Effect of Antimuscarinic Agents on the Contractile Responses to Cholinomimetics in the Rat Anococcygeus Muscle

Abstract

The effects of antimuscarinic agents alone and in the presence of neostigmine on the contractile responses to exogenously applied cholinomimetics or (‐)‐noradrenaline were studied in the rat anococcygeus muscle. Atropine (1 × 10_9‐1 × 10−6m) alone, in the presence of hexamethonium (1 × 10−4m), or phentolamine (1 × 10−6m), inhibited responses to acetylcholine but not to (—)‐noradrenaline. The inhibitory effect with the higher concentrations of atropine (1 × 10−8— × 10−6m), was seen as an increase in the slopes of the concentration‐response curves. Atropine (1 × 10−8m) alone inhibited the responses to methacholine and carbachol without altering the slopes of the concentration‐response curves. Homatropine (1 × 10−6m) alone had no effect on responses to (‐)‐noradrenaline and inhibited responses to acetylcholine and methacholine. The inhibitory effect on responses to acetylcholine but not to methacholine, included an increase in the slopes of the concentration‐response curves. Neostigmine (1 × 10−6m) alone had no effect on responses to (—)‐noradrenaline and potentiated responses to acetylcholine and methacholine. The potentiating effect included an increase in the slopes of the concentration‐response curves. In the presence of neostigmine (1 × 10−6m), atropine (1times10−9m‐1times 10−6m) caused a parallel concentration‐dependent shift of the concentration‐response curves to acetylcholine. The pA2 values, in the presence of neostigmine, were independent of the concentration of atropine and of the agonist (acetylcholine, methacholine, or carbachol) used. In the presence of neostigmine (1 × 10−6m), homatropine (1 × 10−6m) also failed to alter the slopes of the concentration‐response curves to acetylcholine and was approximately 100 times less potent than atropine as an antimuscarinic agent. These results illustrate that, in the rat anococcygeus muscle, it is necessary to inhibit acetylcholinesterase before determining the relative potencies of antagonists at muscarinic receptors.

Non‐specific, time‐dependent desensitization of the vas deferens and anococcygeus preparations of the rat to α1‐adrenoceptor antagonists and atropine

“…The Kbe value of atropine was 0.54 nmol 1- (Table 2), a value already reported in this tissue (Doggrell, 1981). The 4 values Kbe values 100 nmol 1-'/(DRe-1) are given in Table 1.…”

“…In the (0-2.5 h) period, the Kbe value of AR-C239 was 0.80 nmol 1-l (Table 2), which shows that this drug is much more potent than thymoxamine (Kbe=30nmolI-, Table 1). The Kbe value of atropine was 0.54 nmol 1- (Table 2), a value already reported in this tissue (Doggrell, 1981). The 4 values Kbe values 100 nmol 1-'/(DRe-1) are given in Table 1.…”

“…This mechanism is unlikely, because putative acceptors for antagonists were blocked or unavailable in that (a) the P-adrenoceptors of the rat vas deferens would be occupied by propranolol, and (b) P-receptor mediated effects are not important in the rat anococcygeus muscle (Gillespie, 1972). Furthermore, thymoxamine (Leighton et al, 1979) and AR-C 239 (Huchet, Andrejak and Schmitt, unpublished observation ) share with MA and PE (Drew, 1977;Leighton et al, 1979) a 100-1000 fold greater activity on a1-adrenoceptors than on a2-adrenoceptors; whereas, carbachol (Doggrell, 1981), thymoxamine at 400 nmol -1 (Drew etal., 1978) and MA (Leighton, 1982) have no affinity for neuronal uptake sites. The drugs used in the study, carbachol, (McGrath & Olverman, 1977;Burnstock et al, 1978) MA (Doggrell & Woodruff, 1978) and presumably thymoxamine do not release noradrenaline or acetylcholine.…”

“…Additional experiments were carried out on the rat anococcygeus muscle, a tissue consisting almost entirely of longitudinal muscle (Gillespie, 1972) with the competitive ax-adrenoceptor antagonist, AR-C 239 (2-[2-[4(0-methoxyphenyl)-piperazine-1-Yl]-ethyl]4, 4-dimethyl-1,3(2H-4H) isoquinolinedione; Mouille etal., 1980;Huchet, Andr&e jack & Schmitt, unpublished observations) and with atropine (Arunlakshana & Schild, 1959;Doggrell, 1981). Control muscles of these experiments received their first dose of agonist at the 5th h.…”

Neostigmine augments responses of the rat anococcygeus muscle to field stimulation

“…Doggrell (1981) has shown that neostigmine (10-6M) did not alter contractile responses to (-)-noradrenaline itself.…”