Effect of acetylcholine on the norepinephrine-induced positive chronotropy and increase in cyclic nucleotides of isolated rabbit sinoatrial node.

Transmural stimulation of, or application of nicotine to, the isolated rabbit sinoatrial (SA) node resulted in initial negative and late positive chronotropy. Simultaneous application of acetylcholine and norepinephrine produced a similar biphasic chronotropic effect. These procedures produced an initial increase in cyclic guanosine 3':5'-monophosphate (cyclic GMP) and a delayed elevation in cyclic adenosine 3':5'-monophosphate (cyclic AMP). The initial and late effects on rate and nucleotide levels were inhibited by pretreatment with atropine and propranolol, respectively. Pretreatment with atropine shortened the time of maximum increase in cyclic AMP level and heart rate from 3 to 1 minute after the simultaneous application of acetylcholine and norepinephrine and enhanced the positive chronotropic effect. Physostigmine prolonged the duration of the increase in cyclic GMP and negative chronotropic effect after the simultaneous application. These results suggest that when acetylocholine and norepinephrine are present simultaneously in the SA node region, the former interacts predominantly with muscarinic receptors and stimulates the cyclic GMP system, which in effect delays the cyclic AMP elevation and reduces the positive chronotropic effect of norepinephrine. However, these effects of acetylcholine cannot be explained solely on the basis of changes in the cyclic GMP level, because sodium nitroprusside produced a marked elevation of the cyclic GMP levels without decreasing the heart rate and did not affect the norepinephrine-induced increase in pacemaker rate and cyclic AMP. Sodium nitroprusside may affect cyclic GMP pools other than those susceptible to acetylcholine. These cyclic GMP pools may not exert chronotropic effects.