Activation of renal mechanosensitive neurons involves bradykinin, protein kinase C, PGE2, and substance P

2000 ◽  
Vol 278 (4) ◽  
pp. R937-R946 ◽  
Author(s):  
Ulla C. Kopp ◽  
Donna M. Farley ◽  
Michael Z. Cicha ◽  
Lori A. Smith
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Receptor Antagonist ◽  
Renal Nerve ◽  
Kinase C ◽  
Renal Nerve Activity ◽  
Substance P Receptor ◽  
Pelvic Perfusion ◽  
Pelvic Pressure

Increased renal pelvic pressure or bradykinin increases afferent renal nerve activity (ARNA) via PGE2-induced release of substance P. Protein kinase C (PKC) activation increases ARNA, and PKC inhibition blocks the ARNA response to bradykinin. We now examined whether bradykinin mediates the ARNA response to increased renal pelvic pressure by activating PKC. In anesthetized rats, the ARNA responses to increased renal pelvic pressure were blocked by renal pelvic perfusion with the bradykinin B2-receptor antagonist HOE 140 and the PKC inhibitor calphostin C by 76 ± 8% ( P < 0.02) and 81 ± 5% ( P < 0.01), respectively. Renal pelvic perfusion with 4β-phorbol 12,13-dibutyrate (PDBu) to activate PKC increased ARNA 27 ± 4% and renal pelvic release of PGE2 from 500 ± 59 to 1,113 ± 183 pg/min and substance P from 10 ± 2 to 30 ± 2 pg/min (all P < 0.01). Indomethacin abolished the increases in substance P release and ARNA. The PDBu-mediated increase in ARNA was also abolished by the substance P-receptor antagonist RP 67580. We conclude that bradykinin contributes to the activation of renal pelvic mechanosensitive neurons by activating PKC. PKC increases ARNA via a PGE2-induced release of substance P.

A role for protein kinase C in bradykinin-mediated activation of renal pelvic sensory receptors

1995 ◽  
Vol 269 (2) ◽  
pp. R331-R338 ◽  
Author(s):  
U. C. Kopp ◽  
L. A. Smith
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Feedback Inhibition ◽  
Normal Diet ◽  
Sensory Receptors ◽  
Renal Nerve ◽  
Kinase C ◽  
Renal Nerve Activity ◽  
Pelvic Perfusion ◽  
20 Nm

In anesthetized rats, activation of renal pelvic sensory receptors by bradykinin results in an increase in afferent renal nerve activity (ARNA) that is dependent on intact renal prostaglandin synthesis. Since bradykinin is a known activator of the phosphoinositide system, we examined whether the increase in ARNA produced by bradykinin involved activation of protein kinase C (PKC). Renal pelvic perfusion with the phorbol ester 4 beta-phorbol 12,13-dibutyrate (PDBu, 1 microM) increased ARNA (31 +/- 3%, P < 0.01) in rats fed a normal diet but not in rats fed an essential fatty acid-deficient (EFAD) diet. Renal pelvic perfusion with the PKC inhibitors calphostin C (1 microM), staurosporine (20 nM), and H-7 (40 microM) reduced the ARNA responses to bradykinin (20 microM) by 69 +/- 10, 76 +/- 10, and 77 +/- 10%, respectively (all P < 0.01). Pretreatment with PDBu (1 microM), known to cause a feedback inhibition of bradykinin-mediated activation of the phosphoinositide system, reduced the ARNA response to bradykinin by 73 +/- 6% (P < 0.01). Pretreatment with 4 alpha-phorbol 12,13-didecanoate was without effect. These findings suggest that activation of PKC contributes importantly to the activation of renal pelvic sensory receptors by bradykinin, likely via release of arachidonic acid.

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

1993 ◽  
Vol 264 (3) ◽  
pp. R647-R653 ◽  
Author(s):  
U. C. Kopp ◽  
L. A. Smith
Keyword(s):  
Substance P ◽  
Receptor Antagonist ◽  
Receptor Activation ◽  
Sensory Receptor ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Reflex Responses ◽  
Renal Nerve Activity ◽  
Substance P Receptor ◽  
Pelvic Perfusion

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)

Renal sensory receptor activation causes prostaglandin-dependent release of substance P

1996 ◽  
Vol 270 (4) ◽  
pp. R720-R727 ◽  
Author(s):  
U. C. Kopp ◽  
D. M. Farley ◽  
L. A. Smith
Keyword(s):  
Substance P ◽  
De Novo ◽  
Receptor Activation ◽  
Sensory Receptor ◽  
Renal Nerve ◽  
Time Control ◽  
Renal Nerve Activity ◽  
Substance P Receptor ◽  
Pelvic Perfusion

Renal mechanoreceptor (MR) activation by increased ureteral pressure (increases UP) results in an increase in afferent renal nerve activity (ARNA) that is blocked by substance P receptor blockade and prostaglandin (PG) synthesis inhibition. To examine the interaction between substance P and PGs, the release of substance P and PGE into the renal pelvis was studied before and during renal pelvic perfusion with indomethacin. Before indomethacin, increases UP increased ARNA 43 +/- 6% and renal pelvic release of substance P from 11 +/- 3 to 29 +/- 8 pg/min and PGE from 319 +/- 71 to 880 +/- 146 pg/min. Indomethacin blocked the increases in ARNA and release of substance P and PGE produced by increases UP. Time control experiments showed reproducible increases in ARNA and release of substance P and PGE during increases UP. Mechanical stimulation of the renal pelvic wall in vitro resulted in an increase in PGE release from 110 +/- 8 to 722 +/- 152 pg/min, which was abolished by indomethacin, suggesting a de novo PGE synthesis. The data suggest that increases UP results in a renal pelvic release of PGE, which facilitates the release of substance P and activation of renal pelvic MR.

scholarly journals Protein kinase C-dependent and -independent mechanisms regulating the parotid substance P receptor as revealed by differential effects of protein kinase C inhibitors

1988 ◽  
Vol 256 (2) ◽  
pp. 677-680 ◽  
Author(s):  
H Sugiya ◽  
J W Putney
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Time Course ◽  
Phorbol Esters ◽  
Inhibitory Effect ◽  
Protein Kinase C Inhibitors ◽  
Kinase C ◽  
Substance P Receptor ◽  
Rat Parotid

Substance P-induced inositol trisphosphate (InsP3) formation was inhibited by 1 microM-4 beta-phorbol 12,13-dibutyrate (PDBu) in rat parotid acinar cells. The inhibitory effect of PDBu was reversed by the protein kinase C inhibitors H-7 or K252a. Substance P also elicits a persistent desensitization of subsequent substance P-stimulated InsP3 formation. However, this desensitization was not inhibited by H-7. In addition, H-7 had no effect on the time course of substance P-induced InsP3 formation. These results suggest that, although activation of protein kinase C by phorbol esters can inhibit the substance P receptor-linked phospholipase C pathway, this mechanism apparently plays little, if any, role in regulating this system after activation by substance P.

scholarly journals Neurokinin-1 Receptor Antagonist Treatment in Polymicrobial Sepsis: Molecular Insights

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Akhil Hegde ◽  
Yung-Hua Koh ◽  
Shabbir M. Moochhala ◽  
Madhav Bhatia
Keyword(s):  
Transcription Factors ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Receptor Antagonist ◽  
Polymicrobial Sepsis ◽  
Neurokinin 1 Receptor ◽  
Post Surgery ◽  
Kinase C ◽  
Neurokinin 1

Neurokinin-1 receptor blocking has been shown to be beneficial against lung injury in polymicrobial sepsis. In this paper, we evaluated the possible mediators and the mechanism involved. Mice were subjected to cecal ligation and puncture (CLP-) induced sepsis or sham surgery. Vehicle or SR140333 [1 mg/kg; subcutaneous (s.c.)] was administered to septic mice either 30 min before or 1 h after the surgery. Lung tissue was collected 8 h after surgery and further analyzed. CLP alone caused a significant increase in the activation of the transcription factors, protein kinase C-α, extracellular signal regulated kinases, neurokinin receptors, and substance P levels in lung when compared to sham-operated mice. SR140333 injected pre- and post surgery significantly attenuated the activation of transcription factors and protein kinase C-αand the plasma levels of substance P compared to CLP-operated mice injected with the vehicle. In addition, GR159897 (0.12 mg/kg; s.c.), a neurokinin-2 receptor antagonist, failed to show beneficial effects. We conclude that substance P acting via neurokinin-1 receptor in sepsis initiated signaling cascade mediated mainly by protein kinase C-α,led to NF-κB and activator protein-1 activation, and further modulated proinflammatory mediators.

Bradykinin-mediated activation of renal sensory neurons due to prostaglandin-dependent release of substance P

1997 ◽  
Vol 272 (6) ◽  
pp. R2009-R2016 ◽  
Author(s):  
U. C. Kopp ◽  
D. M. Farley ◽  
L. A. Smith
Keyword(s):  
Substance P ◽  
Sensory Receptors ◽  
Nerve Activity ◽  
Renal Nerve ◽  
P Release ◽  
Renal Nerve Activity ◽  
Substance P Receptor ◽  
Pelvic Perfusion ◽  
Substance P Release ◽  
Substance P Receptors

In anesthetized rats, renal pelvic administration of bradykinin results in a prostaglandin (PG)-dependent increase in afferent renal nerve activity (ARNA). We now measured renal pelvic release of PGE and substance P during renal pelvic administration of bradykinin. Bradykinin increased ARNA and renal pelvic release of PGE by 497 +/- 252 pg/min and substance P. by 10.7 +/- 7.2 pg/min. Renal pelvic perfusion with indomethacin abolished the bradykinin-mediated increase in ARNA and reduced renal pelvic release of PGE and substance P by 76 +/- 11 and 72 +/- 8%, respectively. To examine whether the increased substance P release contributed to bradykinin-mediated activation of renal sensory receptors, renal pelvis was perfused with the substance P-receptor antagonists CP-96,345, CP-99,994, or RP-67580. The ARNA response to bradykinin was reduced 73 +/- 11, 55 +/- 12, and 64 +/- 10% by CP-96,345, CP-99,994, and RP-67580, respectively. The inactive enantiomers CP-96,344 and RP-68651 had no effect. These data suggest that bradykinin increases renal pelvic release of PGE, which facilitates the release of substance P, which in turn stimulates substance P receptors. Thus the ARNA response to bradykinin is largely mediated by activation of substance P receptors.

scholarly journals Activation of endothelin A receptors contributes to impaired responsiveness of renal mechanosensory nerves in congestive heart failureThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (6) ◽  
pp. 622-629 ◽  
Author(s):  
Ulla C. Kopp ◽  
Michael Z. Cicha ◽  
Susan Y. Jones
Keyword(s):  
Substance P ◽  
Sensory Nerve ◽  
Reflex Response ◽  
Nerve Activity ◽  
Renal Nerve ◽  
P Release ◽  
Renal Nerve Activity ◽  
Pelvic Perfusion ◽  
Substance P Release ◽  
Pelvic Pressure

Increasing renal pelvic pressure results in PGE2-mediated release of substance P, leading to increases in afferent renal nerve activity (ARNA) and natriuresis, that is, a renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF. Endothelin (ET)-1 contributes to the pathological changes in cardiac and renal function in CHF. Therefore, we examined whether the ETA receptor antagonist BQ123 altered the responsiveness of renal mechanosensory nerves in CHF. The ARNA responses to increasing renal pelvic pressure were suppressed in CHF but not in sham-CHF rats. In CHF, increasing renal pelvic pressure by 7.5 mm Hg before and during renal pelvic perfusion with BQ123 increased ARNA 12% ± 3% and 21% ± 3% (p < 0.05 vs. vehicle). In isolated renal pelvises from CHF rats, PGE2 increased substance P release from 5 ± 0 to 7 ± 1 pg/min without BQ123 and from 4 ± 1 to 9 ± 1 pg/min with BQ123 in the bath (p < 0.01 vs. vehicle). BQ123 had no effect on the ARNA responses or substance P release in sham-CHF. In conclusion, activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF rats by a mechanism(s) at the renal sensory nerve endings.

scholarly journals Two modes of regulation of the phospholipase C-linked substance-P receptor in rat parotid acinar cells

1988 ◽  
Vol 253 (2) ◽  
pp. 459-466 ◽  
Author(s):  
H Sugiya ◽  
J F Obie ◽  
J W Putney
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Acinar Cells ◽  
Control Mechanisms ◽  
Dependent Manner ◽  
Parotid Acinar Cells ◽  
Kinase C ◽  
Substance P Receptor ◽  
Rat Parotid

In rat parotid acinar cells prelabelled with [3H]inositol, substance P (100 nM) induced the formation of [3H]inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Ins(1,4,5)P3 reached a maximum 7 s after substance P stimulation, and thereafter decreased and reached a stable value at 60 s. When the cells were exposed to substance P for 10, 30, 60, or 300 s, washed, and re-exposed to this peptide, the formation of [3H]inositol trisphosphate (InsP3) was attenuated in a time-dependent manner. In the cells pretreated as described above, the number of [3H]substance-P-binding sites (Bmax) was also decreased. Possible role(s) of Ca2+ and protein kinase (protein kinase C) control mechanisms in regulating substance P responses were investigated. Desensitization of substance P-induced InsP3 was not affected by the Ca2+ ionophore ionomycin, nor was it dependent on Ca2+ mobilization. On the other hand, in the presence of 4 beta-phorbol 12,13-dibutyrate (PDBu) and 12-O-tetradecanoyl-4 beta-phorbol 13-acetate, known activators of protein kinase C, substance P-induced InsP3 formation was inhibited. However, PDBu had no effect on [3H]substance P binding, whether present during the assay or when cells were pretreated. The persistent desensitization of InsP3 formation induced by substance P was not affected by PDBu. These results suggest that the persistent desensitization of InsP3 formation induced by substance P is a homologous process involving down-regulation of the substance P receptor; the mechanism does not appear to involve, or to be affected by, the Ca2+ or protein kinase C signalling systems. Protein kinase C activation can, however, inhibit substance P-induced InsP3 formation, which may indicate the presence of a negative-feedback control on the substance P pathway.

scholarly journals Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor

2004 ◽  
Vol 86 (1) ◽  
pp. 69-76 ◽  
Author(s):  
Klaus Lieb ◽  
Yvonne Treffurth ◽  
Maike Hamke ◽  
Ravi Shankar Akundi ◽  
Matthias Von Kleinsorgen ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Substance P Receptor
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