Effects of pirenzepine and AF-DX 116 on ganglionic transmission in the cardiac sympathetic nerves of the dog: interaction of M1 and M2 receptors with nicotinic receptors.

Effects of the selective M1 receptor antagonist pirenzepine and the selective M2 receptor antagonist AF-DX 116 on ganglionic transmission were examined in anesthetized dogs, in order to elucidate a functional role of M1 and M2 receptors. Preganglionic or postganglionic stimulation of the cardiac sympathetic nerves (SNS, 0.5-16 Hz) produced frequency-dependent increases in heart rate. Pirenzepine (3-100 microgram/kg) caused dose-dependent and significant inhibition of positive chronotropic response to preganglionic SNS but not to postganglionic SNS. AF-DX 116 (10-100 micrograms/kg) had no effect on the preganglionic SNS-induced tachycardia. The simultaneous administration of pirenzepine (30 micrograms/kg) and hexamethonium (C6, 1 mg/kg), and the subsequent administration of 10 mg/kg of C6, inhibited more potently the tachycardic responses to preganglionic SNS than each dose of C6 did by itself. The enhancement by pirenzepine of the C6-induced inhibition was evident at high frequencies (8 and 16 Hz) of SNS. In contrast, the blocking effect of C6 (1 and 10 mg/kg) on ganglionic transmission was significantly attenuated by AF-DX 116 (30 micrograms/kg). The attenuation by AF-DX 116 was observed at a wide range of stimulation frequency (0.5-8 Hz). These results suggest that M1 receptors play a facilitatory role in ganglionic transmission but M2 receptors do not contribute to the transmission when nicotinic pathway is intact. However, the activation of M2 receptors would further suppress ganglionic transmission when nicotinic transmission is inhibited. Under these conditions, activation of M1 receptors would mediate the transmission elicited by high frequency of stimulation.