P₂‐receptor modulation of noradrenergic neurotransmission in rat kidney

Abstract

1 ATP has previously been shown to act as a sympathetic cotransmitter in the rat kidney. The present study analyses the question of whether postganglionic sympathetic nerve endings in the kidney possess P 2 -receptors which modulate noradrenaline release. Rat kidneys were perfused with Krebs-Henseleit solution containing the noradrenaline uptake blockers cocaine and corticosterone and the a 2 -adrenoceptor antagonist rauwolscine. The renal nerves were electrically stimulated, in most experiments by 30 pulses applied at 1 Hz. The out¯ow of endogenous noradrenaline (or, in some experiments, of ATP and lactate dehydrogenase) as well as the perfusion pressure were measured simultaneously. 2 The P 2 -receptor agonist adenosine-5'-O-(3-thiotriphosphate) (ATPgS, 3 ± 30 mM) reduced the renal nerve stimulation (RNS)-induced out¯ow of noradrenaline (estimated EC 50 =8 mM). The P 2 -receptor antagonist cibacron blue 3GA (30 mM) shifted the concentration-inhibition curve for ATPgS to the right (apparent pK B value 4.7). 3 Cibacron blue 3GA (3 ± 30 mM) and its isomer reactive blue 2 (3 ± 30 mM) signi®cantly increased RNSinduced out¯ow of noradrenaline in the presence of the P 1 -receptor antagonist 8-(p-sulphophenyl)theophylline (8-SPT, 100 mM) by about 70% and 90%, respectively. The P 2 -receptor antagonist suramin (30 ± 300 mM) only tended to enhance RNS-induced out¯ow of noradrenaline. When the nerves were stimulated by short pulse trains consisting of 6 pulses applied at 100 Hz (conditions under which autoinhibition is inoperative), reactive blue 2 did not aect the RNS-induced out¯ow of noradrenaline. 4 RNS (120 pulses applied at 4 Hz) induced the out¯ow of ATP but not of the cytoplasmatic enzyme lactate dehydrogenase. 5 ATPgS (3 ± 30 mM) concentration-dependently reduced pressor responses to RNS at 1 Hz. Cibacron blue 3GA, reactive blue 2 as well as suramin also reduced pressor responses to RNS (maximally by 50 to 70%). 6 This study in rat isolated kidney, in which the release of endogenous noradrenaline was measured, demonstrates that renal sympathetic nerves possess prejunctional P 2 -receptors that mediate inhibition of transmitter release. These prejunctional P 2 -receptors are activated by endogenous ligands, most likely ATP, released upon nerve activity. Both, P 2 -receptor agonists and P 2 -receptor antagonists reduced pressor responses to RNS either by inhibiting transmitter release or by blocking postjunctional vasoconstrictor P 2 -receptors.

The Renal Microcirculation

“…There are abundant fibers in subadventitial layers of the arcuate and interlobular arterioles and the afferent arteriole receives nearly three-fold greater density of innervation than the efferent arteriole. Adenosine triphosphate (ATP) is coreleased with NE from some nerve endings [107][108][109] . Interestingly, microvascular innervation by Type 1 fibers appears to be restricted to afferent arterioles with no innervation of efferent arterioles by this fiber type [105] .…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…a 2A -Adrenoceptor activation inhibits both NA and ATP release from mouse renal sympathetic nerves (Vonend et al, 2007). P2 receptor antagonists enhanced noradrenergic pressor responses of rat perfused kidney to sympathetic nerve stimulation by blocking prejunctional receptors (Bohmann et al, 1997).…”

Mechanism of the inhibitory action of ATP in rat hippocampus

“…For example, ATP inhibits Ca 2+ currents in PC12 cells , adrenal chromaffin cells [Currie and Fox, 1996;Powell et al, 2000], sympathetic neurons [Filippov et al, 1997], and superior cervical ganglion neurons [Filippov et al, 2000]. In addition, ATP inhibited the exocytosis in adrenal chromaffin cells [Powell et al, 2000], noradrenergic transmission in the rat kidney [Bohmann et al, 1997], and the evoked release of noradrenaline and serotonin in the rat cortex [von Kügelgen et al, 1994. In our hippocampal neurons, ATP might act on VGCs and inhibit release of glutamate, which may underlie the ATP-evoked inhibition of the Ca 2+ oscillation.…”