Premium
EGFR tyrosine kinase inhibitor tyrphostin AG‐1478 causes moderate hypomagnesemia and cardiac dysfunction
Author(s) -
Mak I. Tong,
Kramer Jay H.,
Chmielinska Joanna J.,
Spurney Chris F.,
Weglicki William B
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.644.29
EGF receptor activation enhances the transient receptor potential melastatin 6 (TRPM6) function for active Mg‐absorption in the kidney and colon. Rats (200g) received tyrphostin AG‐1478 (50 mg/kg i.p. 3X/wk) for 5 wks. Plasma Mg (AA) decreased rapidly by 15% (p<0.05) at wk 1, 27% (p<0.01) at wk 2, and remained 24–28% lower (p<0.05) wk 3 to 5. The lipid peroxidation marker 8‐isoprostane (by EIA kit) rose 58% (NS) at wk 2, 168% (p<0.05) at wk 3 and 113% (p=0.06) at wk 5. At wk 5, neutrophils isolated from the tyrphostin group displayed a 2.26‐fold (p<0.01) higher basal level of O 2 − generation (as cytochrome c reduction). RBC total glutathione remained unchanged; but the GSSG/GSH ratio in the tyrphostin samples increased 2.5‐fold (p>0.05). At 5 wk, echocardiographic parameters reveal both LV ejection fraction and % fraction shortening were reduced 7.7% and 13.8% (both p<0.05) indicative of modest but significant LV systolic dysfunction, while mitral valve E/A wave ratio decreased 13% (NS) suggestive of LV diastolic dysfunction. In conclusion: tyrphostin inhibits the TRPM6 channel function resulting in moderate but sustained hypomagnesemia. Since hypomagnesemia alone could trigger neurogenic inflammation in the heart (Cardiovsc Res. 31:677–82, 1996), we suggest that tyrphostin‐induced Mg loss may contribute in part, to the observed systemic oxidative stress and cardiac dysfunction. (Supported by NIH‐HL 062282‐09)