Abstract 1573: Gadolinium Limits Myocardial Infarction in the Rat: Dose-Response, Temporal Relations and Mechanisms
The lanthanide cation, gadolinium (Gd) attenuates post-ischemic cardiac contractile dysfunction (stunning). This study tested the hypothesis that Gd also preconditions the myocardium, reducing infarct size following ischemia-reperfusion (IR), and it explored potential mechanisms underlying Gd-induced cardioprotection. Regional myocardial infarction was induced in anesthetized, open-chest rats by occluding the anterior descending artery for 30 minutes and reperfusing for 120 minutes. Rats (n=6/group) were administered Gd (1 to 100 μmol/kg) as a single bolus intravenously 15 minutes prior to ischemia. Control animals received no Gd. Hearts were excised after 120 minutes of reperfusion and both area at risk (AAR) and infarct size (IS) determined. Increased resistance to myocardial ischemia was determined by a reduction in the ratio of IS/AAR (%). Gd decreased infarct size in a “U”-shaped, dose-dependent manner. The minimum dose of Gd that reduced IS/AAR was 5 μmol/kg (52±5% vs. 64±4%). The dose of Gd that resulted in the maximum reduction in IS/AAR (44±4%) was 20 μmol/kg. Gd also reduced infarct size when given 15 minutes prior to reperfusion (44±3%) but not when given 10 seconds after reperfusion (60±3%). Inhibition of JAK-2 with AG-490 (3 mg/kg) abolished Gd-induced cardioprotection. The p42/44 MAPK inhibitor, PD98059 (1 mg/kg) also abrogated the effect of Gd to reduce infarction, but PD98059 alone had no effect on infarction. Western analysis demonstrated that reperfusion was associated with phosphorylation of both p42 MAPK and p44 MAPK in controls. Gd further increased the extent of phosphorylation of p44 MAPK but not p42 MAPK during reperfusion. The effect of Gd to reduce infarct size was also abolished by the KATP channel blocker glibenclamide (3 mg/kg), but not by the free radical scavengers 2-mercaptoproprionyl glycine (20 mg/kg) or N-acetyl cysteine (150 mg/kg). These results suggest broad potential roles for Gd in IR, as it is cardioprotective when given prior to ischemia or prior to reperfusion. The mechanism underlying Gd-induced preconditioning appears to be multi-factorial, involving both the JAK-2 and p44 MAPK pathways, as well as KATP channels, but does not involve reactive oxygen species.