Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448.
ATP-sensitive potassium channel (KATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference KATP openers (e.g., cromakalim, pinacidil) are potent relaxants of smooth muscle, their utility for treating myocardial ischemia may be limited by hypotension. Efforts aimed at development of a cardioprotective KATP opener with less vasorelaxant activity led to identification of the arylcyanoguanidine analogue BMS-180448. In globally ischemic rat hearts, BMS-180448 was cardioprotective (EC25 for increasing time to contracture = 2.5 microM), with potency equal to that of cromakalim (EC25 = 4.9 microM) despite being significantly less potent as a peripheral smooth muscle relaxant (methoxamine-constricted rat aorta). The cardioprotective effects of BMS-180448 in isolated perfused rat heart were abolished by the KATP blockers glyburide and sodium 5-hydroxydecanoate, indicating KATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single KATP opening by BMS-180448 in guinea pig cardiac myocytes. In anesthetized dogs, cromakalim was > 100-fold more potent than BMS-180448 in decreasing blood pressure (BP). In anesthetized dogs subjected to 90-min coronary occlusion/reperfusion, BMS-180448 reduced infarct size (IS) by 50% without hemodynamic effects. BMS-180448 provides the opportunity to explore the cardioprotective actions of this class of agents without the possible complications (hypotension, coronary steal) that may be caused by the currently available KATP openers.
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
McCullough
J R
JR
D'Alonzo
A J
AJ
Sargent
C A
CA
Atwal
K S
KS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D019806:Cromakalim; D003652:Decanoic Acids / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D003652:Decanoic Acids; D006146:Guanidines; D006880:Hydroxy Acids; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; C084684:BMS 180448; D005905:Glyburide