Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

This study was designed to determine if chronotropic responses induced by neurally released acetylcholine are modified by subtype-selective blockade of cardiac muscarinic cholinoreceptors. In anesthetized cats, a single burst of vagal stimulation was generated with an incremental time delay after the P wave of the atrial electrogram (P-Stimulus interval). The slope of the relationships between P-Stimulus and P–P intervals was used to assess changes in responsiveness of cardiac pacemaker to vagal effects throughout the cardiac cycle. An increase in P-Stimulus interval over the initial portion (∼120 ms) of the cardiac cycle produced a significant increment in lengthening of the P–P interval. Once the maximal negative chronotropic response was achieved, a further increase in P-Stimulus interval by only ∼25 ms resulted in profound (by 80–90%) reductions in vagal effects, thus yielding a bimodal vagal phase response curve. Antagonists of M₁ (pirenzepine), M₂ (methoctramine and gallamine), and M₃ (4-DAMP) muscarinic cholinoreceptors produced a reduction in the magnitude of maximal lengthening of cardiac cycle as well as an increase in latency of vagal effects. However, the increment in prolongation of P–P interval induced by a given change in timing of vagal stimulation during cardiac cycle was reduced by M₁ and M₂ muscarinic receptor blockers, but was unaffected by 4-DAMP. None of the antagonists modified the range of P-Stimulus intervals over which the maximum-to-minimum change of vagal responses occurred. Taken together, these data suggest different contribution of various subtypes of cardiac muscarinic receptors into the negative chronotropic responses induced by brief bursts of vagal stimulation.