BRL 34915 (cromakalim) activates ATP-sensitive K+ current in cardiac muscle.
The mechanism by which the antihypertensive agent BRL 34915 (cromakalim) affects action potential duration (APD) and effective refractory period (ERP) in isolated cardiac muscle was investigated. BRL 34915 (greater than or equal to 3 microM) shortened ERP of ferret (Mustela putorius furo) and guinea pig (Cavia porcellus) papillary muscles in a concentration-dependent fashion. The reduction in ERP resulted from a decrease in APD. ERP and APD of papillary muscles were also reduced during hypoxia produced by bubbling the physiological bathing solution with N2 instead of O2. Reduction of APD during hypoxia has previously been attributed to activation of ATP-sensitive K+ channels in heart. Glyburide, an inhibitor of ATP-sensitive K+ channels, prevented or reversed the shortening of ERP and APD produced by hypoxia and BRL 34915, respectively. These results suggest that BRL 34915 acts by opening ATP-sensitive K+ channels in heart. The actions of BRL 34915 were temperature-dependent, decreasing ERP 64% at 37 degrees C, but having no effect at 22 degrees C. The effect of BRL 34915 on K+ currents was tested directly in voltage-clamped guinea pig ventricular myocytes. As observed with the papillary muscles, BRL 34915 was without effect at 22 degrees C. At 36 degrees C, BRL 34915 (after a delay) increased outward currents positive to, and less so at potentials negative to, the K+ current reversal potential. The normal inwardly rectifying current-voltage relationship for peak K+ currents during 200-msec pulses was changed to one that was nearly ohmic. The current activated by BRL 34915 was blocked by glyburide. The data support the hypothesis that BRL 34915, like hypoxia, activates ATP-sensitive K+ channels in the heart. Based upon the profound temperature sensitivity of BRL 34915 action, this activation may be indirect, perhaps by means of modulation of an enzymatic activity that regulates gating of these channels. BRL 34915 and glyburide will be valuable tools for studying the role of ATP-sensitive K+ channels in normal and abnormal cardiac function.
Sanguinetti
M C
MC
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Scott
A L
AL
Zingaro
G J
GJ
Siegl
P K
PK
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D004594:Electrophysiology; D005289:Ferrets; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D007473:Ion Channels; D011758:Pyrroles; D019806:Cromakalim; D000255:Adenosine Triphosphate; D011188:Potassium; D005905:Glyburide