Increased blocking activity of combined tachykinin NK1- and NK2-receptor antagonists on hyperventilation-induced bronchoconstriction in the guinea pig.
In vivo anesthetized guinea pigs were used to investigate the effect of tachykinin NK1- and NK2-receptor antagonists, as a single dose or in combination, against hyperventilation-induced bronchoconstriction (HIB). Guinea pigs were ventilated with a rodent ventilator and placed in a whole-body plethysmograph. Hyperventilation was induced by increasing the respiratory rate from 50 to 185 breaths/min for 10 min that produced a 177+/-45% increase in pulmonary resistance (RL) and a 68+/-7% decrease in lung compliance (CDyn). Intravenous (0.03-0.3mg/kg) and oral (0.3-10mg/kg) pretreatments with the tachykinin NK2-antagonist SR 48968 produced a dose-dependent inhibition of HIB whereas pretreatments with the tachykinin NK1-antagonist CP 99994 (1mg/kg intravenously and 30 mg/kg orally) had no effect on HIB. Intravenous and oral combinations of inactive and low doses of CP 99994 and SR 48968 produced a greater inhibition of HIB than SR 48968 alone. Also, the tachykinin NK3-antagonist SB 223412 (1-3mg/kg intravenously and 30 mg/kg orally) did not significantly reduce HIB although a trend was observed at the highest dose tested intravenously (3mg/kg). We conclude that HIB in the guinea pig is mostly mediated by the tachykinin NK2-receptors and to a lesser extent by the tachykinin NK1-receptors. Because the hyperventilation response in guinea pigs may be a surrogate for exercise-induced obstructive airway disease in human, these results suggest that combined use of dual tachykinin NK1- and NK2-receptor antagonists may provide greater benefit than treatment with single activity tachykinin NK-receptor antagonist.
Corboz
M R
MR
Pulmonary and Peripheral Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. michel.corboz@spcorp.com <michel.corboz@spcorp.com>
Fernandez
X
X
Hey
John A
JA
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006985:Hyperventilation / Q000150:complications*; D007275:Injections, Intravenous; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D012129:Respiratory Function Tests
D001549:Benzamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011804:Quinolines; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; C106716:SB 223412; C073839:SR 48968