Hypertension is the most important risk factor involved in the development of left ventricular hypertrophy (LVH) as a response to chronic pressure overload (Aronow, 2017). The abnormalities of the ventricle, generated by fibrosis and geometrical changes, contribute to the progression of heart failure (Gradman and Alfayoumi, 2006). The sustained hypertrophic stimulation and the increase of oxidative stress, which cannot be adequately countered by intrinsic antioxidant systems, worse the cardiac function (Takimoto and Kass, 2007). It has been demonstrated that blood pressure lowering treatment with angiotensin II receptor blockers (ARB) reduces LVH and improves cardiac function (Brown et al., 2001). The ARB Candesartan (Cand), independently of its blood pressure lowering effect, attenuates reactive oxidative species (ROS) production. However, its low affinity to the angiotensin II receptor in comparison to other ARB leads to a slight improvement in heart function (Sakamoto et al., 2015).

Bioinorganic compounds in medicine offer possibilities for designing therapeutic agents with increased efficiency, bioavailability, and low toxicity (Bruijnincx and Sadler, 2008; Mjos and Orvig, 2014). Considering that Zinc is the second most important transition metal in the body, and, because it is a d10 transition metal, it exclusively forms a Zn2+ ion and typically assembles coordination complexes in a tetrahedral geometry, maintaining the structure and stability of molecules with Nitrogen, Oxygen and Sulfur groups (Pace and Weerapana, 2014). Considering these facts, our strategy to enhance the pharmaceutical properties, consisted of the introduction of a structural modification of candesartan (Cand) with Zn(II) coordination (ZnCand), Fig. 1, to obtain a new compound with more beneficial effects on the hypertensive cardiovascular injury. We have previously reported the synthesis, the physicochemical characterization and the antitumoral activity of the ZnCand complex ([ZnCand(H2O)2].2H2O) (Martínez et al., 2021a). Additionally, we evaluated the biodistribution capacity through the serum albumin interaction (Martínez et al., 2022). Besides, we have demonstrated that the complexation of an ARB (Telmisartan) with Zinc (ZnTelm) ameliorates its antihypertensive properties (Martínez et al., 2021b). In the present work, we examined in vitro the interaction of ZnCand to the angiotensin II receptor, type 1 (AT1 receptor), the ROS production and the contractile response of the human mesangial cell line, HMC. Moreover, we performed in vivo studies in spontaneous hypertensive rats (SHR), elucidating its antihypertensive and antihypertrophic effects. We also compared the effects of ZnCand against free Cand, to demonstrate that the structural changes induced on the antihypertensive drug upon metal coordination are responsible for the improvement of the biological effects proposed for ZnCand.