Angiotensin blocks substance P release from renal sensory nerves by inhibiting PGE2-mediated activation of cAMP.
Activation of renal sensory nerves involves PGE2-mediated release of substance P (SP) via activation of the cAMP-PKA pathway. The PGE2-mediated SP release is suppressed by a low- and enhanced by a high-sodium (Na+) diet, suggesting an inhibitory effect of ANG. We now examined whether ANG II is present in the pelvic wall and inhibits PGE2-mediated SP release by blocking PGE2-mediated increases in cAMP. ANG II levels in renal pelvic tissue were 710 +/- 95 and 260 +/- 30 fmol/g tissue in rats fed a low- and high-Na+ diet, respectively. In a renal pelvic preparation from high-Na+-diet rats, 0.14 microM PGE2 produced an increase in SP release from 7 +/- 1 to 19 +/- 3 pg/min that was blocked by 15 nM ANG II. Treating pelvises with pertussis toxin (PTX) abolished the effects of ANG II. In pelvises from low-Na+ rats, neither basal nor bradykinin-mediated SP release was altered by PGE2. However, the bradykinin-mediated release of SP was enhanced by the permeable cAMP analog CPT-cAMP, from 4 +/- 1 to 11 +/- 2 pg/min, a response similar to that in normal-Na+-diet rats. In vivo, renal pelvic administration of PGE2 enhanced the afferent renal nerve activity (ARNA) response to bradykinin in normal- but not in low-Na+ diet rats. CPT-cAMP produced similar enhancement of the ARNA responses to bradykinin in normal- and low-Na+-diet rats, 1,670 +/- 490 and 1,760 +/- 400%.s (area under the curve of ARNA vs. time). Similarly, the ARNA responses to increases in renal pelvic pressure were similarly enhanced by CPT-cAMP in normal- and low-Na+-diet rats. In conclusion, renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing PGE2-mediated activation of adenylyl cyclase via a PTX-sensitive mechanism.
Dept. of Internal Medicine, Medical Center, University of Iowa Roy J. and Lucille Carver College of Medicine, Iowa City 52242, USA. ukopp@blue.weeg.uiowa.edu
Ulla C
UC
Kopp
Michael Z
MZ
Cicha
Lori A
LA
Smith
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004032:Diet; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007682:Kidney Pelvis / Q000294:innervation; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000008:administration & dosage / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism*
D000804:Angiotensin II; D013373:Substance P; D012964:Sodium; D000242:Cyclic AMP; D037342:Pertussis Toxin; D015232:Dinoprostone; D001920:Bradykinin