Acute methamphetamine exposure inhibits cardiac contractile function.
Methamphetamine, a commonly seen substance of abuse, has been reported to exert detrimental effect on bodily function including the cardiovascular system although its mechanism of action is poorly understood. This study was designed to examine the direct impact of methamphetamine on isolated whole heart and single cardiomyocyte contractile function. Murine hearts and isolated cardiomyocytes from adult FVB mice were exposed to various concentrations of methamphetamine for 30min prior to the assessment of mechanical function using a Langendroff apparatus and an IonOptix Myocam system, respectively. Cardiac contractile properties analyzed included maximal velocity of left ventricular pressure development and decline (+/-dP/dt), peak shortening amplitude (PS), maximal velocity of shortening/relengthening (+/-dLdt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), resting and electrically stimulated increase of intracellular Ca(2+) as well as intracellular Ca(2+) decay. Our results revealed that acute methamphetamine exposure depressed +/-dP/dt, PS and rise of intracellular Ca(2+) without affecting +/-dLdt, TPS, TR(90), resting intracellular Ca(2+) and intracellular Ca(2+) decay. Furthermore, methamphetamine nullified the adrenergic agonist norepinephrine-elicited positive cardiomyocyte contractile response, including elevated PS, +/-dLdt and shortened TR(90) without affecting TPS. Western blot analysis showed unchanged expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban, associated with upregulated Na(+)-Ca(2+) exchanger levels following acute methamphetamine exposure. In addition, methamphetamine promoted overt cardiomyocyte protein damage evaluated by carbonyl formation. Taken together, these results demonstrate direct cardiac depressant effect of methamphetamine in myocardium and isolated cardiomyocytes, possibly associated with protein damage and dampened adrenergic response.
Turdi
Subat
S
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
Schamber
Robbie M
RM
Roe
Nathan D
ND
Chew
Herbert G
HG
Culver
Bruce
B
Ren
Jun
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000494:pharmacology*; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
D000697:Central Nervous System Stimulants; D018398:Homeodomain Proteins; C107836:Tlx2 protein, mouse; D008694:Methamphetamine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D009638:Norepinephrine