Hypotensive effect of an M2-selective muscarinic antagonist in anaesthetized guinea-pigs

1. In order to determine an involvement of muscarinic M2 receptors in the regulation of systemic arterial blood pressure, we investigated the cardiovascular effects of the M2-selective antagonist methoctramine and other agents in anaesthetized guinea-pigs. 2. Intravenous injection of methoctramine, atropine, pirenzepine (an M1-selective muscarinic antagonist) or 4-DAMP (an M3-selective muscarinic antagonist) each significantly increased heart rate in comparison to vehicle controls. 3. Methoctramine produced significant, dose-dependent decreases in mean arterial blood pressure, with an ED50 of 0.1 mg kg-1. Atropine decreased blood pressure only at high doses. Pirenzepine and 4-DAMP did not alter blood pressure, indicating that M1 or M3 receptor antagonism was not responsible for the cardiovascular effects of methoctramine. 4. The hypotensive effect of methoctramine was unaltered by indomethacin pretreatment, ruling out an alteration in arachidonic acid metabolism as the mechanism of action. 5. In contrast to methoctramine, mecamylamine (a nicotinic ganglionic receptor antagonist) greatly decreased heart rate and slightly decreased blood pressure, suggesting that ganglionic blockade was not the mechanism for the cardiovascular effects of methoctramine. 6. Methoctramine (0.3 mg kg-1) pretreatment did not alter the hypertensive effect of intravenous noradrenaline, demonstrating that methoctramine did not directly inhibit vascular reactivity and indicating an indirect hypotensive of action of methoctramine. 7. In summary, the results suggest that the hypotensive action of methoctramine resulted from selective M2 receptor antagonism. Therefore, muscarinic M2 receptors appear to play a role in the regulation of systemic arterial blood pressure in guinea-pigs. However, the anatomical site(s) of action of methoctramine remains to be determined.