The Interaction of Amine Local Anaesthetics With Muscarinic Receptors

Taylor, William G.; Wolf, Anne; Young, J. M.

doi:10.1111/j.1476-5381.1980.tb10943.x

Cited by 20 publications

(5 citation statements)

References 19 publications

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“…A primary action of this substance is to inhibit the activity of cytochrome P450-dependent mono-oxygenases (Mannering, 1971) although it does have other actions including binding to muscarinic cholinoceptors (Taylor et al, 1980). An endothelial cytochrome P450 has been reported (Singer et al, 1984;Abraham et al, 1985) and some workers have found that inhibitors of this cytochrome, including SKF-525A, inhibit endothelium-dependent relaxation (Peach et al, 1985).…”

Section: Resultsmentioning

confidence: 99%

Endothelium‐dependent modulation of the pressor activity of arginine vasopressin in the isolated superior mesenteric arterial bed of the rat

Randall

Kay

Hiley

1988

British J Pharmacology

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1Pressor responses to arginine vasopressin (AVP) were determined in the rat isolated superior mesenteric arterial bed perfused with Krebs-Henseleit solution and compared with those to noradrenaline. 2 In control preparations the maximum pressor response to the peptide was 34 + 3 mmHg and the ED50 was 21 + 4 mu (n = 11). The maximal pressor response to noradrenaline (30 pg) was 100 + 6 mmHg (n = 8). After removal of the functional endothelium with the detergent CHAPS, the maximum pressor response to AVP increased to 64 + 4 mmHg and the ED50 decreased to 7.7 + 2.0 mu (n = 11) but the response to 10Oug noradrenaline was unaffected. 3 Nordihydroguaiaretic acid (2.5pM) significantly increased the maximum pressor response to AVP from 41 + 2 mmHg to 86 + 8 mmHg (n = 9); the ED50 was unchanged. Methylene blue (50 pM) also increased the maximum response from 41 + 3 mmHg to 87 + 13 mmHg (n = 8) without affecting the ED50. Neither treatment significantly affected the response to lOpg noradrenaline.4 Neither indomethacin (1OpM) nor BW755C (1OpM) had significant effects upon either the maximal response or ED50 for AVP nor did they affect the response to lOpg noradrenaline. 5 In 6 preparations SKF-525A significantly increased both the ED50, from 9.8 + 2.1 to 22 + 2 mu, and the maximum response, from 36 + 2 to 70 + 3 mmHg. 6 It is concluded that the pressor response to AVP in this vascular bed is modulated, in the presence of functional endothelium, by the simultaneous release of endothelium-derived relaxing factor.

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Section: Resultsmentioning

confidence: 99%

Endothelium‐dependent modulation of the pressor activity of arginine vasopressin in the isolated superior mesenteric arterial bed of the rat

Randall

Kay

Hiley

1988

British J Pharmacology

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“…Since A23187-induced relaxations mediated by EDNO were unaffected, it seems unlikely that proadifen reduces the formation of EDNO by acting on endothelial NO-synthase. The inhibitory effects of proadifen may be related to its anti-muscarinic properties (Taylor et al, 1980) or to an interaction with other processes involved in muscarinic receptor-response coupling, eventually leading to increased Ca21 levels in endothelial cells. Such properties could also contribute to the ability of proadifen to inhibit EDHF-mediated responses, since an increase in endothelial Ca2+ concentration seems to be important not only for the synthesis of NO, but also for the formation of EDHF (Suzuki & Chen, 1990).…”

Section: Discussionmentioning

confidence: 99%

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Zygmunt

Edwards

Weston

et al. 1996

British J Pharmacology

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1 The possibility that the endothelium-derived hyperpolarising factor (EDHF) in the rat hepatic artery is a cytochrome P450 mono-oxygenase metabolite of arachidonic acid was examined in the present study. In this preparation, acetylcholine elicits EDHF-mediated relaxations in the presence of the nitric oxide (NO) synthase and cyclo-oxygenase inhibitors No-nitro-L-arginine (L-NOARG) and indomethacin, respectively.2 17-Octadecynoic acid (17-ODYA, 50 gM), a suicide-substrate inhibitor of the cytochrome P450 mono-oxygenases responsible for the production of 5, 8, 11,[12][13][14], had no effect on acetylcholine-induced relaxations in the presence of L-NOARG (0.3 mM) plus indomethacin (10 gM). Furthermore, 5, 8, 11, Clotrimazole (3 gM) was without effect on these responses. The relaxant actions of the NO donor, 3-morpholino-sydnonimine, were unaffected by proadifen (10 gM). 5 The relaxant effects of the opener of ATP-sensitive potassium channels, levcromakalim, were abolished by proadifen (10 gM) and strongly attenuated by clotrimazole (3 gM). Proadifen (10 gM) also abolished the hyperpolarization induced by levcromakalim (1 gM). 6 The lack of effect of 17-ODYA on relaxations mediated by EDHF, together with the failure of extracellularly-applied EETs to produce relaxation, collectively suggest that EDHF is not an EET in the rat hepatic artery. It seems likely that inhibition of ion channels in the smooth muscle rather than reduced EDHF formation in the endothelium offers a better explanation for the actions of the cytochrome P450 inhibitors proadifen and clotrimazole.

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“…Thus our results can be compared with those obtained with other types of receptor, i.e. muscarinic receptors, where tetracaine and procaine interact competitively (Aguilar et al 1980;Fairhurst et a1 1980;Taylor et a1 1980; Hisayama et al 1989). These studies on muscarinic receptors show pKi values for each drug to be around 5.0, a little larger than the values obtained for histamine HI receptors in our study ( Table 1).…”

Section: Discussionmentioning

confidence: 79%

Interaction of Local Anaesthetics with Histamine H1 Receptors in Guinea-pig Ileum

Horio

Nagare

Ishida

et al. 1997

Journal of Pharmacy and Pharmacology

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The interaction of amine local anaesthetics and related compounds with histamine H1 receptors was investigated in guinea-pig ileal longitudinal muscle. Quinacrine, chloroquine, tetracaine and procaine inhibited [3H]mepyramine binding to solubilized membrane from ileal muscle with pKi values of 5.27 +/- 0.11, 5.66 +/- 0.01, 4.28 +/- 0.08 and 3.97 +/- 0.11, respectively. The pKB values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 5.49 +/- 0.11, 6.14 +/- 0.09, 4.86 +/- 0.06 and 4.58 +/- 0.06, respectively, in reasonable agreement with the pKi values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H1 receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization. The results suggested that most of these local anaesthetics interacted competitively at histamine H1 receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allosterically and inhibited desensitization through a separate action.

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The Interaction of Amine Local Anaesthetics With Muscarinic Receptors

Cited by 20 publications

References 19 publications

Endothelium‐dependent modulation of the pressor activity of arginine vasopressin in the isolated superior mesenteric arterial bed of the rat

Endothelium‐dependent modulation of the pressor activity of arginine vasopressin in the isolated superior mesenteric arterial bed of the rat

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Interaction of Local Anaesthetics with Histamine H1 Receptors in Guinea-pig Ileum

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