Effect of Doxorubicin on the Reactivity of Rat Mesenteric Arteries

Doxorubicin is widely used as an antitumor drug, but it has a negative effect on the cardiovascular system. While special attention has mainly been paid to its cardiotoxic effect, the mechanisms of its action on vessels are not well understood. In this in vivo study, we assessed the vascular reactivity of rat mesenteric arteries to vasoactive agents and the involvement of mechanisms of endothelium-dependent vasodilation in rats treated with a single dose of doxorubicin. Experimental Wistar rats received a single intraperitoneal injection of doxorubicin (4 mg/kg), while control animals were i.p. injected with a physiological saline in the same volume. After 6 weeks, the reactivity of mesenteric arteries to acetylcholine (ACh), sodium nitroprusside, and phenylephrine was examined. To elucidate the mechanisms of endothelium-dependent vasodilation, the following blockers were used: L-NAME for endothelial NO synthase, indomethacin for cyclooxygenase, tetraethylammonium for large-conductance Ca2+-activated K+ channels. To assess arterial reactivity in vivo, microphotographic and video records of the diameter of mesenteric arteries were obtained using a Biomed MC-1T-ZOOM microscope with a Basler acA4600-10uc camera and processed using the MultiMedia Catalog software. Doxorubicin modified the reactivity of rat mesenteric arteries of rats, increasing their phenylephrine-induced vasoconstriction and inhibiting ACh-induced endothelium-dependent vasodilation. At the same time, doxorubicin administration led to a decrease in the efficiency of NO-dependent mechanisms of vascular tone regulation, as assessed by the difference in the amplitude of ACh-induced vasodilation before and after L-NAME application, as well as to a decrease in the sodium nitroprusside-induced arterial relaxation, as compared to control animals. Doxorubicin had no effect on the efficiency of prostaglandin-, small- and intermediate-conductance Ca2+-activated K+ channel-mediated mechanisms of endothelium-dependent vasodilation.