
authors: G
authors: Nosalova
mesh_terms: D000109:Acetylcholine; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006168:Guinea Pigs; D006632:Histamine; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010047:Ovalbumin; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010993:Plethysmography, Whole Body; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D019343:Citric Acid; D006632:Histamine; D010047:Ovalbumin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D020889:Rolipram; D000109:Acetylcholine