Original ArticleEGFR-TKI, Erlotinib, Causes Hypomagnesemia, Oxidative Stress, and Cardiac Dysfunction Attenuation by NK-1 Receptor BlockadeMak, I. Tong PhD*; Kramer, Jay H. PhD*; Chmielinska, Joanna J. PhD*; Spurney, Christopher F. MD†; Weglicki, William B. MD*,‡Author Information *Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC; †Division of Cardiology, Children's National Medical Center, Washington, DC; and ‡Department of Medicine, The George Washington University, Washington, DC. Reprints: William B. Weglicki, MD, Department of Biochemistry and Molecular Medicine, Division of Experimental Medicine, The George Washington University Medical Center, 2300 Eye St NW, Ross Hall, Rm 439, Washington, DC 20037 (e-mail: firstname.lastname@example.org). Supported by the US Public Health Service (grant numbers NIH RO1-HL-62282 and 1 R21 HL108311). The authors report no conflicts of interest. Received June 16, 2014 Accepted August 11, 2014 Journal of Cardiovascular Pharmacology: January 2015 - Volume 65 - Issue 1 - p 54-61 doi: 10.1097/FJC.0000000000000163 Buy Metrics Abstract Abstract: To determine whether the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation, and cardiac stress, erlotinib was administered to rats (10 mg·kg−1·d−1) for 9 weeks. Plasma magnesium decreased progressively between 3 and 9 weeks (−9% to −26%). Modest increases in plasma substance P (SP) occurred at 3 (27%) and 9 (25%) weeks. Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac perivascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg·kg−1·d−1), attenuated erlotinib-induced hypomagnesemia up to 42%, reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished. Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (−11%) and % fractional shortening (−17%) by 7 weeks of erlotinib treatment and significant reduction (−17.5%) in mitral valve E/A ratio at week 9 indicative of systolic and early diastolic dysfunction. Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy. Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction and partially attenuated the anatomical changes. Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress and mild-to-moderate cardiac dysfunction, which can largely be corrected by the administration of the SP receptor blocker. © 2015 by Lippincott Williams & Wilkins.