Norepinephrine (NE)‐mediated activation of renal sensory nerves is controlled by a crosstalk between the PLC/PKC and adenylyl cyclase/cAMP/PKA transduction pathways

Abstract

NE increases and decreases afferent renal nerve activity (ARNA) by activating α1-adrenoceptors (AR) and α2-AR, respectively, on renal sensory nerves. Stimulation of α1-AR activates PLC and PKC leading to increased PGE2 release which in turn activates the adenylyl cyclase (AC)/cAMP/PKA transduction cascade resulting in increases in substance P release and ARNA. Activation of α2-AR results in decreased substance P release in association with decreased PGE2 release. To examine the mechanisms involved in the α2-mediated reduction in substance P and PGE2 release, renal pelvises were pretreated with pertussis toxin (PTX), deactivator of Gi proteins. PTX enhanced the NE-induced activation of the renal sensory nerves to a similar extent as an α2-AR antagonist. These data suggest that NE-mediated activation of α2-AR, coupled to Gi proteins, leads to reduction in AC activity. In isolated renal pelvises, NE 2 pM failed to increase substance P and PGE2 release. However in the presence of the AC activator forskolin, 2 pM NE increased renal pelvic release of PGE2 from 97±8 to 274±30 pg/min and substance P from 5±1 to 10±1 pg/min (P<0.01, n=8). The forskolin-induced enhancement of the NE-induced increases in PGE2 and substance P release were abolished by indomethacin (P<0.01, n=6), the AC inhibitor dideoxyadenosine (n=4) and the PLC inhibitor U73122 (P<0.01, n=9). Likewise, in vivo studies showed that renal pelvic perfusion with forskolin resulted in enhanced ARNA responses to 2 pM NE that were reduced by U73122. Conclusion NE-mediated activation of renal sensory nerves involves a positive feedback loop consisting of AC facilitating the α1-AR-stimulation of PLC/PKC which in turn leads to increased PGE2 release with subsequent release of substance P and increased ARNA. This is counter regulated by α2-AR mediated inhibition of AC.