CO liberated from a carbon monoxide-releasing molecule exerts a positive inotropic effect in doxorubicin-induced cardiomyopathy.
Carbon monoxide (CO) liberated by a water-soluble carbon monoxide-releasing molecule (CORM-3) induces a positive inotropic effect with a negative chronotropic effect in normal rat hearts. However, the efficacy of CORM-3 under conditions of chronic cardiac insufficiency is unknown. In a rat model of doxorubicin-induced cardiomyopathy, CORM-3 (20 microg/min) produced a positive inotropic effect as demonstrated by significant increases in systolic pressure (P < 0.05) and pressure derivative (dp/dt max) over time (P < 0.05). A similar dose of CO-depleted negative control (inactive CORM-3) failed to cause any change in these parameters. When the inotrope dobutamine was added at a dose of 10 microM following CORM-3, there was no additional increase in systolic pressure or dp/dt max. However, significant rises in systolic pressure and dp/dt max were observed after dobutamine administration to the hearts previously treated with inactive CORM-3. These results suggest that CORM-3 produces a positive inotropic effect in doxorubicin cardiomyopathy rat hearts, similar to that reported previously in normal hearts. The inotropic effect produced by CO in the doxorubicin cardiomyopathy heart was mimicked by a classical inotrope (dobutamine), suggesting that either a maximal inotropic effect is achieved at this dose of CORM-3 or both drugs utilize shared signaling pathways in cardiac muscle.
Musameh
Muntaser D
MD
Department of Surgery, Royal Free and University College London Medical School, Hampstead, London, UK. montaser1@hotmail.com
Green
Colin J
CJ
Mann
Brian E
BE
Motterlini
Roberto
R
Fuller
Barry J
BJ
D000818:Animals; D002248:Carbon Monoxide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054715:Cardiotoxins / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew
D002316:Cardiotonic Agents; D054715:Cardiotoxins; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; D004317:Doxorubicin