Abstract TAC300: Treatment with emetine attenuates blood pressure development in spontaneously hypertensive rats

Nearly half of all US adults have hypertension which greatly increases the risk of other comorbidities and is a significant contributor to all cause mortality. Even with decades of thorough investigation, more work is needed to better understand the mechanisms involved in the onset and progression of hypertension. Previous work in the lab found that reduced Golgi calcium stores were associated with altered smooth muscle cell (SMC) calcium signaling, impaired contractility, reduced arterial remodeling, and lower diastolic blood pressure in a model of salt sensitive hypertension. Emetine is a compound found in ipecac that has been used for decades as an emetic and antiparasitic. While its use has been mostly discontinued due to toxicity at high doses, it has received renewed interest for antiviral and anticarcinogenic properties at less toxic low doses. A group studying pulmonary arterial hypertension (PAH) utilized emetine in a rat model of PAH and observed that chronic treatment reduced remodeling in pulmonary arteries and reduced several inflammatory and proliferative proteins. Altogether, this data indicates that disruption of lumenal Golgi calcium stores may affect vascular remodeling and ameliorate blood pressure development, which led us to our hypothesis that chronic emetine treatment would ameliorate systemic hypertension. To test this, we surgically implanted spontaneously hypertensive rats (SHRs) with telemeters and treated them with emetine (0.05 mg/kg bodyweight) or vehicle by oral gavage each day. Blood pressure measurements revealed that emetine treated rats had reduced mean arterial pressure compared to the vehicle group (151 ± 4 vs 143 ± 2 mmHg) and there were no differences in bodyweight, kidney weight, or heart weight. Tissue histology analysis revealed that emetine did not result in kidney or heart damage at this dosage and time course, and there was no effect on aorta remodeling. To look at potential acute effects of emetine application, we performed wire myography on rat aortas. We observed that acute emetine application had no effect on aortas in basal conditions; in contracted vessels that were pretreated with phenylephrine it resulted in a dose-depended relaxation, with an EC 50 of around 100 µM. Our initial data indicate that emetine may have a beneficial effect on systemic hypertension, but further work is necessary to fully characterize its physiological effects and uncover the underlying mechanisms.