Glyburide-reversible cardioprotective effect of BMS-180448 is independent of action potential shortening.
OBJECTIVE
We determine if action potential duration (APD) shortening and cardioprotection are separable phenomena in ATP-sensitive potassium channel (KATP) openers which protect ischemic myocardium via a glyburide-reversible mechanism.


METHODS
We determined the effect of the weakly vasodilating KATP opener, BMS-180448, and the less cardiac-selective cromakalim, on APD in normal, hypoxic or ischemic guinea pig papillary muscles or isolated hearts and compared their APD effects with their cardioprotective activity in isolated guinea pig hearts.


RESULTS
In isolated ischemic guinea pig hearts, cromakalim and BMS-180448 had similar cardioprotective potencies (EC25 of 3.2 and 3.3 microM, respectively, for increasing time to the onset of contracture). At 10 microM, BMS-180448 produced no APD shortening, yet was equally protective at this concentration compared to cromakalim, which produced profound APD shortening under either hypoxic or ischemic conditions. The cardioprotective effects of both compounds at 10 microM were abolished by 0.3 microM glyburide.


CONCLUSIONS
APD shortening is not correlated with cardioprotective activity for BMS-180448 and cromakalim while their cardioprotective effects are abolished by glyburide. These results suggest the possibility of reduced proarrhythmic activity in some KATP openers and that their cardioprotective activity is not associated with sarcolemmal KATP opening.
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
D'Alonzo
A J
AJ
Hess
T
T
Sleph
P G
PG
Darbenzio
R B
RB
D000200:Action Potentials / Q000187:drug effects*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009203:Myocardial Infarction / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000378:metabolism*; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D000255:Adenosine Triphosphate; C084684:BMS 180448; D005905:Glyburide