Abstract
Cardiovascular disease is the leading cause of death in cancer survivors. The short-term and long-term cardiotoxic effects of targeted chemotherapeutics is not well known. Everolimus, an inhibitor to mammalian target of rapamycin (mTOR) complex 1, is a targeted therapy approved for the treatment of metastatic breast, colon, renal cell and pancreatic cancer. Clinical retrospective reviews suggest heart failure and hypertension as cardiotoxic effects of everolimus. Our lab previously showed that everolimus exposure on normotensive vessels increased sensitivity to adrenergic stimuli in a time and concentration dependent manner. We hypothesized that everolimus leads to enhanced contractility and impaired relaxation in hypertensive vessels. We studied the effects of everolimus on the contractility and relaxation of mesenteric resistance arteries (MRA) of male Wistar rats (12-15 weeks old, n=4) and spontaneously hypertensive rats (SHR) (15-18 weeks old, n=2) on a wire myograph. Two concentrations of everolimus were evaluated, 0.1μM and 0.1nM, during a one-hour incubation. Normotensive MRA exposed to everolimus (0.1μM) showed a decreased contractile response to phenylephrine (LogEC50 + SEM, Ctrl:-5.627 + 0.07 vs Drug: -5.390 + 0.10) but no difference when exposed to 0.1nM. SHR MRA showed no difference in PE-induced contraction at 0.1μM (LogEC50 + SEM, Ctrl:-5.638 + 0.08 vs Drug:-6.286 + 0.36) or 0.1nM (LogEC50 + SEM, Ctrl:-5.638 + 0.08 vs Drug:-5.332 + 0.16). No differences were observed in endothelium dependent relaxation response to acetylcholine (ACh) for either drug concentration in the normotensive vessels; however, SHR MRA exhibited enhanced sensitivity to ACh with everolimus exposure (LogEC50 + SEM, Ctrl: -6.851 + 0.15 vs Drug:-9.233 + 0.37 at 0.1nM; LogEC50 + SEM, Ctrl: -6.851 + 0.15 vs Drug:-8.244 + 0.34 at 0.1μM). Our data show that everolimus affects contractility in normotensive vessels, while affecting the dilatory response in SHR vessels with an improvement in endothelium-dependent relaxation. Everolimus may be a good therapeutic agent for hypertensive cancer patients. However, long term treatments with this targeted therapy need to be evaluated for vascular dysfunction induction, which could be associated with cardiotoxicity.
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