Vasoactive Effects of Chronic Treatment with ACE Inhibitor Zofenopril in Zucker Obese Diabetic Rats: The Role of Nitroso and Sulfide Signalization

Type 2 diabetes (T2D) associated with obesity is accompanied not only by metabolic but also cardiovascular disorders, including impaired vascular function. In addition to nitric oxide (NO), another gaseous transmitter, hydrogen sulfide (H2S), plays a key role in vascular homeostasis, but its function under pathological conditions is not fully understood. Escalated metabolic disorder associated with T2D could disrupt sulfide signaling and shift the balance between its pathological and compensatory action. The aim of the study was to investigate the role of H2S and NO signaling in the vascular function of obese Zucker diabetic fatty (ZDF) rats and to evaluate the impact of chronic treatment with zofenopril, an ACE inhibitor containing a sulfhydryl group. Cardiometabolic and biochemical parameters, as well as reactivity of the isolated thoracic aorta after 4 weeks of treatment, were assessed. Obese rats exhibited increased systolic blood pressure (SBP), cardiac and renal hypertrophy, increased adiposity, dyslipidemia, and impaired glucose tolerance compared with controls. Endothelium-dependent relaxation was reduced, with loss of H2S-derived relaxant component and dysregulation of NO signaling. Zofenopril significantly reduced SBP, attenuated cardiac and renal hypertrophy, and restored endothelial and contractile function. At the molecular level, it increased the expression of H2S-synthesizing enzymes, restored H2S-dependent vasorelaxation, and normalized NOS activity with a predominance of eNOS. In conclusion, zofenopril restored the balance of H2S and NO signaling in obese ZDF rats, thereby providing cardiovascular protection independent of improvements in glycemia or lipid profile. This dual mechanism may represent a promising therapeutic approach in preventing complications of obesity-induced T2D.