ATP And Activation Of P2X1 And P2X7 Renal Receptors. A New Concept In The Pathophysiology Of Renal Vasoconstriction In Angiotensin II‐Induced hypertension

Background The participation of ATP in the renal dysfunction observed in hypertension has not been completely elucidated. It is known that sheer stress stimulates the release of ATP by endothelial cells; indeed, renal interstitial fluid ATP concentration increased in response to elevation of arterial pressure, as well as in the AngII‐induced hypertension; these findings suggest that activation of P2X receptors may be relevant on altered renal function in the setting of hypertension. P2X1, P2X4 and P2X7 have been pointed out as responsible, since P2X1 activation induces renal vasoconstriction, P2X4 activation induces vasodilation by release of nitric oxide, and P2X7 receptors are promoters of inflammation and release of inflammatory cytokines, and are located in the tubulointertitial inflammation observed in Ang II‐mediated hypertension. To further study the participation of ATP receptors in the renal vasoconstriction observed in the AngII‐induced hypertension, we evaluated the contribution of P2X1, P2X7 and P2X4 in glomerular hemodynamics. Methods Micropuncture studies were performed in anesthetized AngII–infused rats 13–14 days after aminipump implant which delivered 430 nM/kg/min of the peptide and in Sham rats. In all groups (n=7–8), sham and hypertensive rats received vehicle or NF449 a P2X1 antagonist (30 nM), A‐438079, a specific P2X7 inhibitor (30 μM), ivermectin, a P2X4 agonist/all osteric modulator (3 μM), and PSB12054, a P2X4 inhibitor (4.2 μM). All the inhibitors and the agonist were infused acutely into the aorta above the left renal artery 1 h before the micro puncture studies started. Results NF449, A4380, and ivermectin reversed the arteriolar vasoconstriction induced by AngII, resulting in a reduction of afferent and efferent resistances, an increase of glomerular plasma flow and glomerular capillary pressure, a rise of ultrafiltration coefficientas well as single nephron glomerular filtration rate. Whole glomerularfiltration rate increased with NF449 and A438079. In Sham rats the compounds induced minor changes in glomerular hemodynamics; only The P2X4 antagonist PSB12054 induced renal vasoconstriction in the sham rats with no effects in the hypertensiverats. Mean arterial pressure was not altered by the compounds in neither AngIIn or Sham rats. No changes in urinary nitrites (as an indirect evaluation of renal nitric oxide production) were observed with either of the compounds. Conclusions P2X1 and P2X7 participate in the initial renal vasoconstriction that leads to renal injury in the AngII‐dependent hypertension. These effects seem to be reversed by a direct effect of blockade of the receptors, since it is not mediated by nitric oxideproduction. These receptors are essential to regulate renal hemodynamics in hypertension, and their blockade could be a useful maneuver to prevent renal injury inhypertensive patients. Support or Funding Information This study was supported by grant number 219981 to (M. Franco) from the National Council of Science and Technology (CONACYT), Mexico