Characterization of Tachykinin Receptors Mediating Bronchomotor and Vasodepressor Responses to Neuropeptide γ and Substance P in the Anaesthetized Rabbit

Abstract

The effects of iv injections of two endogenous tachykinins, substance P (SP) and neuropeptide γ and the highly selective tachykinin agonists [Sar9,Met(O2)11]-SP, [Lys5,MeLeu9,Nle10]-NKA(4–10) and senktide, on total lung resistance (RL), dynamic lung compliance (Cdyn) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on RL, Cdynor blood pressure. The other four agonists caused dose-dependent increases in RLand Cdyn, with [Sar9,Met(O2)11]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar9,Met(O2)11]-SP, SP and neuropeptide γ also decreased blood pressure. Phosphoramidon (1 mg/kg) potentiated the changes in RLand Cdynevoked by [Sar9,Met(O2)11]-SP and SP, with very marked enhancement of responses to neuropeptide γ. Responses to [Lys5,MeLeu9,Nle10]-NKA(4–10) were unaffected, suggesting that this NK-2 selective agonist may not be catabolized by neutral endopeptidase (NEP). In the presence of phosphoramidon, the non-peptide tachykinin NK-1 receptor selective antagonist CP 96345 (80 nmol/kg) reduced all responses to [Sar9,Met(O2)11]-SP and SP, whereas the NK-2 selective antagonist SR 48968 (40 nmol/kg) inhibited the bronchomotor but not the vasodepressor responses to neuropeptide γ and [Lys5,MeLeu9,Nle10]-NKA(4–10). The fall in blood pressure induced by neuropeptide γ was diminished by CP 96345, whereas bronchoconstriction was unaffected, indicating possible differences in NK-1 receptors in the vasculature and airways. Electrical stimulation of the distal ends of vagus nerves caused increases in RLwhich were abolished by atropine (1 mg/kg).