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Notes: Summary 1. In trabecular muscles obtained from the right ventricle of untreated dogs 4-aminopyridine (4-AP) (0.1–10 mM) increased the force of contraction elicited by electrical driving at 0.5 Hz. 2. This effect was associated with increases in mean velocities of force development and relaxation. The time to peak force was not changed by 4-AP and the relaxation time was increased by 3 and 10 mM 4-AP. 3. In ventricular muscles treated with the β-adrenoceptor blocking agent, pindolol, or in those obtained from dogs pretreated with reserpine the positive inotropic effect was reduced. 4. In such muscles 4-AP scarcely increased the mean velocity of force development and slightly increased the time to peak force. Marked prolongation of the relaxation time and a decrease in mean velocity of relaxation were characteristic of isometric contractions of such muscles in the presence of 4-AP. 5. These results indicate that the positive inotropic effect of 4-AP is sum of two effects, one being due to the release of endogenous catecholamines and the other to a possible direct action on cardiac muscle. 6. In muscles treated with pindolol or those obtained from dogs pretreated with reserpine 10 mM 4-AP elevated the resting force. 7. These observations suggest that 4-AP causes a persisting elevation of cytosolic Ca2+ in cardiac muscle cells. 8. In pindolol-treated muscles 4-AP prolonged the action potential duration. However, the prolongation of the action potential duration produced by 4-AP was much smaller than that of the relaxation time. Even with 10 mM 4-AP the resting membrane potential remained unchanged. 9. The above results suggest that the effects of 4-AP on the contraction and resting force of ventricular muscle may not be secondary to the effect on the transmembrane potential. 10. All the results taken together suggest that the primary action of 4-AP on ventricular muscle may not be to allow increased or prolonged entry of extracellular Ca2+ but rather may be either to promote the release of Ca2+ from intracellular binding or storage sites or to slow the binding of Ca2+ to intracellular structures. The prolongation of the action potential duration may be a consequence of change in calcium binding to the plasma membrane.

Notes: Summary 1. The present experiments were attempted to determine whether the (+)-enantiomer of verapamil would act predominantly as an inhibitor of the slow calcium channel or the fast sodium channel. For this purpose the effect of (+)-verapamil on atrioventricular (AV) conduction was compared with those of (-)-verapamil, a relatively pure inhibitor of the slow calcium channel, and of tetrodotoxin (TTX), a relatively pure inhibitor of the fast sodium channel by the use of the isolated, blood-perfused AV node preparation of the dog. To obtain a clue to settle the above question, their effects on blood flow through the nutrient arteries of the preparation were also investigated. 2. In the dog heart the upper part of the AV node is perfused through the posterior septal artery (PSA), whereas the more distal conduction system and the myocardium of the ventricular septum are supplied by the anterior septal artery (ASA). In conduction of cardiac impulses the slow calcium channel plays an important role in the upper part of the AV node whereas the fast sodium channel does so in the distal conduction system. 3. The isolated, blood-perfused AV node preparation consists of the right atrium and ventricular septum and permits administration of drugs individually into the PSA and the ASA. Changes in AV conduction time obtained with injection of drugs into the PSA reflect the effect on the slow calcium channel, whereas those obtained with injection into the ASA reflect the action on the fast sodium channel. 4. Single injections of (+)-verapamil (0.1–10 μg) into the PSA produced a dose-dependent increase in AV conduction time, and in high doses it caused a second or third degree block of AV conduction. Prolongation of AV conduction time was due entirely to that of the intervals between bipolar electrograms of the right atrium and those of the right bundle branch (A-B interval). 5. Single injection of (-)-verapamil (0.1–3 μg) into the PSA produced an effect on AV conduction qualitatively similar to that of (+)-verapamil. (-)-Verapamil was about 6 times more potent and far longer-acting than (+)-verapamil. 6. Single injection of (+)-verapamil (0.1–30 μg) into the ASA affected neither AV conduction time nor the shape of bipolar electrograms of the right bundle branch and of the underlying ventricular myocardium. 7. Essentially similar negative results were obtained with (-)-verapamil (0.1–30 μg) injected into the ASA. 8. TTX (1–30 μg) injected into the PSA or the ASA equally produced a dose-dependent increase in AV conduction time. Prolongation of AV conduction time caused by TTX injected into the PSA was due entirely to that of the A-B intervals, whereas that produced by injection into the ASA was due exclusively to that of intervals between bipolar electrograms of the right bundle branch and those of the underlying ventricular myocardium (B-V interval). The latter change was associated with alteration of the shape of bipolar electrograms of the right bundle branch and those of the ventricular septum. 9. Thus, it is unlikely that (+)-verapamil acts as an inhibitor of the fast sodium channel but rather likely that it acts as an inhibitor of the slow calcium channel like its (-)-enantiomer. Difference in action between them was only quantitative. 10. The results also suggest that in addition to the dominant slow calcium channel the fast sodium channel plays a subsidiary role in conduction through the AV node. 11. Both enantiomers of verapamil injected into the PSA or the ASA produced a dose-dependent increase in blood flow through the respective artery. In this regard (-)-verapamil was about 3 times as potent as (+)-verapamil. 12. Intra-arterial TTX was entirely ineffective in increasing blood flow through the PSA or the ASA. 13. The above results support the conlusion that (+)-verapamil is an inhibitor of the slow calcium channel.