Release of endothelium-derived hyperpolarizing factor (EDHF) by M3 receptor stimulation in guinea-pig coronary artery

1. The muscarinic receptor subtype(s) involved in the release of endothelium-derived hyperpolarizing factor (EDHF) were studied in the guinea-pig coronary artery by recording the membrane potential in the smooth muscle cells with intracellular microelectrodes. 2. Acetylcholine (ACh, pD2 6.68) was 10 times more potent than the M2 agonist, oxotremorine (pD2 5.65) and 500 fold more potent than the M1 agonist, McN-A-343 (pD2 3.95) in evoking the EDHF hyperpolarization. 3. The M3 muscarinic antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) was the most potent (pA2 9.5) in inhibiting the release of EDHF evoked by ACh, being more potent than pirenzepine (pA2 6.7), and AFDX-116 (pA2 6.1) which preferentially block M1 and M2 receptors, respectively. 4. These results suggest that EDHF is released from the endothelium of the guinea-pig coronary artery upon the activation of the muscarinic M3 receptor subtype.