Estrutura e função vascular na insuficiência cardíaca induzida pela doxorrubicina

Abstract

Doxorubicin is an effective anthracycline antibiotic widely used in the treatment of various types of cancer, but its clinical use may be limited by its known toxic effects on the heart. Because the circulatory system is a closed system, we can not overlook the influence of vascular function on cardiac function. In fact, epidemiological studies show an inverse association between endothelial function and heart failure severity. However, to date, investigations about vascular changes following doxorubicin treatment are scarce. The present study aimed to investigate the alterations in vascular structure and vascular function induced by doxorubicin in rodents. For this, male Sprague Dawley rats (250-300 g) were distributed between DOX (initial n = 20) and control (initial n = 13) groups and received intraperitoneal injections of DOX (1 mg.kg-1.day-1 during 10 days, total dose, 10 mg.kg-1) or saline solution (NaCl 0.9%), respectively. Body mass and mean arterial pressure of these animals were measured regularly throughout the experimental protocol. Four weeks after the last injection of DOX or saline, euthanasia was performed with an overdose of sodium thiopental (90 mg.kg-1, i.p.). The mesenteric arterial bed of the animals was removed and isolated for vascular reactivity, which was evaluated with the administration of the following vasopressors: norepinephrine, phenylephrine, potassium chloride (KCl) and vasopressin. The animals in DOX group presented a reduction in body mass and mean arterial pressure in relation to control group. Histological data showed that both the thoracic and femoral aortic arteries of the DOX group had a higher deposition of collagen fibers in the tunica media when compared to the control group. In addition, the micrographs suggest that in the DOX group, the femoral artery presents a thicker tunica media with a consequent reduction in the lumen diameter, which was not evidenced in the aorta artery of these animals. From the functional point of view, the DOX group had a lower vasopressor response when stimulated with increasing doses of phenylephrine, norepinephrine and KCl; and, paradoxically, greater vasopressin response when stimulated with increasing doses of vasopressin. Our results suggest that in addition to the known adverse effects on the heart, doxorubicin causes a vascular remodeling that may contribute to the observed contractile dysfunction. The paradoxical constricting response to vasopressin may be important from a therapeutic point of view, although the mechanisms still need to be investigated.