Effects of the substance P receptor antagonist CP-96,345 on renal sensory receptor activation

In anesthetized rats, we examined the effects of the substance P (SP) receptor antagonist CP-96,345 on the renorenal reflex responses to renal mechanoreceptor (MR) stimulation produced by increased ureteral pressure. Renal pelvic administration of SP at 0.16, 0.8, 4.0, 20, and 100 micrograms/ml increased ipsilateral afferent renal nerve activity (ARNA) in a concentration-dependent fashion, 45 +/- 28, 134 +/- 26, 185 +/- 24, 185 +/- 25, and 274 +/- 39%, respectively. Renal pelvic perfusion with CP-96,345 at 0.01, 0.1, and 1.0 mg/ml dose-dependently reduced the ARNA response to 4.0 micrograms/ml SP, by 5 +/- 17, 46 +/- 9, and 72 +/- 12%, respectively. Increasing ureteral pressure three times in the presence of renal pelvic perfusion with vehicle, 1 mg/ml CP-96,345, and vehicle, increased ARNA 77 +/- 21, 29 +/- 13, and 101 +/- 36%, respectively. Thus CP-96,345 produced a reversible blockade of the ARNA responses to renal MR stimulation. Increasing ureteral pressure three times in the presence of renal pelvic perfusion with vehicle, CP-96,345 (1 mg/ml), and CP-96,345 + 25-40 micrograms/ml SP, increased ARNA 108 +/- 15, 43 +/- 14, and 153 +/- 63%, respectively. Thus CP-96,345 produced a competitive blockade of the ARNA responses to renal MR stimulation. The contralateral diuretic and natriuretic responses to increased ureteral pressure were also blocked in a reversible and competitive fashion by CP-96,345. The inactive 2R,3R enantiomer of CP-96,345, CP-96,344 (1 mg/ml). had no effect on the ipsilateral ARNA or the contralateral renal excretory responses to increased ureteral pressure.(ABSTRACT TRUNCATED AT 250 WORDS)