Angiotensin II and neurohumoral control of the renal medullary circulation

Angiotensin II (AngII) has multiple actions in the renal medullary circulation. It can induce vasodilatation and blunt the response of medullary blood flow (MBF) to renal nerve activation, through AT(1)-receptor mediated release of nitric oxide and/or vasodilator prostaglandins. These actions require high intravascular and/or intratubular AngII concentrations, so are not apparent under physiological conditions. Nevertheless, these mechanisms blunt the responsiveness of MBF to AT(1)-receptor mediated vasoconstriction. When these protective mechanisms fail, as when oxidative stress reduces nitric oxide bioavailability in the medullary circulation, AngII reduces MBF. If sustained, reduced MBF leads to development of hypertension. Chronic renin-angiotensin system (RAS) activation induces oxidative stress in the kidney. MBF might therefore be reduced in models of hypertension associated with RAS activation both because AngII levels per se are increased, and because of increased responsiveness of MBF to AngII-induced vasoconstriction. Endogenous AngII enhances the responsiveness of MBF to renal nerve stimulation, while nitric oxide blunts it. Chronic RAS activation and/or oxidative stress should therefore be expected to enhance MBF responses to renal nerve stimulation. Consistent with this, reductions in MBF induced by renal nerve stimulation are enhanced in rabbits with AngII-induced hypertension, renovascular hypertension, or after 9 weeks of fat-feeding. We conclude that the ability of endogenous AngII to reduce MBF and enhance the response of MBF to activation of the renal nerves could contribute to development of hypertension under conditions of RAS activation, especially if accompanied by increased renal sympathetic nerve activity.