Angiotensin in the Kidney: A Key to Understanding Hypertension?

A crosstransplantation study between genetically matched angiotensin AT1 receptor knockout and wild-type mice revealed that renal AT1 receptors are required for the development of angiotensin II-induced hypertension (Crowley et al., 2006). However, in this experimental setting, hypertension-related left ventricular hypertrophy seemed to depend on blood pressure elevation rather than on the expression of AT1 receptors in the heart

Key advances in antihypertensive treatment

Although various effective treatments for hypertension are available, novel therapies to reduce elevated blood pressure, improve blood-pressure control, treat resistant hypertension, and reduce the associated cardiovascular risk factors are still required. A novel angiotensin-receptor blocker (ARB) was approved in 2011, and additional compounds are in development or being tested in clinical trials. Several of these agents have innovative mechanisms of action (an aldosterone synthase inhibitor, a natriuretic peptide agonist, a soluble epoxide hydrolase inhibitor, and an angiotensin II type 2 receptor agonist) or dual activity (a combined ARB and neutral endopeptidase inhibitor, an ARB and endothelin receptor A blocker, and an endothelin-converting enzyme and neutral endopeptidase inhibitor). In addition, several novel fixed-dose combinations of existing antihypertensive agents were approved in 2010-2011, including aliskiren double and triple combinations, and an olmesartan triple combination. Upcoming fixed-dose combinations are expected to introduce calcium-channel blockers other than amlodipine and diuretics other than hydrochlorothiazide. Finally, device-based approaches to the treatment of resistant hypertension, such as renal denervation and baroreceptor activation therapy, have shown promising results in clinical trials. However, technical improvements in the implantation procedure and devices used for baroreceptor activation therapy are required to address procedural safety concerns

AT2 receptor agonists: hypertension and beyond

Research about the angiotensin AT2 receptor (AT2R) has been hampered in the past by the lack of a specific and selective agonist with in-vivo stability. Such an eagerly awaited agonist, compound 21, has recently become available, giving momentum to AT2R research which so far has resulted in 14 original publications. This article is intending to review those publications which address AT2R function by direct in-vivo stimulation instead of indirect approaches such as receptor blockade or genetic alteration of AT2R expression.Studies reviewed in this article looked at the effect of AT2R stimulation in disease models of hypertension, renal disease, stroke, Alzheimer's disease and myocardial infarction. AT2R stimulation does not have an antihypertensive effect, but promoted tissue protection in all models in which it was tested. Antiinflammation and antiapoptosis seem important features of the AT2R underlying improved outcome in experimental disease models.Availability of nonpeptidic, orally active AT2R agonists will facilitate future AT2R research and hopefully contribute to the clarification of many still open questions regarding AT2R signalling and function. Furthermore, AT2R agonists represent a potential novel class of drugs and are expected to enter a phase I clinical study in 2012