Acute Cocaine Exposure Up-Regulates Complement Expression in Rabbit Heart 1

ABSTRACT 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 M), the synthetic isomer (ϩ)-cocaine (10 M), or procaine hydrochloride (10 or 30 M). Compared with controls perfused with drug-free buffer, both cocaine and procaine significantly (P Ͻ .05) increased myocardial C1q, C1r, C8, and C9 mRNA expression, whereas 10 M (ϩ)-cocaine had no effect on complement mRNA expression. Cocaine also significantly increased (P Ͻ .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 M cocaine and 10 M procaine. In vivo heparin administration (300 U/kg i.v.), 2 h before removal of the heart and exposure to 1 M 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. The association between cocaine abuse and myocardial disease has been evolving in the literature for several years. The most prominent pharmacologic actions of cocaine are its ability to block sodium channels, which underlie its anesthetic properties The present investigation examines the effects of acute cocaine exposure on complement synthesis by the isolated heart. Complement activation is largely responsible for tissue destruction in the reperfused myocardium . Previously, our laboratories determined that the heart increases complement mRNA expression and protein synthesis in response to ischemia/reperfusion . Because myocardial ischemia has been linked to cocaine abuse, it is possible that ischemia/reperfusion injury contributes to the detrimental effects of cocaine on the heart. Cocaine-mediated toxicity is thought to be due in part to the formation of free radicals arising from its metabolism by cytochrome P-450 ABBREVIATIONS: MAC, membrane attack complex; K-H, Krebs-Henseleit; MPG, 2-N-mercaptopropionyl glycine; bp, base pair(s); RT-PCR, reverse transcription-polymerase chain reaction; CPP, coronary perfusion pressure; %LVDP, percentage of baseline left-ventricular developed pressure; KATP, ATP-sensitive potassium channel

Effects of the AT(1)-receptor antagonist eprosartan on the progression of left ventricular dysfunction in dogs with heart failure

1. We examined the effects of eprosartan, an AT(1) receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). 2. Dogs were randomized to 3 months of oral therapy with low-dose eprosartan (600 mg once daily, n=8), high-dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). 3. In the placebo group, LV end-diastolic (EDV) and end-systolic (ESV) volumes increased after 3 months (68±7 vs 82±9 ml, P<0.004, 43±1 vs 58±7 ml, P<0.003, respectively), and EF decreased (37±1 vs 29±1%, P<0.001). In dogs treated with low-dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high-dose eprosartan, EF increased (38±1 vs 42±1%, P<0.004) and ESV decreased (41±1 vs 37±1 ml, P<0.006), Eprosartan also decreased interstitial fibrosis and cardiomyocyte hypertrophy. 4. We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF