No loss of cardioprotection by postconditioning in connexin 43-deficient mice.

In situ hearts and isolated cardiomyocytes from heterozygous connexin 43-deficient (Cx43+/-) mice cannot be protected by ischemic preconditioning or diazoxide. We have now addressed the role of connexin 43 in ischemic postconditioning (PC). Wild type (WT) and Cx43+/- mice were subjected to 30 min coronary occlusion and 120 min reperfusion, with and without a PC protocol of three cycles of 10 s coronary occlusion/10 s reperfusion. Infarct size (TTC staining) was reduced by PC from 54+/-5 to 37+/-3% of area at risk in WT. Likewise, infarct size was reduced by PC from 53+/-4 to 34+/-3% of area at risk in Cx43+/-. We conclude that connexin 43 is no prerequisite for PC's protection. To this end, the signal transduction of ischemic preconditioning and postconditioning differs.

Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization.

BACKGROUND: The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction. METHODS AND RESULTS: Microembolization was induced by injecting microspheres (42-microm diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n=7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n=7) or 30 minutes after (n=5) microembolization. In addition, chronically instrumented dogs received either placebo (n=4) or methylprednisolone (n=4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0+/-2.1% (mean+/-SEM) at baseline to 5.8+/-0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0+/-0.7% at 4 to 6 hours after microembolization back to baseline (19.1+/-1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction. CONCLUSIONS: Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.

Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine.

Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-alpha, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-microm diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6+/-4.9% (mean+/-SD) at baseline to 4.1+/-3.7% at 8 hours after microembolization. Leukocyte count, TNF-alpha, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3+/-2.6% at baseline) with intracoronary administration of L-NAME (20.8+/-3.4%) and 17.7+/-2.3% at 8 hours after microembolization; TNF-alpha and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7+/-4.6% at baseline) with intravenous administration of NOE (19.5+/-5.7%) and 16.4+/-6.3% at 8 hours after microembolization; TNF-alpha, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-alpha, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.