Subclassification of muscarinic receptors in the heart, urinary bladder and sympathetic ganglia in the pithed rat

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Abstract
In pithed normotensive rats muscarinic receptors were characterized heart, urinary bladder and sympathetic ganglia; the selectivity of some classical muscarinic agents for these subtypes was investigated. The potencies in decreasing heart rate, increasing bladder pressure and increasing diastolic blood pressure were measured for the following, intraarterially administered cholinergic agonists: McN-A-343 ([4-m-chlorophenylcarbamoyloxy]-2-butynyltrimethylammonium), pilocarpine, carbachol, oxotremorine, arecoline, acetyl-β-methylcholine and acetylcholine. The selective M1-antagonist pirenzepine, the mixed M1/M2-antagonist dexetimide and the cardioselective M2-antagonist gallamine were used as tools for identification of the receptors. All data were obtained after intravenous pretreatment with a high dose of atenolol to eliminate tachycardia induced by stimulating sympathetic ganglionic muscarinic receptors. Dexctimide strongly antagonized the bradycardia as well as the increase in bladder pressure induced by pilocarpine, carbachol, oxotremorine, arecoline, acetyl-β-methylcholine and acetylcholine, whereas pirenzepine was much less effective. Gallamine antagonized the bradycardia, whereas no influence was found on the bladder contraction. Pilocarpine acted as a partial agonist in reducing heart rate as well as in increasing bladder pressure, whereas McN-A-343 was almost ineffective in doses up to 1 mg/kg. The hypertensive response to pilocarpine and carbachol was less pronounced than that produced by McN-A-343. Pirenzepine and dexetimide significantly antagonized the hypertensive response to McN-A-343 and pilocarpine, whereas gallamine was much less effective. The hypertensive response induced by carbachol was totally blocked by hexamethonium. The other agonists used in this study did not produce a significant increase in diastolic blood pressure in doses that produced a maximal effect on heart rate and urinary bladder pressure. Simultaneously, intraarterially infused acetylcholine dose-dependently and reversibly decreased the pressor response to intravenously administered McN-A-343. These data suggest that muscarinic receptors in rat sympathetic ganglia belong to the M1-subtype, whereas the muscarinic receptors in rat heart and urinary bladder represent heterogenous populations of M2-receptors. The agonists used in this study, though, could not discriminate between these heterogenous M2-receptors. Like McN-A-343, pilocarpine appears to be a rather selective M1-agonist. In this study the M1/M2 selectivity of muscarinic agents with pronounced M2-agonist activity could not be evaluated since M2-receptor stimulation interferes with the hypertensive response to M1-receptor stimulation.