The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused mice .

Inflammatory mechanisms and oxidative stress seem to contribute to the pathogenesis of hypertension. ITH13001 is a melatonin-phenyl-acrylate hybrid that moderately induces the antioxidant transcription factor Nrf2 and has a potent oxidant scavenging effect compared to other derivatives of its family. Herein, we investigated the effect of ITH13001 on hypertension and the associated cardiovascular alterations. Angiotensin II (AngII)-infused mice were treated with ITH13001 (1 mg/Kg/day, i.p.) for two weeks. The ITH13001 treatment prevented: 1) the development of hypertension, cardiac hypertrophy and increased collagen and Bnp expression in the heart; 2) the reduction of elasticity, incremental distensibility, fenestrae area, intraluminal diameter and endothelial cell number in mesenteric resistance arteries (MRA); 3) the endothelial dysfunction in aorta and MRA; 4) the plasma and cardiovascular oxidative stress and the reduced aortic NO bioavailability; 5) the increased cardiac levels of the cytokines IL-1β , IL-6 and Ccl2 , the T cell marker Cd3 , the inflammasome NLRP3, the proinflammatory enzymes iNOS and COX-2, the TLR4 adapter protein MyD88 and the NFkB subunit p65; 6) the greater aortic expression of the cytokines Tnfα, Ccl2 and IL-6 , Cd3 , iNOS, MyD88 and NLRP3. Although ITH13001 increased nuclear Nrf2 levels and HO-1 expression in vascular smooth muscle cells, both cardiac and vascular Nrf2 , Ho-1, and Nqo1 levels remained unmodified, irrespective of AngII infusion. Summarizing, ITH13001 improved hypertension-associated cardiovascular alterations independently of Nrf2 pathway activation, likely due to its direct antioxidant and anti-inflammatory properties. Therefore, ITH13001 could be a useful therapeutic strategy in patients with resistant hypertension. Significance Statement Despite the existing therapeutic arsenal, only half of the patients treated for hypertension have adequately controlled blood pressure; therefore, the search for new compounds to control this pathology and the associated damage to end-target organs (cerebral, cardiac, vascular, renal) is of particular interest. The present study demonstrates that a new melatonin derivative, ITH13001, prevents hypertension development and the associated cardiovascular alterations, due to its antioxidant and anti-inflammatory properties, making this compound a potential candidate for treatment of resistant hypertension patients.