An excitatory muscarinic response in neonatal XXXX ventricular myocytes and its modulation by sympathetic innervation.

@entity1169 @entity19260 @entity268 @entity7425 @entity3159 @entity19495 @entity4140 @entity35 @entity2661 @entity934
Previously, we demonstrated that low concentrations of @entity934 (< or = 10(-9) M) increased automaticity in neonatal but not in adult @entity35 ventricular myocardium. In the present study, we used cultured neonatal @entity35 ventricular myocytes grown alone or in the presence of dissociated sympathetic neurons as an experimental model to study the ontogeny of the muscarinic response. McN A343 (< or = 10(-9) M), an M1 selective agonist, increased spontaneous rate from 51 +/- 4 to 56 +/- 5 beats per minute (bpm), and this excitatory response was blocked by 10(-9) M @entity4140 , an M1 selective antagonist, but not by the M2 selective antagonist @entity19495 , nor by the alpha 1 adrenergic antagonist @entity3159 and the beta adrenergic antagonist @entity1169 (all 10(-7) M) In innervated myocytes, McN A343 also increased rate from 48 +/- 6 to 55 +/- 6 bpm. However, this effect was blocked by either 10(-9) M @entity4140 or 10(-7) M @entity1169 . After pretreatment with 10 ng/ml of pertussis toxin, the McN A343-induced excitatory response in non-innervated myocytes was absent, thus suggesting that this response involved a pertussis toxin-sensitive G protein dependent pathway. McN A343 failed to stimulate @entity19260 or @entity268 accumulation in non-innervated myocytes. These results demonstrate the following. (1) The muscarinic excitatory response is mediated via direct stimulation of a post-synaptic M1 receptor in non-innervated myocytes. (2) The excitatory response after innervation is related to the release of @entity2661 , possibly through activation of muscarinic receptors located at the pre-synaptic sympathetic nerve terminals. (3) Sympathetic innervation prevents the functional expression of the post-synaptic myocardial M1 receptor. (4) The intracellular pathway for the post-synaptic M1 excitatory response involves a pertussis toxin-sensitive G protein, but does not depend on obvious changes in @entity268 or @entity7425 hydrolysis.
