Effects of Glibenclamide on Negative Cardiac Responses to Cholinergic and Purinergic Stimuli and Cromakalim in the Isolated Dog Heart

We investigated the effects of an ATP-sensitive K+ channel blocker, glibenclamide, on the negative chronotropic and inotropic responses to intracardiac parasympathetic nerve stimulation, acetylcholine (ACh, a muscarinic receptor agonist), ATP (a P2-purinergic receptor agonist), adenosine (a P1-purinergic receptor agonist) and cromakalim (a potassium channel opener) in the isolated, blood-perfused canine right atrium or left ventricle. A high dose of glibenclamide (3 μmol) did not affect the negative chronotropic and inotropic responses to parasympathetic stimulation (frequencies of 1-30 Hz), although it slightly but significantly attenuated the negative cardiac responses to exogenous ACh (0.3-10 nmol). Furthermore, adenosine (0.03-0.3 μmol)-induced negative chronotropic and inotropic responses were significantly inhibited by glibenclamide (3 μmol), but ATP (0.01-1 μmol)-induced negative cardiac responses were not affected. A cumulative administration of cromakalim (0.01-1 μmol) dose-dependently caused much greater decreases in the contractile force of atrial and ventricular muscles than in sinus rate. Glibenclamide (0.3-3 μmol) similarly blocked the negative chronotropic and inotropic responses to cromakalim in a dose-dependent manner. These results suggest that glibenclamide modifies the negative cardiac responses to parasympathetic activation both in pre- and postjunctional sites and the responses to adenosine but not to ATP at K+ channels in the dog heart, although the modifications are minor under physiological conditions.