BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts.
OBJECTIVE
BAY 58-2667 (BAY-58) directly activates soluble guanylyl cyclase without tolerance in a nitric oxide (NO)-independent manner, and its haemodynamic effect is similar to that of nitroglycerin. We tested whether BAY-58 could make both rabbit and rat hearts resistant to infarction when given at the end of an ischaemic insult.


RESULTS
All hearts were exposed to 30 min regional ischaemia followed by 120-(isolated hearts) or 180-(in situ hearts) min reperfusion. BAY-58 (1-50 nM) infused for 60 min starting 5 min before reperfusion significantly reduced infarction from 33.0 +/- 3.2% in control isolated rabbit hearts to 9.5-12.7% (P < 0.05). In a more clinically relevant in situ rabbit model, infarct size was similarly reduced with a loading dose of 53.6 microg/kg followed by a 60 min infusion of 1.25 microg/kg/min (41.1 +/- 3.1% infarction in control hearts to 16.0 +/- 4.4% in treated hearts, P < 0.05). BAY-58 similarly decreased infarction in the isolated rat heart, and protection was abolished by co-treatment with a protein kinase G (PKG) antagonist, or a mitochondrial K(ATP) channel antagonist. Conversely, N(omega)-nitro-L-arginine-methyl-ester-hydrochloride, a NO-synthase inhibitor, failed to block BAY-58's ability to decrease infarction, consistent with the latter's putative NO-independent activation of PKG. Finally, BAY-58 increased myocardial cGMP content in reperfused hearts while cAMP was unchanged.


CONCLUSIONS
When applied at reperfusion, BAY-58 is an effective cardioprotective agent with a mechanism similar to that of ischaemic pre-conditioning and, hence, should be a candidate for treatment of acute myocardial infarction in man.
Krieg
Thomas
T
Department of Cardiology, Ernst-Moritz-Arndt University, Loefflerstr. 23, 17487 Greifswald, Germany. krieg@uni-greifswald.de
Liu
Yanping
Y
Rütz
Thomas
T
Methner
Carmen
C
Yang
Xi-Ming
XM
Dost
Turhan
T
Felix
Stephan B
SB
Stasch
Johannes-Peter
JP
Cohen
Michael V
MV
Downey
James M
JM
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
D001565:Benzoates; D002316:Cardiotonic Agents; C480588:BAY 58-2667; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D006152:Cyclic GMP