In vitro contractile effects of neurokinin receptor blockade in the human ureter

Purpose: We identified the predominance of neurokinin-2 receptors and evalu ated the inhibition of spontaneous contraction via the blockade of neurokin in-2 receptors in human ureteral segments. Materials and Methods: Excess ureteral segments from human subjects undergo ing donor nephrectomy or reconstructive procedures were suspended in tissue baths containing Krebs buffer. After spontaneous contractions were recorde d, tissues were incubated with 1 muM. solutions of phosphoramidon and capto pril (to inhibit peptide degradation) and either the neurokinin-1 receptor antagonist CP 99,994, the neurokinin-2 receptor antagonist SR 48,968, the n eurokinin-3 receptor antagonist SR 142,801 or dimethyl sulfoxide (control) for 1 hour. Contraction magnitude and frequency were again recorded and com pared with spontaneous levels. Concentration-response curves to the tachyki nins substance P, and neurokinins A and B were determined in the presence a nd absence of antagonists. Results: Neurokinin A increased contractility at lower concentrations than substance P or neurokinin B (p <0.013). Neurokinin-2 receptor blockade prod uced a 100-fold rightward shift of the concentration-response curves (p <0. 013), while neurokinins 1 and 3 receptor blockade had no effect. SR 48,968 significantly reduced contractility during the 1-hour incubation period, ca using a 97% reduction in spontaneous rates compared with a 29% reduction in control tissues. CP 99,994 and SR 142,801 had no significant effect. Conclusions: Neurokinin-2 is the predominant receptor subtype responsible f or tachykinin induced contraction of human ureteral smooth muscle. In vitro treatment with the neurokinin-2 antagonist SR 48,968 reduces the spontaneo us contraction rate by 97% in vitro. Neurokinin-2 receptor antagonists may have clinical applications for ureteral disease.