Impaired substance P release from renal sensory nerves in SHR involves a pertussis toxin-sensitive mechanism.
Stretching the renal pelvic wall activates renal mechanosensory nerves by a PGE2-mediated release of substance P via activation of the cAMP-PKA pathway. Renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing the PGE2-mediated activation of adenylyl cyclase via a pertussis toxin (PTX)-sensitive mechanism. In SHR, activation of renal mechanosensory nerves is impaired. This is due to suppressed release of substance P in response to increased pelvic pressure. The present study was performed to investigate whether the PGE2-mediated release of substance P was suppressed in SHR vs. WKY and, if so, whether the impaired PGE2-mediated release of substance P was due to ANG II activating a PTX-sensitive mechanism. In an isolated renal pelvic wall preparation, PGE2, 0.14 microM, increased substance P release from 9 +/- 3 to 22 +/- 3 pg/min (P < 0.01) in Wistar-Kyoto rats (WKY), but had no effect in spontaneously hypertensive rats (SHR). A tenfold higher concentration of PGE2, 1.4 microM, was required to increase substance P release in SHR, from 7 +/- 1 to 22 +/- 3 pg/min (P < 0.01). In SHR, treating renal pelvises with losartan enhanced the release of substance P produced by subthreshold concentration of PGE2, 0.3 microM, from 16 +/- 2 to 26 +/- 3 pg/min (P < 0.01). Likewise, treating renal pelvises with PTX enhanced the PGE2-mediated release of substance P from 10 +/- 1 to 33 +/- 3 pg/min (P < 0.01) in SHR. In WKY, neither losartan nor PTX had an effect on the release of substance P produced by subthreshold concentrations of PGE2, 0.03 microM. In conclusion, the impaired responsiveness of renal sensory nerves in SHR involves endogenous ANG II suppressing the PGE2-mediated release of substance P via a PTX-sensitive mechanism.
Kopp
Ulla C
UC
Dept. of Internal Medicine, VA Medical Center, Bldg. 3, Rm 226, Highway 6W, Iowa City, IA 52246, USA. ulla-kopp@uiowa.edu
Cicha
Michael Z
MZ
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D015232:Dinoprostone / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000378:metabolism*; D066298:In Vitro Techniques; D007682:Kidney Pelvis / Q000294:innervation*; D019808:Losartan / Q000494:pharmacology; D009475:Neurons, Afferent / Q000378:metabolism*; D009994:Osmolar Concentration; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011921:Rats, Inbred WKY; D013373:Substance P / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D013373:Substance P; D037342:Pertussis Toxin; D019808:Losartan; D015232:Dinoprostone; D002118:Calcium