Acute cocaine exposure up-regulates complement expression in rabbit heart.
The exact mechanism of the cardiotoxic actions of cocaine remains unclear. The finding that the heart may be a source of injurious complement components led us to investigate whether cocaine promotes myocardial expression of complement. Rabbit isolated hearts were perfused for 70 min with either cocaine hydrochloride (1 or 10 microM), the synthetic isomer (+)-cocaine (10 microM), or procaine hydrochloride (10 or 30 microM). Compared with controls perfused with drug-free buffer, both cocaine and procaine significantly (P <. 05) increased myocardial C1q, C1r, C8, and C9 mRNA expression, whereas 10 microM (+)-cocaine had no effect on complement mRNA expression. Cocaine also significantly increased (P <.05) C3 mRNA transcription. In addition, in vivo administration of cocaine (1 mg/kg) for three consecutive days significantly increased myocardial complement mRNA expression. Cocaine and procaine also increased membrane attack complex (MAC) formation in the myocardium. The antioxidant 2-N-mercaptopropionyl glycine, attenuated the increases in complement mRNA expression induced by 1 microM cocaine and 10 microM procaine. In vivo heparin administration (300 U/kg i.v.), 2 h before removal of the heart and exposure to 1 microM cocaine, did not inhibit C1q, C1r, C3, and C8 mRNA transcription, but decreased MAC expression. It was determined previously that heparin reduces myocardial ischemia/reperfusion injury. Our results suggest that cocaine may cause myocardial injury by up-regulating local complement expression, possibly via the production of reactive oxygen species. Furthermore, the glycosaminoglycan heparin may modulate the cytotoxic effects of cocaine by impeding formation of the MAC.
Tanhehco
E J
EJ
University of Michigan Medical School, Department of Pharmacology, Ann Arbor, MI, USA.
Yasojima
K
K
McGeer
P L
PL
Lucchesi
B R
BR
D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000494:pharmacology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010477:Perfusion; D011343:Procaine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D008625:Tiopronin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D015938:Complement Membrane Attack Complex; D012333:RNA, Messenger; D011343:Procaine; D006493:Heparin; D003165:Complement System Proteins; D008625:Tiopronin; D003042:Cocaine