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Comparative electrophysiologic and coronary hemodynamic effects of diltiazem, nisoldipine and verapamil on myocardial tissue

1982; Elsevier BV; Volume: 49; Issue: 3 Linguagem: Inglês

10.1016/s0002-9149(82)80020-9

1879-1913

David A. Lathrop, J. Roberto Valle-Aguilera, Ronald W. Millard, Winston E. Gaum, David W. Hannon, Paul Francis, Haruaki Nakaya, Arnold Schwartz,

Cardiac Arrhythmias and Treatments

The effects of diltiazem, nisoldipine (a nifedipine derivative) and verapamil on electrical and mechanical activity were studied in isolated canine Purkinje fibers and in isolated human atrial appendage. The actions of these three drugs on atrioventricular (A-V) conduction and coronary resistance were studied in open chest dogs in which autonomic effects were minimized by alpha and beta receptor blockade, bilateral vagotomy and atrial pacing after crushing of the sinus node. In isolated canine Purkinje fibers superfused with 5.4 mM of potassium in Tyrode's solution, normal action potentials and tension development were observed. Administration of diltiazem, nisoldipine and verapamil produced complete excitation/contraction uncoupling. The 50 percent effective concentrations for each drug in relation to tension development were calculated to be: diltiazem, 3 × 10−7M; nisoldipine, 1.4 × 10−8M; and verapamil, 4.2 × 10−8M. The ease with which the effects of the drugs could be washed out differed among the three agents. The percent of control tension achieved during washout was 40 percent for diltiazem, 75 percent for nisoldipine and 90 percent for verapamil. The reductions in tension development were accompanied by reductions in plateau amplitude and action potential duration at 50 percent of repolarization. Action potential duration at 90 percent of repolarization was significantly decreased by diltiazem, unchanged by nisoldipine and significantly increased by verapamil. In potassium-depolarized, isoproterenol-restored canine Purkinje fibers that demonstrated slow channel-dependent electrical activity, diltiazem, nisoldipine and verapamil all blocked action potential and subsequent tension development. These effects of diltiazem were completely reversed after 30 minutes of washout, but the effects of nisoldipine and verapamil were more difficult to reverse. In human atrial tissue, these three agents also abolished spontaneous slow channel-dependent action potentials. All three drugs produced excitation-contraction uncoupling and blocked slow channel-dependent electrical activity in canine and human cardiac tissue presumably by blocking the slow inward current. The different effects of each drug on action potential configuration suggest that each drug may also significantly affect other membrane currents. In intact open chest dogs, each drug lengthened atrial-His conduction times without affecting intraatrial or intraventricular conduction times. Coronary resistance was also decreased by each drug. High concentrations of each drug produced second degree A-V block and severe hypotension. As with the studies in isolated tissues the decreasing order of potency was nisoldipine, verapamil and diltiazem. The effects of diltiazem, nisoldipine (a nifedipine derivative) and verapamil on electrical and mechanical activity were studied in isolated canine Purkinje fibers and in isolated human atrial appendage. The actions of these three drugs on atrioventricular (A-V) conduction and coronary resistance were studied in open chest dogs in which autonomic effects were minimized by alpha and beta receptor blockade, bilateral vagotomy and atrial pacing after crushing of the sinus node. In isolated canine Purkinje fibers superfused with 5.4 mM of potassium in Tyrode's solution, normal action potentials and tension development were observed. Administration of diltiazem, nisoldipine and verapamil produced complete excitation/contraction uncoupling. The 50 percent effective concentrations for each drug in relation to tension development were calculated to be: diltiazem, 3 × 10−7M; nisoldipine, 1.4 × 10−8M; and verapamil, 4.2 × 10−8M. The ease with which the effects of the drugs could be washed out differed among the three agents. The percent of control tension achieved during washout was 40 percent for diltiazem, 75 percent for nisoldipine and 90 percent for verapamil. The reductions in tension development were accompanied by reductions in plateau amplitude and action potential duration at 50 percent of repolarization. Action potential duration at 90 percent of repolarization was significantly decreased by diltiazem, unchanged by nisoldipine and significantly increased by verapamil. In potassium-depolarized, isoproterenol-restored canine Purkinje fibers that demonstrated slow channel-dependent electrical activity, diltiazem, nisoldipine and verapamil all blocked action potential and subsequent tension development. These effects of diltiazem were completely reversed after 30 minutes of washout, but the effects of nisoldipine and verapamil were more difficult to reverse. In human atrial tissue, these three agents also abolished spontaneous slow channel-dependent action potentials. All three drugs produced excitation-contraction uncoupling and blocked slow channel-dependent electrical activity in canine and human cardiac tissue presumably by blocking the slow inward current. The different effects of each drug on action potential configuration suggest that each drug may also significantly affect other membrane currents. In intact open chest dogs, each drug lengthened atrial-His conduction times without affecting intraatrial or intraventricular conduction times. Coronary resistance was also decreased by each drug. High concentrations of each drug produced second degree A-V block and severe hypotension. As with the studies in isolated tissues the decreasing order of potency was nisoldipine, verapamil and diltiazem.