The direct myocardial depressant action of muscarinic stimulation on canine atrial muscle appears related to elevated cyclic GMP, whereas indirect action in both atrial and ventricular muscle may be due to reduced cyclic AMP.
1 The relation between force of contraction and cyclic nucleotide levels during muscarinic receptor stimulation, and after administration of sodium nitroprusside was assessed in canine isolated atrial and ventricular muscle.2 The pD(2) value (negative logarithm of ED(50)) for carbachol to decrease force of atrial contraction was similar to that required to inhibit adenosine 3',5'-monophosphate (cyclic AMP)-mediated positive inotropic responses in ventricular muscle.3 The cyclic AMP level of atrial muscle did not significantly change during carbachol-induced negative inotropic action, whilst the guanosine 3',5'-monophosphate (cyclic GMP) level was elevated immediately after administration.4 Sodium nitroprusside elevated cyclic GMP levels (without changing cyclic AMP levels) both in atrial and ventricular muscle. The force of atrial contraction was significantly reduced by the drug, whilst ventricular contractile force was unaffected.5 8-Bromo-cyclic GMP markedly decreased contractile force in atrial muscle. In contrast, similar concentrations of 8-bromo-cyclic GMP had no effect on ventricular contractile force.6 The positive inotropic action of phenylephrine on canine cardiac muscle, which is mediated through beta-adrenoceptors, was unaffected either by sodium nitroprusside or by 8-bromo-cyclic GMP.7 The present results suggest that the effect of muscarinic receptor stimulation in canine atrial and ventricular muscle is related to different changes in intracellular cyclic nucleotide metabolism. The direct myocardial depressant action on atrial muscle seems to be related to an elevation of cyclic GMP level, whilst a reduction of cyclic AMP may be responsible for the indirect action (;accentuated antagonism') in both atrial and ventricular muscle.
Endoh et al. (Mon,) studied this question.