Inhibition of heme oxygenase-1 impairs cardiac muscle sensitivity to beta-adrenergic stimulation.
Heme 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).


CONCLUSIONS
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.
Segers
Vincent F M
VF
Laboratory of Physiology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
Lemmens
Katrien
K
Hendrickx
Jan
J
Sys
Stanislas U
SU
De Keulenaer
Gilles W
GW
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008652:Mesoporphyrins / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000201:enzymology; D010210:Papillary Muscles / Q000187:drug effects / Q000201:enzymology*; D011817:Rabbits
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D008652:Mesoporphyrins; C427471:chromium mesoporphyrin; D007545:Isoproterenol