Pinacidil Attenuates Positive Inotropic but Not Chronotropic Responses to Norepinephrine in Isolated Dog Atrial and Ventricular Preparations

Abstract

We investigated whether pinacidil, a K⁺_ATP channel opener like acetylcholine and adenosine, attenuated the positive chronotropic and inotropic responses to norepinephrine in isolated, blood-perfused dog atrial and ventricular preparations. Pinacidil (0.01-0.3 μmol) decreased atrial and ventricular contractile force to a much greater extent than sinus rate in a dose-related manner. Pinacidil dose-dependently attenuated increases in atrial and ventricular forces induced by norepinephrine but not increases in sinus rate. Pinacidil similarly attenuated the positive atrial and ventricular inotropic responses to Bay k 8644 and CaCl₂. The pinacidil doses producing a fifty percent decrease (ED₅₀) of the atrial and ventricular contractile force were not significantly different from the respective pinacidil doses producing a fifty percent inhibition (ID₅₀) of the positive inotropic responses to norepinephrine, Bay k 8644 and CaCl₂. Ouabain (5 and 15 nmol) did not affect the decreases in atrial and ventricular contractile force in response to pinacidil. These results suggest that the K⁺_ATP-channel activator pinacidil, unlike acetylcholine or adenosine, functionally attenuates increases in ventricular and atrial contractile force in the responses to norepinephrine and other cardiotonics due to shortening of the action potential duration induced by K⁺_ATP-channel activation in the dog heart.