Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes.
In a previous article (Escande et al. 1988a), we have shown that cromakalim (BRL 34915), a potassium channel opener (PCO), is a potent activator of ATP-sensitive K+ channels in cardiac cells. In the present article, the influence on K+ channels of two other potassium channel openers chemically unrelated to cromakalim, RP 49356 and pinacidil, has been investigated in patch-clamped isolated cardiac myocytes. In the whole-cell configuration, K+ currents were recorded in the presence of 50 microM TTX and 3 microM nitrendipine or 3 mM cobalt. Like cromakalim, RP 49356 or pinacidil activated a time-independent outward current at 33-35 degrees C but not at 19-21 degrees C, which showed little voltage-dependency in the potential range -60 to +60 mV. Its amplitude was a function of the agonist concentration, e.g. it was 2.1 +/- 0.4 nA at +60 mV with 30 microM RP 49356 and 4.3 +/- 0.8 nA with 300 microM. In control conditions, glibenclamide, a blocker of K+-ATP channels in pancreatic and heart cells, affected neither the inward rectifier, iK1, nor the delayed K+ current, iK. At 3 microM, glibenclamide fully prevented the effects of 300 microM RP 49356 or pinacidil. At lower concentrations, glibenclamide partially counteracted the activation by PCOs of a K+ current. In the cell-attached configuration, externally applied RP 49356 or pinacidil caused opening of large channels which reversed around O mV in a high K+ external medium. In inside-out patches, both RP 49356 or pinacidil activated K+-ATP channels by increasing the time period for which the channels remained in the open state. It is concluded that, like cromakalim, RP 49356 and pinacidil are potent activators of K+-ATP channels in cardiac myocytes.
Escande
D
D
Rhône-Poulenc Santé, Centre de Recherche de Vitry, Vitry-sur-Seine, France.
Thuringer
D
D
Le Guern
S
S
Courteix
J
J
Laville
M
M
Cavero
I
I
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010847:Picolines / Q000494:pharmacology*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011714:Pyrans / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D013382:Subtraction Technique
D001578:Benzopyrans; D006146:Guanidines; D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D011758:Pyrroles; D019806:Cromakalim; C061043:aprikalim; D020110:Pinacidil; D000255:Adenosine Triphosphate; D005905:Glyburide