Positive inotropic effects of carbon monoxide-releasing molecules (CO-RMs) in the isolated perfused rat heart.
OBJECTIVE
Carbon monoxide (CO) generated by the enzyme haeme oxygenase-1 (HO-1) during the breakdown of haeme is known to mediate a number of biological effects. Here, we investigated whether CO liberated from two water soluble carbon monoxide-releasing molecules (CO-RMs) exerts inotropic effects on the myocardium.


METHODS
Rat isolated hearts perfused either at constant flow or constant pressure were used to test the effect of CO-RMs.


RESULTS
CORM-3, a fast CO releaser, produced a direct positive inotropic effect when cumulative doses (3, 10 and 30 microg min(-1)) or a single dose (5 microM) were infused at either constant coronary pressure (CCP) or constant coronary flow (CCF). The inotropic effect mediated by CORM-3 was abolished by blockade of soluble guanylate cyclase or Na(+)/H(+) exchanger, but not by inhibitors of L-type Ca(2+) channels and protein kinase C. CORM-3 also caused a slight reduction in heart rate but did not alter coronary flow. In contrast, the slow CO releaser CORM-A1 produced significant coronary vasodilatation when given at the highest concentration (30 mug min(-1)) but exerted no effect on myocardial contractility or heart rate.


CONCLUSIONS
A rapid CO release from CORM-3 exerts a direct positive inotropic effect on rat isolated perfused hearts, whereas CO slowly released by CORM-A1 had no effect on myocardial contractility but caused significant coronary vasodilatation. Both cGMP and Na(+)/H(+) exchange appear to be involved in this effect but further work is needed to determine the relative contribution of each pathway in CO-mediated inotropic effect.
Musameh
M D
MD
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK.
Fuller
B J
BJ
Mann
B E
BE
Green
C J
CJ
Motterlini
R
R
D000470:Alkaloids / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D001880:Boranes / Q000378:metabolism / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism*; D002254:Carbonates / Q000378:metabolism / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects
D000470:Alkaloids; D053119:Benzophenanthridines; D001880:Boranes; D002121:Calcium Channel Blockers; D002254:Carbonates; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; C503854:sodium boranocarbonate; C476530:tricarbonylchloro(glycinato)ruthenium(II); D000584:Amiloride; D002248:Carbon Monoxide; C016299:chelerythrine; D009543:Nifedipine; C039614:ethylisopropylamiloride