Tonic postganglionic sympathetic inhibition induced by afferent renal nerves?
Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptor-dependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10(-7) m; 10 μL; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4±13.0 mV*s (baseline) to 12.8±3.2 mV*s (minimum; P<0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3±19.4 mV*s; P<0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic outflow.
Department of Internal Medicine 4, Nephrology and Hypertension, Friedrich-Alexander University Erlangen, Ulmenweg 1, 91054 Erlangen, Germany. Tilmann.Ditting@t-online.de
Tilmann
T
Ditting
Wolfgang
W
Freisinger
Kirsten
K
Siegel
Christian
C
Fiedler
Lisa
L
Small
Winfried
W
Neuhuber
Sonja
S
Heinlein
Peter W
PW
Reeh
Roland E
RE
Schmieder
Roland
R
Veelken
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D054833:Isoindoles / Q000494:pharmacology; D007668:Kidney / Q000294:innervation* / Q000502:physiology; D008297:Male; D023421:Models, Animal; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D013373:Substance P / Q000378:metabolism; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects* / Q000502:physiology; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism
D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C493922:Trpv1 protein, rat; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D002211:Capsaicin