P2X₁receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

Abstract

In vitro experiments demonstrate that P2X(1) receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X(1) receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X(1) receptor blockade with IP5I, or A(1) receptor blockade with DPCPX. Both P2X(1) and A(1) receptor stimulation with alpha,beta-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X(1) receptor stimulation. Likewise, administration of DPCPX significantly blocked A(1) receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100-120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80-100 mmHg, suggesting that A(1) receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X(1) receptor activation is important for whole kidney autoregulation in vivo.

Purinergic signalling in the kidney in health and disease

“…The central role of the P2 system is further suggested by the fact that pressure-induced reductions in afferent arteriole diameter are abolished in P2X1-deficient mice [152]. Pharmacological [272] or pathological [119] manoeuvres that impair P2X1 receptor signalling will also blunt whole kidney autoregulation of blood flow, both in vivo and in vitro. Finally, mice with a targeted deletion of the ectonucleotidase NTPDase1 exhibit enhanced pressureinduced vasoconstriction in the mesenteric artery [183].…”

Vascular smooth muscle cells from small human omental arteries express P2X1 and P2X4 receptor subunits

“…It is now established that P2X receptors, ligand-gated Ca 2+ -permeable cation channels expressed in the plasma membrane of vascular smooth muscle cells (VSMC), are responsible for vasoconstrictor responses induced by neuronal released ATP. In muscular arteries, it is proposed that activation of P2X receptors leads to membrane depolarisation, followed by an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and vasoconstriction, which evokes a rise in blood pressure [17,24]. Therefore P2X receptors may represent an important therapeutic target for treatment of hypertension.…”

Regulation of Renal Hemodyamics by Purinergic Receptors in Angiotensin II -Induced Hypertension

“…However, we cannot rule out that, in the presence of NO blockade the effect of endogenous vasoconstrictor mediators could be enhanced and alter renal function. It is recognized that the renal vasoconstriction observed in the Sham rats with PPADS (Franco et al 2011) was not observed by Tanaka el al (Takenaka et al, 2008) or Osmond and Inscho (Osmond & Inscho, 2010); these authors used an intravenous bolus, each 20 min with a lower dose than ours. Under those conditions, lower concentrations of PPADS possible reach the kidney; however the dose used in those studies (Osmond & Inscho, 2010) were sufficient to block P2 receptors as evidenced by the blockade of the vasoconstrictor response to ,methylene ATP; thus an explanation for the divergent effects of PPADS in Sham rats remains to be elucidated.…”