Zinc complexation improves angiotensin II receptor type 1 blockade and in vivo antihypertensive activity of telmisartan

• Published in: Future medicinal chemistry 2021-01, Vol.13 (1), p.13-23
• Main Authors: Martínez, Valeria R, Aguirre, María V, Todaro, Juan S, Lima, Augusto Martins, Stergiopulos, Nikolaos, Ferrer, Evelina G, Williams, Patricia Am
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Arteries - metabolism; Calcium - metabolism; Cell Line; Coordination Complexes - chemistry; Disease Models, Animal; Humans; Hypertension - drug therapy; Male; Protein Binding; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Telmisartan - chemistry; Telmisartan - pharmacology; Transfection; Zinc - chemistry
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2020-0093

Angiotensin II receptor blockers were designed as therapeutic agents to block the binding site of the angiotensin II receptor type 1 (AT1R). The structure of telmisartan was modified by coordination to the biometal Zn(II), resulting in the compound ZnTelm. Its antihypertensive activity and cellular mechanisms in comparison to telmisartan were studied.  Compared with telmisartan, ZnTelm displayed stronger binding to AT1R (binding studies on AT1R-transfected human embryonic kidney cells) and a greater reduction of reactive oxygen species and cytosolic calcium concentration induced by angiotensin II. The antihypertensive activity of the complex (assessed in an N(G)-Nitro-L-arginine methyl ester-induced hypertension model) was significantly higher. ZnTelm also reduced hypertrophy in aortic artery rings and tubular collagen deposition. ZnTelm enhances the AT1R blockade and consequently its antihypertensive effect.