A method to measure dual NK1/NK2-antagonist activity in dogs

The major pulmonary effects of tachykinins are produced by activation of both NK1- and NK2-receptors. A variety of animal models have been used to profile activity of the tachykinins, particularly rodents and guinea pigs, but little information exists regarding methods to evaluate NK1- and NK2-receptor antagonist activity in dogs. This study describes a simple method in dogs to measure NK1- and NK2-receptor agonist and antagonist activity of drugs in the same preparation. We measured pulmonary resistance (RL), dynamic lung compliance (CDyn), minute volume (MV), and mean arterial blood pressure (MAP) before and after challenge with aerosolized NKA (1%) and i.v. SP (100 ng/kg) to quantify responses to the tachykinin challenge. Challenge with NKA produced an increase in RL and a decrease in CDyn, and this bronchospasm was inhibited by the NK2-antagonist SR 48968 (ID50 RL=1.3 mg/kg and ID50 CDyn=1.3 mg/kg, p.o.). The NK1-antagonist, CP 99994 was inactive against NKA-induced bronchospasm at doses up to 10 mg/kg, p.o. When the dogs were challenged with SP, there was a fall in MAP and an increase in MV and both responses were inhibited by CP 99994 (ID50 MV=2.3 mg/kg and ID50 BP=4.5 mg/kg, p.o.), but not by SR 48968 at doses up to 3 mg/kg, p.o. These results identify that NK2-receptors mediate the bronchoconstrictor effect of NKA, and NK1-receptors mediate the hypotension and respiratory stimulation due to SP in dogs. This method offers many advantages for evaluating the effects of tachykinin antagonists including the fact that it is relatively simple to perform and has the capacity to assess both NK1 and NK2 antagonist activity in the same preparation.