Effect of Empagliflozin on Reactivity of Mesenteric Arteries and Skin Microvessels in Rats Treated with Doxorubicin

The potential protective effect of empagliflozin (EMPA) on the functional state of various types of vessels was assessed in Wistar rats that received a single injection of the anthracycline antibiotic doxorubicin (DOX), an anticancer chemotherapeutic agent widely used in clinical practice. The rats were divided into 3 groups, by 15 animals per group. Rats in the DOX group were once injected intraperitoneally with DOX (4 mg/kg), while animals in the DOX+EMPA group, following a single DOX administration (4 mg/kg), received EMPA (1 mg/kg) daily over 5 weeks through a gastric tube. The control group consisted of intact animals. After 4 weeks of the experiment, the rats were examined for the indices of the initial cutaneous microcirculation and their changes after acetylcholine (ACh) and sodium nitroprusside (NP) iontophoresis using laser doppler flowmetry (LDF). A week after LDF, the mesenteric artery dilation was assessed by the changes in the vascular diameter before and after ACh or NP exposures, without blockers and under conditions of pre-incubation of vessels with the NO synthase (NOS) blocker L-NAME. In the control group of rats, ACh iontophoresis evoked an increase in perfusion intensity by 78.5%, while in the DOX group, the change was less pronounced (by 55.2%). EMPA prevented a decrease in the skin microvascular response to ACh; the perfusion index in rats of the DOX+EMPA group increased by 82.8%. After NP iontophoresis, the increase in the microcirculation index in the DOX+EMPA group did not differ from the control, while being significantly lower in the DOX group. ACh-induced dilation of the mesenteric arteries in the DOX group was 24.3% lower than in the control. In DOX-treated rats, EMPA administration improved arterial reactivity. Compared to the vascular reactivity without blockers, incubation of vessels with L-NAME reduced the amplitude of ACh-induced dilation in all groups, although to a lesser extent in the DOX group (45.6%). After EMPA administration, the differences in the relaxation amplitude before and after NOS blockade increased (54.4%), but did not reach the control values (64.1%). Thus, DOX treatment led to a decrease in the reactivity of various types of vessels to the effect of vasodilators ACh and NP. EMPA had a protective effect in DOX-treated animals, improving the dilation of mesenteric arteries and skin microvessels. Presumably, the effect of EMPA is associated with an improvement of the efficiency of NO-dependent vasorelaxant mechanisms disrupted by DOX treatment.