The cellular electrophysiologic mechanism of the dual actions of disopyramide on rabbit sinus node function.

Abstract

To determine the contribution of disopyramide's suggested opposing direct depressant and indirect acceleratory actions on sinus node function, we studied the effects of disopyramide, 1 x 10(-7) to 1 x 10(-4) M, on isolated rabbit sinus node preparations using standard microelectrode techniques. Transmembrane potentials were recorded simultaneously from the sinus node and adjoining crista terminalis area. Disopyramide, as much as 1 x 10(-5) M, had no effects on the sinus cycle length. At a concentration of 1 x 10(-4) M, sinus cycle length was significantly prolonged due to prolongation of the sinus nodal action potential duration. During cholinergic blockade with atropine, 1 x 10(-6) M, disopyramide, 1 x 10(-7) to 1 x 10(-4) M, significantly prolonged sinus cycle length as a result of a prolongation of the sinus nodal action potential duration and a decrease of the slope of phase 4 depolarization. During cholinergic stimulation with carbamyl choline, 1 x 10(-9) M, disopyramide, 1 x 10(-7) to 1 x 10(-6) M, tended to reverse carbamyl choline-induced prolongation of the sinus cycle length (NS). This acceleratory action of disopyramide was caused by a significant increase of the slope of phase 4 depolarization. Disopyramide, 1 x 10(-7) to 1 x 10(-4) M, had no significant effects on corrected sinus node recovery time or on sinoatrial conduction time under any conditions studied. We conclude that disopyramide has a direct depressant action on normal sinus node cells at the upper therapeutic and toxic levels, which is enhanced during cholinergic blockade, and that disopyramide's acceleratory action appears only at much lower concentrations and only during cholinergic stimulation.

Electrical current-induced atrial and pulmonary vein action potential duration shortening and repetitive activity

“…Several of the findings in the present study strongly indicate that EC-induced shortening of the APD result from local release of ACh, which activates I KACh in atrial cells (17). The ability of atropine, a competitive muscarinic ACh receptor blocker (16,25,26), to completely block APD shortening and membrane hyperpolarization provides strong evidence that the EC-induced APD shortening is ACh mediated.…”

“…We tested the influence of muscarinic cholinergic blockade with atropine (2 M) and ␤-adrenergic receptor blockade with propranolol (2 M) on five isolated heart preparation on EC-induced changes on atrial and ventricular myocardial cell APD and MDP. We also tested the effect of total autonomic blockade by combining atropine (2 M) with propranolol (2 M) in these five preparations (16).…”

Cellular mechanisms of differential action potential duration restitution in canine ventricular muscle cells during single versus double premature stimuli.

“…Thirty adult mongrel dogs of either sex (weight, [15][16][17][18][19][20] kg) were anesthetized with sodium pentobarbital (30-35 mg/kg i.v.). The hearts were rapidly removed through a left thoracotomy and immediately immersed in cooled, oxygenated Tyrode's solution.…”

Hemodynamic and renal effects of low-dose brain natriuretic peptide infusion in humans: a randomized, placebo-controlled crossover study

“…We also tested the effect of total autonomic blockade by combining atropine (2 M) with propranolol (2 M) in these five preparations (16).…”

“…The ability of atropine, a competitive muscarinic ACh receptor blocker (16,25,26), to completely block APD shortening and membrane hyperpolarization provides strong evidence that the EC-induced APD shortening is ACh mediated.…”