Abstract P525: Mtor Inhibitor Everolimus Decreases Aortic Sensitivity To Phenylephrine In Normotensive Rats

Abstract

While targeted chemotherapeutics have improved cancer clinical outcomes, many of these agents have the drawback of cardiovascular complications. It has been established that the mTOR complexes have a pivotal role in many types of cancer, promoting cell growth, proliferation, and survival. Inhibitors of this pathway such as first generation Everolimus, and second generation PP242, have inhibited cancer cell proliferation and cancer progression. When compared with other target chemotherapeutics such as VEGF and tyrosine kinase inhibitors, first generation mTOR inhibitors have demonstrated decreased incidence of cardiovascular complications, however the specific vascular effects of mTOR inhibitors have not been investigated. Therefore, Everolimus, an inhibitor of mTORC1, and PP242, an inhibitor of mTORC1 and mTORC2, were evaluated for their effects on vascular reactivity of rat aorta. Previous studies have demonstrated that mTORC2 displayed cardioprotective effects. Therefore, we hypothesize that Everolimus, which does not inhibit mTORC2, will have a decreased contractile response to Phenylephrine (PE) and increased Acetylcholine (Ach)-induced relaxation. On the contrary, since PP242 inhibits mTORC2, we hypothesize that PP242 will increase contractile response to PE, and will decrease ACh-induced relaxation. Concentration response curves to PE (1nM - 30μM), and Ach (1nM - 30μM) were conducted in isolated aortic rings from male normotensive Wistar rats (12-15 weeks old) on a pin myograph ex vivo after 1 hour of incubation with each drug. Aortic rings treated with 31 μM of Everolimus showed decreased sensitivity to PE (LogEC 50 = -7.322 ±0.078 vs. treated: -6.578 ± 0.1116 p<0.05). No differences were observed in the contractile responses to PE for Everolimus (0.1 nM) or PP242 (245 nM) (p>0.05). Similarly, no differences were observed in the endothelium-dependent relaxation response to Ach for all three treatments. These results suggest that Everolimus may be a good therapeutic choice for cancer patients also suffering from cardiovascular dysfunction.