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Curr Drug Targets. 2019 Aug 21. doi: 10.2174/1389450120666190821152000. [Epub ahead of print]

Angiotensin Type 1 Receptor Blockers in Heart Failure.

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Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. United States.


Homeostasis in the cardiovascular system is maintained by physiological functions of the Renin Angiotensin Aldosterone System (RAAS). In pathophysiological conditions, over activation of RAAS leads to an increase in the concentration of Angiotensin II (AngII) and over activation of Angiotensin Type 1 Receptor (AT1R) resulting in vasoconstriction, sodium retention and change in myocyte growth. In the heart it causes cardiac remodeling which result in left ventricular hypertrophy, dilation and dysfunction which eventually leads to Heart Failure (HF). Inhibition of RAAS using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) have shown to significantly reduce morbidity and mortality due to HF. ACEi have been shown to have higher drug withdrawal rates due to discomfort when compared to ARBs; therefore, ARBs are the preferred choice of physicians for the treatment of HF in combination with other anti-hypertensive agents. Out of eight FDA approved ARBs, irbesartan and telmisartan are shown to have PPARϒ agonistic properties resulting in improved insulin intolerance. Olmesartan treatment also improves insulin sensitivity and produces anti-atherogenic and anti-inflammatory effects in patients with diabetic nephropathy. All the ARBs demonstrate beneficial effects similar to ACEi in the treatment of HF except lower doses of losartan which leads to increase mortality in HF patients. Valsartan in combination with sacubril therapy has shown to be a promising therapy for HF. Eprosartan has an effect on the sympathetic nervous system when compared to other ARBs and it is also able to reduce catecholamine release in animal models. Therefore, eprosartan therapy may have an additional beneficial effect in the treatment of heart failure. However, eprosartan has the shortest bioavailability (< 6 hours) when compared to other ARBs. Large numbers of studies that show beneficial effects on animals have been reported but there are limited studies on humans. Hence, more human studies are warranted. Recently, crystal structures of AT1R in inactive and active state structure have been solved. Using these crystal structures and cheminformatics tools, exploring structures similar to eprosartan with an increase in bioavailability and affinity may enhance the treatment of HF.


AT1R; AngII; Angiotensin receptor blockers; GPCRs; heart failure; hypertension

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