Biased agonism/antagonism at the AngII-AT1 receptor: Implications for adrenal aldosterone production and cardiovascular therapy

Many of the effects of angiotensin II (AngII), including adrenocortical aldosterone release, are mediated by the AngII type 1 receptor (AT(1)R), a receptor with essential roles in cardiovascular homeostasis. AT(1)R belongs to the G protein-coupled receptor (GPCR) superfamily, mainly coupling to the G(q/11) type of G proteins. However, it also signals through beta arrestins, oftentimes in parallel to eliciting G protein-dependent signaling. This has spurred infinite possibilities for cardiovascular pharmacology, since various beneficial effects are purportedly exerted by AT(1)R via beta arrestins, unlike AT(1)R-induced G protein-mediated pathways that usually result in damaging cardiovascular effects, including hypertension and aldosterone elevation. Over the past decade however, a number of studies from our group and others have suggested that AT(1)R-induced beta arrestin signaling can also be damaging for the heart, similarly to the G protein-dependent one, with regard to aldosterone regulation. Additionally, AT(1)R-induced beta arrestin signaling in astrocytes from certain areas of the brain may also play a significant role in central regulation of blood pressure and hypertension pathogenesis. These findings have provided the impetus for testing available angiotensin receptor blockers (ARBs) in their efficacy towards blocking both routes (i.e. both G protein- and beta arrestin-dependent) of AT(1)R signaling in vitro and in vivo and also have promoted structure-activity relationship (SAR) studies for the AngII molecule in terms of beta arrestin signaling to certain cellular effects, e.g. adrenal aldosterone production. In the present review, we will recount all of these recent studies on adrenal and astrocyte AT(1)R-dependent beta arrestin signaling while underlining their implications for cardiovascular pathophysiology and therapy.