Glomerular arteriolar vasoconstriction and tubulointerstitial injury are observed before glomerular damage occurs in models of hypertension. High interstitial ATP concentrations, caused by the increase in arterial pressure, alter renal mechanisms involved in the long-term control of blood pressure, autoregulation of glomerular filtration rate and blood flow, tubuloglomerular feedback (TGF) responses, and sodium excretion. Elevated ATP concentrations and augmented expression of P2X receptors have been demonstrated under a genetic background or induction of hypertension with vasoconstrictor peptides. In addition to the alterations of the microcirculation in the hypertensive kidney, the vascular actions of elevated intrarenal angiotensin II levels may be mitigated by the administration of broad purinergic P2 antagonists or specific P2Y12, P2X1, and P2X7 receptor antagonists. Furthermore, the prevention of tubulointerstitial infiltration with immunosuppressor compounds reduces the development of saltsensitive hypertension, indicating that tubulointerstitial inflammation is essential for the development and maintenance of hypertension. Inflammatory cells also express abundant purinergic receptors, and their activation by ATP induces cytokine and growth factor release that in turn contributes to augment tubulointerstitial inflammation. Collectively, the evidence suggests a pathophysiological activation of purinergic P2 receptors in angiotensin-dependent hypertension. Coexistent increases in intrarenal angiotensin II and activates Ang II AT1 receptors, which interacts with over-activated purinergic receptors in a complex manner, suggesting convergence of their post-receptor signaling processes.
Perinatal taurine depletion and high sugar diets blunted baroreflex function and heightens sympathetic nerve activity in adult rats. Cardiac ischemia/reperfusion also produces these disorders and taurine treatment appears to improve these effects. This study tests the hypothesis that perinatal taurine exposure predisposes recovery from reperfusion injury in rats on either a basal or high sugar diet. Female Sprague-Dawley rats were fed normal rat chow with 3% beta-alanine (taurine depletion, TD), 3% taurine (taurine supplementation, TS) or water alone (control, C) from conception to weaning. Male offspring were fed normal rat chow and water containing 5% glucose (G) or water alone (W) throughout the experiment. At 7-8 weeks of age, all rats were anesthetized and their trachea clamped until cardiac arrest occurred and mean arterial pressure fell below 60 mm Hg. The clamp was immediately released and cardiopulmonary resuscitation was performed with cardiac function returning within 4 min. Twenty-four hours later, arterial pressure, heart rate, and baroreflex function were measured in conscious and one day later in anesthetized conditions. Basic blood chemistry and circulating markers of cardiac injury were also measured. Baroreflex sensitivity was depressed moderately in CG and TDW, and severely in TDG. TSW displayed increased baroreflex and high sugar intake returned it to CW. Sympathetic nerve activity increased and parasympathetic decreased in TDW but not TSW and these effects were exacerbated sharply in TDG and slightly in TSG. Arterial pressure and heart rate increased in all groups but to a lesser degree in TDG. Plasma aspartate aminotransferase increased in all groups except TSW, but the increase was nearly 3X greater in TDG vs. any other group. Creatine kinase-MB increased in all groups except TSG and was far greater in TD than other groups. Troponin-T and brain natriuretic peptide were greatly increased in TDG compared to all other groups. Thus, perinatal taurine depletion increases injury from cardiac ischemia/reperfusion, and in adult rats on a high sugar diet, these effects are greatly exacerbated.
In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (AT1Rs), 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, P2X1R and P2X7R inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of AT1R influence. To evaluate the interactions between P2XRs and AT1Rs 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 P2X1Ri (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 P2X1Ri increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor AT1Ri (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2X1Ri increased AAD by 21 ± 14%; combination with P2X1Ri plus P2X7Ri (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2X1R, P2X7R, and AT1R actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of AT1Rs on AAR in ANG II-dependent hypertension.
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