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)
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City.
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UC
Kopp
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Smith
D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004231:Diuresis; D007668:Kidney / Q000294:innervation / Q000502:physiology*; D008297:Male; D008465:Mechanoreceptors / Q000502:physiology; D009318:Natriuresis; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D011984:Sensory Receptor Cells / Q000502:physiology*; D014513:Ureter / Q000502:physiology
D001713:Biphenyl Compounds; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; C066892:CP 96345