Binding to AT 1R results in vasoconstriction and aldosterone secretion, leading to salt and water retention and ultimately increasing arterial blood pressure. Ang II, the main vasoactive peptide of angiotensin metabolites in the systemic RAS, elicits its downstream physiologic and pathophysiological effects predominantly via the angiotensin II type 1 receptor (AT 1R), which is ubiquitously expressed in the cardiovascular system. Ang I is then converted to the potent vasoconstrictor, angiotensin II (Ang II Ang 1-8), by the zinc metalloprotease, ACE, which is highly expressed by endothelial and epithelial cells in the vasculature, kidneys, and lungs ( Skeggs et al., 1956) and shed into the circulation by unknown proteases ( Ehlers et al., 1996 Woodman et al., 2000). ![]() Renin, an aspartyl protease, is responsible for hydrolyzing the serum globulin, angiotensinogen, releasing the peptide angiotensin I (Ang I Ang 1-10) ( Page and Helmer, 1940). A reduction in renal blood flow or blood sodium levels leads to the release of renin into the circulation, mostly from renal juxtaglomerular cells in the walls of the afferent arterioles of the kidney ( Davis and Freeman, 1976). The systemic renin-angiotensin system (RAS) plays a central role in regulating extracellular fluid volume and arterial vasoconstriction ( Fig. Peptidases and receptors within these systems are important drug targets for the treatment of various cardiovascular diseases, including hypertension, heart failure, and coronary artery syndrome. Hence, there is a growing need for novel antihypertensive and cardiovascular drugs that are effective, affordable, and safe with no adverse side effects and that reduce the need for the administration of multiple drugs.īlood pressure and cardiovascular function are regulated by multiple interacting systems, including in large part the enzyme-catalyzed formation and degradation of vasoactive peptides and hormones in overlapping regulatory systems ( Fig. Suboptimal control of hypertension is associated with target organ damage leading to heart failure, ischemic heart disease, stroke, kidney dysfunction, retinopathy, and vascular dementia, all of which are major causes of disability and premature death. In addition, patients receiving treatment may suffer from significant side effects such as angiotensin-converting enzyme (ACE) inhibitor–induced persistent cough and, more rarely, life-threatening angioedema ( Simon et al., 1992 Agah et al., 1997 Bas, 2017 Stone and Brown, 2017). This contributes to the growing global burden of cardiovascular disease ( Oparil et al., 2018). Hypertension is the main risk factor for cardiovascular disease despite the availability of more than 100 commercial drugs and drug combinations for treating hypertension, a substantial proportion of the hypertensive population has uncontrolled or suboptimally controlled hypertension ( Oparil and Schmieder, 2015). Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.Ĭardiovascular disease is responsible for more than 30% of all deaths worldwide, most of which occur in developing countries ( Benjamin et al., 2017). These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT 1R axis. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. ![]() Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT 1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate.
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