Role of Perindopril in Mitigating Doxorubicin's Vascular Toxicity in a Rat Model

Doxorubicin (DOX), a widely used anthracycline in cancer therapy, is associated with significant cardiovascular toxicity. While its cardiotoxic effects are well documented, the mechanisms and prevention of DOX-induced vascular toxicity remain insufficiently explored. Angiotensin-converting enzyme inhibitors (ACEIs), such as perindopril (PER), are commonly used in cardiovascular disease management and may offer vascular protection during chemotherapy. Female ovariectomized Wistar rats were treated with i.v. DOX and/or p.o. PER over five weeks. Cardiac and vascular function were assessed using high-frequency ultrasound and ECG. Vascular reactivity was evaluated in isolated aortal rings using phenylephrine (PE), acetylcholine (ACh), L-N-Nitro arginine methyl ester hydrochloride (L-NAME), and verapamil (VER). Oxidative stress was assessed via plasma 4-hydroxy-2-nonenal (4-HNE) levels, and structural changes were monitored through intima-media thickness (IMT) measurements. DOX administration significantly impaired vascular reactivity, as evidenced by increased contractile responses to PE and reduced endothelium-dependent relaxation. These functional alterations were accompanied by elevated plasma 4-HNE levels, indicating enhanced oxidative stress. Co-treatment with PER preserved vascular responsiveness, reduced contractile tension, and significantly lowered 4-HNE concentrations. Structurally, IMT increased in control and PER-only groups, likely due to post-ovariectomy remodelling, while DOX-treated groups showed no IMT progression. PER co-treatment appeared to stabilize IMT values. PER mitigates DOX-induced vascular toxicity, likely through endothelial protection and reduction of oxidative stress. These findings support the potential use of ACEIs as prophylactic agents in patients undergoing anthracycline-based chemotherapy and highlight the need for further translational studies in cardio-oncology.