G.W. De Keulenaer

Inhibition of heme oxygenase–1 impairs cardiac muscle sensitivity to beta–adrenergic stimulation

AbstractHeme oxygenase–1 (HO–1) is the inducible isoform of heme oxygenase and plays a role in defense against cellular stress. The effects of HO–1 on cardiac muscle contractility, however, are unknown.Methods:HO–1 was induced by intraperitoneal injection of hemin in rabbits 24 and 48 h before isolating right ventricular papillary muscles for mechanical in vitro analysis at baseline and during stimulation with isoprenalin. Western blotting and activity measurement con.rmed upregulation of HO–1 in ventricular tissue, and immunohistochemical stainings showed localization in the cardiac endothelium.Results:Baseline mechanical performance of papillary muscles and maximal inotropic response to ISO was not significantly affected by HO–1 induction. Also, the log(EC50) of the ISO concentration–response curve was not affected by HO–1 induction. Inhibition of heme oxygenase with stanneous mesoporphyrin or chromium mesoporphyrin in muscles with induced HO–1, however, shifted the log(EC50) of the ISO concentration–response curve from –6.9 ± 0.2 to –6.0 ± 0.2 (p = 0.008).Conclusion:These results indicate that induction of cardiac HO–1 has no direct effect on baseline contractility. Pharmacological inhibition of HO–1 upon induction, however, diminishes cardiac muscle sensitivity to beta–adrenergic stimulation. These results caution against pharmacologically targeting HO–1 when an activated adrenergic system is important for hemodynamic stability.