Impact of angiotensin-receptor blockers on intrarenal renin-angiotensin system activity in hypertension: A PK/PD modelling study

Abstract

The renin-angiotensin system (RAS) is a primary regulator of volume homeostasis and blood pressure, whose over-activation is commonly associated with hypertension. Indeed, medications that target the RAS are generally effective in reducing blood pressure. However, more can be learned about how these medications influence the intrarenal RAS. Angiotensin-receptor blockers (ARBs) in particular have been shown to exert different effects on the intrarenal and systemic RASs in various experimental models of hypertension. In rats chronically infused with angiotensin II (Ang II), ARBs consistently prevent intrarenal, but not systemic Ang II levels from rising. The former effect is sufficient in pre- venting the development of hypertension. The regulation of intrarenal RAS, independently of the systemic RAS, by ARBs has been hypoth- esized to be mediated by the inhibition of all positive feedback loops inherent to the intrarenal RAS, also known as the "key point break- down effect." To investigate the validity of this hypothesis, we developed a PK/PD model of the ARB Losartan that considers the kidney, and applied the model to study how this class of medication influences intrarenal RAS activity and consequently blood pressure regulation in male rats. Simulations indicate that ARBs more effectively inhibit the activation of the intrarenal RAS because, unlike in the plasma, this pro- cess relies on the accumulation of cell-associated Ang II. We hypothesize that it is by blocking this intracellular uptake pathway, and restrict- ing Ang II to extracellular regions of the kidney where the peptide cannot initiate downstream signalling, that Losartan normalizes blood pressure. While the key point break down effect assists in this response, it alone is not sufficient. Our results highlight the intrarenal RAS as the key pharmacological target of ARB treatment and emphasize the importance of this local tissue RAS in the development of hypertension.