Role of muscarinic M2 and M4 receptors in modulation of neurally-evoked response in guinea pig gastric fundus

The role of M-2 and M-4 muscarinic receptors on the tone and stimulation-induced relaxation of the guinea pig gastric fundus after muscarinic activation by (4-Hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride (McN-A-343) was investigated. Electrical field stimulation (EFS; 2Hz, 0.2 ms, supramaximal current intensity, 10 s train duration) elicited on-contraction, followed by off-relaxation in the circular muscle strips. McN-A-343 (10 mu M) increased the tone (TTX-insensitive) and transformed the EFS-evoked on-contraction into on-relaxation (TTX-sensitive). This on-relaxation consisted of two components: nitrergic and non-nitrergic. Blockade of M-2 receptors by methoctramine did not change the amplitude of EFS-evoked relaxation, but strongly decreased the tone indicating that M-2 receptors are involved in McN-A-343-evoked tone. Conversely, M-4 receptor blockade by tropicamide significantly increased EFS-evoked relaxation without influencing the tone, thus suggesting the participation of M-4 receptors in the neurally-evoked response. In addition after tropicamide the non-nitrergic component of relaxation predominates suggesting that M-4 receptors most likely positively modulate nitric oxide production after muscarinic stimulation by McN-A-343.