Purinergic P2X receptor, purinergic P2X 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 (ATRs), 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, P2XR and P2XR inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of ATR influence. To evaluate the interactions between P2XRs and ATRs 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 P2XRi (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 P2XRi increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor ATRi (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2XRi increased AAD by 21 ± 14%; combination with P2XRi plus P2XRi (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2XR, P2XR, and ATR actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of ATRs on AAR in ANG II-dependent hypertension.