Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction.
OBJECTIVE
Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function.


RESULTS
Echocardiography and Millar pressure-volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased -dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins.


CONCLUSIONS
This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Science Center, 1901 Perdido Street, New Orleans, LA 70112, USA.
Kevin C
KC
Lord
Sylvia K
SK
Shenouda
Elizabeth
E
McIlwain
Dimitrios
D
Charalampidis
Pamela A
PA
Lucchesi
Kurt J
KJ
Varner
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006328:Cardiac Catheterization; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D008694:Methamphetamine; D024101:Mitochondrial Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013318:Stroke Volume; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000187:drug effects
D000975:Antioxidants; D003497:Cyclic N-Oxides; D024101:Mitochondrial Proteins; D013113:Spin Labels; C002744:3-nitrotyrosine; D014443:Tyrosine; D008694:Methamphetamine; C001803:tempol