Novel therapeutics for the treatment of hypertension and its associated complications: peptide- and nonpeptide-based strategies

Abstract

The renin-angiotensin-aldosterone system (RAAS) is responsible for maintaining blood pressure and vascular tone. Modulation of the RAAS, therefore, interferes with essential cellular processes and leads to high blood pressure, oxidative stress, inflammation, fibrosis, and hypertrophy. Consequently, these conditions cause fatal cardiovascular and renal complications. Thus, the primary purpose of hypertension treatment is to diminish or inhibit overactivated RAAS. Currently available RAAS inhibitors have proven effective in reducing blood pressure; however, beyond hypertension, they have failed to treat end-target organ injury. In addition, RAAS inhibitors have some intolerable adverse effects, such as hyperkalemia and hypotension. These gaps in the available treatment for hypertension require further investigation of the development of safe and effective therapies. Current research is focused on the combination of existing and novel treatments that neutralize the angiotensin II type I (AT1) receptor-mediated action of the angiotensin II peptide. Preclinical studies of peptide- and nonpeptide-based therapeutic agents demonstrate their conspicuous impact on the treatment of cardiovascular diseases in animal models. In this review, we will discuss novel therapeutic agents being developed as RAAS inhibitors that show prominent effects in both preclinical and clinical studies. In addition, we will also highlight the need for improvement in the efficacy of existing drugs in the absence of new prominent antihypertensive drugs.

Characterization of Direct Perturbations on Voltage-Gated Sodium Current by Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker

“…In concert with its antagonistic action on MR, ESAX might exert an additional ameliorating action on salt-induced elevation of blood pressure or on kidney injuries [ 1 , 6 , 8 , 10 , 41 , 42 ]. ESAX has indeed reported the ability of alleviating effects in hypertensive patients with normal kidney function and in diabetic patients with albuminuria [ 5 ].…”

“…Through ionic mechanisms demonstrated herein, it or other structurally similar non-steroidal compounds (e.g., apararenone and finerenone), which can be preferentially used for oral intake, is able to adjust the functional activities of different types of endocrine or neuroendocrine cells, if similar in vivo findings exist. To this end, even during its perturbing action on the renin-angiotensin-Aldo system [ 5 , 6 , 42 , 49 ], findings from this study also highlight an important alternative aspect that needs to be taken into consideration, inasmuch as the beneficial effects of ESAX in different pathologic disorders, such as primary hyperaldosteronism, chronic kidney disease, refractory hypertension, and heart failure, have been currently evaluated [ 1 , 3 , 4 , 5 , 6 , 9 , 39 , 49 , 50 , 51 ].…”

Advances in the Treatment Strategies in Hypertension: Present and Future

“…In experimental and clinical settings, stimulation of angiotensin 2 receptors inhibits fibrosis [ 65 ] and induces vasodilatation, natriuresis, and blood pressure reduction [ 66 , 67 ]. Consequently, angiotensin II receptor agonists display an interesting antihypertensive potential and are currently investigated for efficacy and safety [ 68 , 69 ].…”

Lupin-Derived Bioactive Peptides: Intestinal Transport, Bioavailability and Health Benefits

“…This class of drugs act by inhibiting the release of renin, the conversion of angiotensin I to angiotensin II via inhibition of angiotensin-converting enzyme (ACE) and/or blocking of angiotensin receptors (AR), especially angiotensin receptor-1 (AR-1) and mineralocorticoid receptor (MR) that interact with angiotensin II to promote aldosterone secretion [ 136 ]. Several natural products are currently being explored as potential anti-hypertensive agents, including plant-polyphenols and protein-derived peptides [ 137 , 138 , 139 ]. Hydrolysates of lupin proteins exhibited potential anti-hypertensive effects in an in vitro set-up by inhibiting ACE activity with IC 50 value of 226 µg/mL [ 4 ].…”