Antihypertensive and cardiac effect of Zn-Telmisartan in ovariectomized spontaneously hypertensive rats

MARTÍNEZ, VALERIA R; VELEZ RUEDA OMAR; GIRONACCI, M.M.; DIAZ, RG; LOFEUDO JUAN MANUEL; WILLIAMS, P.A.M.; PÉREZ, N.G.; SILVA, MG; DE GIUSTI, V.C.

Congreso; LAHRS Congress. VIRTUAL. 4th Scientific Sessions. Latin American Hearth Rhythm Society; 2021

Latin American Hearth Rhythm Society

 During menopause there exists an imbalance between thepressor Angiotensin II (Ang II) and the protective (Ang 1-7) arms of the renin-angiotensin-system(RAS), which leads to oxidative stress, hypertension and cardiac dysfunction1.Restoring RAS balance would prevent cardiovascular diseases in menopausalwomen. We have previously modified the structure of telmisartan (Telm), an AngII receptor blocker, with Zinc (ZnTelm), demonstrating a higher drugeffectiveness2. In this work, we examined if chronictreatment with ZnTelm, in comparison with Telm alone, was a better alternativeto prevent cardiovascular damage during menopause. Spontaneously hypertensiverats (SHR) (female, 16-week-old, 180-200g) were sham-operated or bilateralovariectomized (OVX-SHR). OVX-SHR rats were randomly divided in 3 groups:no-treated (control), treated with Telm or treated with ZnTelm (10 or 11 mg/kg/daydrinking water for 8 weeks). The procedure was approved by the InstitutionalAnimal Care and Use Committee, Protocol Number: P02-03-2021.  Results (n=6 per group) were analyzed by ANOVA.* p <0.05 vs control and # p<0.05 vs Telm. ZnTelm promoted higherreduction in blood pressure than Telm (in mmHg, control: 185 ± 3, Telm: 128 ± 6*,ZnTelm: 107 ± 5*#). The cardiac hypertrophy decreased by ZnTelm was evidenced byechocardiography and by the cross-sectional area. Isolated papillary musclestreated with ZnTelm exhibited less myocardial stiffness than Telm (control:1.35 ± 0.24, Telm: 1 ± 0.52*, ZnTelm: 0.64 ± 0.08*#). ZnTelm-treatment markedlydecreased myocardial reactive oxygen species (%control, Telm: 73.6±4.7, ZnTelm:48.8 ± 3.4*#) as well as the lipid peroxidation (in % of control: Telm:98.8±3.4 and ZnTelm: 55 ± 5.3*#) and increased the reduced and oxidized glutathione ratio (GSH/GSSG)(control: 3.64 ± 0.26, Telm:4.77 ± 0.02, Zntelm: 6.69 ± 0.09*#). Radioimmunoassaymeasurement of cardiac Angiotensins demonstrated that ZnTelm induced a decreasein AngII level (in pg/mg, control: 0.87 ± 0.02, Telm: 0.34±0.05, ZnTelm: 0.24 ±0.04*#), and an increase in Ang 1-7 (in pg/mg, control: 8.6 ± 0.1, Telm: 22.01  ± 0.3, ZnTelm: 24.2 ± 0.8*#). Our resultssuggest that the addition of zinc into the structure of an antihypertensivedrug improves its activity, stimulating the protective RAS axis, thereby strengtheningits cardioprotective benefits such as reducing oxidative stress and improvingdiastolic cardiac function. Further experiments are needed to elucidate itsmechanism of action.