Pharmacological Tests of the Mechanism of the Periodic Rhythm Caused by Veratramine in the Sinoatrial Node of the Guinea Pig

Abstract

1. We investigated the effects of several drugs and extracellular ions on the periodic sinoatrial node rhythm caused by high concentrations of veratramine (>2 μM) in isolated guinea pig sinus atria. 2. During the active phase of this rhythm, pacemaker activity appeared to be due to transient afterdepolarizations resembling the delayed afterdepolarizations attributed to Ca ++-induced Ca ++ release in cardiac tissue. 3. Ryanodine (200–2200 nM) did not decrease the transient afterdepolarizations, and instead increased the heart rate during the active phase, prolonged the active phase, and sometimes caused conversion to regular rhythm. 4. Dichlorobenzamyl (10–110 μM), a blocker of electrogenic Na +–Ca ++ exchange, did not slow or stop beating during periodic rhythm, but rather increased average heart rate and, at a higher concentration, caused conversion to regular rhythm. 5. Ouabain (0.1 μM), an inhibitor of the sodium pump and electrogenic Na +–K + exchange, had little effect on veratramine periodic rhythm, but at higher concentrations it caused increased average heart rate and conversion to regular rhythm. 6. The chronotropic effect of Ca ++ was normally weakly positive; however, in the presence of veratramine, and before the appearance of periodic rhythm, the chronotropic effect of Ca ++ was weakly negative, and was associated with destabilization of the heart rate, leading to frequency oscillations or periodic rhythm. 7. Veratramine changed the chronotropic effect of K + from weakly negative to moderately positive. 8. When half the Na + or Cl − in the bathing medium was replaced by an impermeant ion, in the absence of veratramine the average heart rate was slightly decreased, whereas, in the presence of veratramine and periodic rhythm the average rate was increased, although the increase was not statistically significant in the case of low Na +. 9. These observations indicate that Ca ++-induced Ca ++ release, Na +–Ca ++ exchange, and probably electrogenic Na +–K + exchange play no important role in generation of periodic rhythm. The increased K + dependence suggests an altered pacemaker mechanism.