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

The potential protective effect of empagliflozin (EMPA) onthe functional state of various types of vessels was assessed inWistar rats that received a single injection of the anthracyclineantibiotic doxorubicin (DOX), an anticancer chemotherapeutic agentwidely used in clinical practice. The rats were divided into 3 groups,by 15 animals per group. Rats in the DOX group were once injected intraperitoneallywith DOX (4 mg/kg), while animals in the DOX+EMPA group, followinga single DOX administration (4 mg/kg), received EMPA (1 mg/kg) dailyover 5 weeks through a gastric tube. The control group consistedof intact animals. After 4 weeks of the experiment, the rats wereexamined for the indices of the initial cutaneous microcirculationand their changes after acetylcholine (ACh) and sodium nitroprusside(NP) iontophoresis using laser doppler flowmetry (LDF). A week afterLDF, the mesenteric artery dilation was assessed by the changesin the vascular diameter before and after ACh or NP exposures, withoutblockers and under conditions of pre-incubation of vessels withthe 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%). EMPAprevented 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 indexin the DOX+EMPA group did not differ from the control, while beingsignificantly lower in the DOX group. ACh-induced dilation of themesenteric arteries in the DOX group was 24.3% lower than in thecontrol. In DOX-treated rats, EMPA administration improved arterialreactivity. Compared to the vascular reactivity without blockers,incubation of vessels with L-NAME reduced the amplitude of ACh-induceddilation in all groups, although to a lesser extent in the DOX group(45.6%). After EMPA administration, the differences in the relaxationamplitude before and after NOS blockade increased (54.4%), but didnot reach the control values (64.1%). Thus, DOX treatment led toa decrease in the reactivity of various types of vessels to theeffect of vasodilators ACh and NP. EMPA had a protective effectin DOX-treated animals, improving the dilation of mesenteric arteriesand skin microvessels. Presumably, the effect of EMPA is associatedwith an improvement of the efficiency of NO-dependent vasorelaxantmechanisms disrupted by DOX treatment.