Mediation by the same muscarinic receptor subtype of phasic and tonic contractile activities in the rat isolated portal vein

The effects of several agonists on the phasic and tonic contractile responses to muscarinic receptor stimulation have been investigated in the rat portal vein in vitro. Neither chemical denervation with 6‐hydroxydopamine nor the presence of the α1‐adrenoceptor antagonist, prazosin, influenced the spontaneous or the stimulated myogenic activity of the portal vein. Indomethacin and NG‐nitro‐l‐arginine were used to investigate the influence of vasoactive factors in this preparation. They slightly increased the frequency and the amplitude of the spontaneous myogenic activity of the portal vein, respectively. NG‐nitro‐l‐arginine but not indomethacin enhanced the maximal phasic response to carbachol. Both indomethacin and NG‐nitro‐l‐arginine failed to influence the tonic response to carbachol. Muscarinic agonists increased phasic activity according to the rank order of potency: acetylcholine > muscarine > methacholine > carbachol > aceclidine > bethanechol. These effects were superimposed on a sustained contracture at higher concentrations. Oxotremorine was more potent than arecoline in increasing the mechanical phasic activity, without inducing a sustained contracture. Pilocarpine and McN A 343 were weak agonists, producing submaximal effects only on phasic activity. The muscarinic antagonists AF‐DX 116, 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP), P‐fluorohexahydrosiladiphenidol (pFHHSiD) and pirenzepine antagonized the phasic and tonic mechanical responses to carbachol. Although the tonic contracture was slightly more sensitive to all antagonists studied, the rank order of potency: 4‐DAMP > pFHHSiD > pirenzepine > AF‐DX 116 was the same for both types of response, which is indicative of a M3‐receptor subtype. The tonic contractile response of the rat portal vein to carbachol was more susceptible to partial receptor inactivation with propylbenzilylcholine mustard than the phasic contractile response. The dissociation constants (KA) obtained from an analysis according to Furchgott & Bursztyn (1967) were found to be 4.32 ± 0.31 μm for the phasic and 3.56 ± 0.21 μm for the tonic type of carbachol‐induced response, respectively. Since the EC50‐values for both carbachol‐induced effects were different (phasic 0.232 ± 0.02 μm; tonic 2.75 ± 0.1 μm) the phasic type of response appears to involve a large receptor reserve. 1993 British Pharmacological Society