Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea‐Pigs

Abstract

The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48h after OA, a significant reduction (P<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (P<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Effects of l‐arginine and phosphodiesterase‐5 inhibitor, sildenafil, on inflammation and airway responsiveness of sensitized BP2 mice

“…Zaprinast is a wellknown relaxant of airway smooth muscle both in vitro and in vivo [26], but has been unable to prevent an antigen-induced airway hyperresponsiveness [27]. Another way to study that signalling pathway is to evaluate the effects of selective PDE5 inhibitors which lead to an increase in intracellular cGMP.…”

“…Conflicting results have been reported for zaprinast, a relatively selective PDE5 inhibitor. Zaprinast is a wellknown relaxant of airway smooth muscle both in vitro and in vivo [26], but has been unable to prevent an antigen-induced airway hyperresponsiveness [27]. Moreover, conflicting results were reported for the effects of zaprinast on antigen-induced airway inflammation.…”

“…All these studies were performed with selective or non-selective NOS inhibitors or with L-arginine, the NO precursor. But zaprinast, a selective PDE5 inhibitor, was ineffective on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs [27]. In fact, most of the studies that evaluated the effects of PDE inhibitors on airways concern the cAMP pathway and only a few studies were performed with PDE5 inhibitors.…”

“…PDE5 inhibition and the subsequent cGMP increase induced a relaxation of guinea-pigs' trachea in vitro and a bronchodilatory activity in vivo [26]. But zaprinast, a selective PDE5 inhibitor, was ineffective on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs [27]. Airway epithelial cells play a key role in airway inflammation and have the capacity to produce many inflammatory mediators.…”