Electromechanical effects of the putative potassium channel activator celikalim (WAY-120,491) on feline atrial and ventricular muscle.
Celikalim (WAY-120,491) is a putative potassium channel activator that has been shown to lower blood pressure in animal models and humans. In the present study, we have examined the effects of celikalim on contractility and ionic currents in feline cardiac muscle. Celikalim was found to decrease contractility in electrically stimulated (2 Hz frequency) left atrial and right ventricular papillary muscle preparations with IC50 values of 0.95 +/- 0.12 microM (n = 6) and 0.29 +/- 0.07 microM (n = 5), respectively. Glyburide (1 microM) reversed the celikalim-induced negative inotropy (left atrial halves). Celikalim was also shown to activate a glyburide-sensitive current in voltage-clamped isolated ventricular myocytes that reversed close to the calculated value of the potassium equilibrium potential (n = 4 cells). In addition, celikalim was found to inhibit voltage-activated calcium current (L-type) in isolated ventricular myocytes (51 +/- 2% inhibition at 1 microM; n = 4 cells). We conclude that celikalim is a potassium channel activator and hypothesize that both the negative inotropy and the glyburide-sensitive current evoked by this drug are mediated by ATP-regulated potassium channels. Inhibition of voltage-activated calcium channels by celikalim may also contribute to the negative inotropy induced by this drug.
Lodge
N J
NJ
Cardiovascular and Metabolic Disorders, Wyeth-Ayerst Research, Princeton, New Jersey.
Colatsky
T J
TJ
Cullinan
C A
CA
Follmer
C H
CH
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002415:Cats; D019806:Cromakalim; D004558:Electric Stimulation; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D020110:Pinacidil; D011188:Potassium / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology
D000959:Antihypertensive Agents; D001578:Benzopyrans; D006146:Guanidines; D007211:Indoles; D011758:Pyrroles; D019806:Cromakalim; C067406:WAY 120491; D020110:Pinacidil; D011188:Potassium