Purinergic P2X1 receptor, purinergic P2X7 receptor, and angiotensin II type 1 receptor interactions in the regulation of renal afferent arterioles in angiotensin II-dependent hypertension

In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (AT 1 Rs), elevating blood pressure and increasing renal afferent arteriolar resistance (AAR). The increased arterial pressure augments interstitial ATP concentrations activating purinergic P2X receptors (P2XRs) also increasing AAR. Interestingly, P2X 1 R and P2X 7 R inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of AT 1 R influence. To evaluate the interactions between P2XRs and AT 1 Rs in mediating the increased AAR elicited by chronic ANG II infusions, experiments using the isolated blood perfused juxtamedullary nephron preparation allowed visualization of afferent arteriolar diameters (AAD). Normotensive and ANG II-infused hypertensive rats showed AAD responses to increases in renal perfusion pressure from 100 to 140 mmHg by decreasing AAD by 26 ± 10% and 19 ± 4%. Superfusion with the inhibitor P2X 1 Ri (NF4490; 1 μM) increased AAD. In normotensive kidneys, superfusion with ANG II (1 nM) decreased AAD by 16 ± 4% and decreased further by 19 ± 5% with an increase in renal perfusion pressure. Treatment with P2X 1 Ri increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor AT 1 Ri (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2X 1 Ri increased AAD by 21 ± 14%; combination with P2X 1 Ri plus P2X 7 Ri (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2X 1 R, P2X 7 R, and AT 1 R actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of AT 1 Rs on AAR in ANG II-dependent hypertension.