Cardioprotective effects of the cyanoguanidine potassium channel opener P-1075.
P-1075 is a cyanoguanidine ATP-sensitive potassium channel opener (KATP) that relaxes smooth muscle and shortens myocardial action potential duration (APD) at concentrations in the nanomolar range. Most KATP openers have antiischemic potencies in the micromolar range. We wished to determine if the relatively high cardiac potency of P-1075 could be translated into high antiischemic potency. Isolated rat hearts were pretreated with 10-300 nM P-1075 followed by 25-min global ischemia and 30-min reperfusion. Before ischemia, P-1075 had little effect on cardiac function, although it did increase coronary flow. During ischemia, P-1075 significantly increased time to contracture in a concentration-dependent manner (EC25 = 57 nM). P-1075 also improved recovery of contractile function significantly and reduced lactate dehydrogenase (LDH) release during reperfusion (at concentrations > or = 60 nM). Treatment with 75 nM P-1075 both before and after ischemia did not add to the protective effects observed after preischemic treatment. Treatment with P-1075 only during reperfusion was not cardioprotective. The protective effects of P-1075 were completely abolished by the KATP blocker glyburide (100 nM). In addition, P-1075 relaxed methoxamine-constricted aorta with a higher potency relative to antiischemic potency. Thus, P-1075 has cardioprotective effects similar to that of other reference KATP openers, except that P-1075 is approximately 100-fold more potent relative to most other tested KATP openers. These results demonstrate that P-1075 is the first KATP opener that protects ischemic myocardium at nanomolar concentrations.
Sargent
C A
CA
Department of Pharmacology, Bristol-Myers Squibb Research Institute, Princeton, New Jersey 08543.
Sleph
P G
PG
Dzwonczyk
S
S
Normandin
D
D
Antonaccio
M J
MJ
Grover
G J
GJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents; D016277:Ventricular Function, Left / Q000187:drug effects
D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D007770:L-Lactate Dehydrogenase