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The interaction of hexamethonium with muscarinic receptor subtypes in vitro
Author(s) -
Eglen R.M.,
Michel A.D.,
Cornett C.M.,
Kunysz E.A.,
Whiting R.L.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb12623.x
Subject(s) - hexamethonium , muscarinic acetylcholine receptor , methoctramine , endocrinology , medicine , carbachol , receptor , muscarinic acetylcholine receptor m2 , atropine , chemistry , biology
1 The action of hexamethonium has been studied at a range of muscarinic receptors in vitro by use of both functional and radioligand binding studies. 2 In functional studies, hexamethonium exhibited little or no significant (P < 0.05) antagonism of contractile responses to carbachol at muscarinic receptors in the guinea‐pig ileum, oesophageal muscularis mucosae, urinary bladder and trachea. However, antagonism was observed at muscarinic receptors in the guinea‐pig left atria mediating negative inotropic responses and the calculated p K B value was 3.80. Hexamethonium also antagonized contractile responses to carbachol in the canine saphenous vein. The p K B value at these receptors was 3.75. 3 In the presence of 3.2 mM hexamethonium, the pA 2 value for methoctramine at atrial muscarinic receptors was reduced by approximately 10 fold (control pA 2 value was 7.81 ± 0.05; pA 2 value in hexamethonium was 6.73 ± 0.04). In contrast at tracheal muscarinic receptors, the pA 2 values for methoctramine were unaffected in the presence of 3.2 mM hexamethonium (control pA 2 = 5.58 ± 0.07; pA 2 value in hexamethonium was 5.63 ± 0.12). All values quoted are mean ± s.e.mean, n = 8. 4 In competition radioligand binding studies, hexamethonium exhibited a higher affinity for cardiac M 2 receptors (p K i = 3.68) than for cerebrocortical M 1 receptors (p K i = 3.28) or for submaxillary gland M 3 receptors (p K i = 2.61). At M 2 receptors hexamethonium at concentrations of 0.1–10 mM, increased the half life of the dissociation rate of [ 3 H]‐N‐methylscopolamine 1.6‐4.3 fold. This was observed at M 3 receptors only at 10 mM, when the half life was increased 1.7 fold. 5 We conclude that hexamethonium, in addition to its well characterized nicotinic antagonist properties, can act as a weak muscarinic antagonist and differentiates between cardiac M 2 receptors and glandular/smooth muscle M 3 receptors. However, hexamethonium differentiates less clearly between M 1 and M 2 receptors. The selectivity between M 2 and M 3 receptors observed in the present study with hexamethonium is comparable to other M 2 selective antagonists such as AF‐DX 116 and himbacine. 6 Caution should be exercised with regard to the inclusion of hexamethonium in functional studies of M 2 muscarinic receptor subtypes at concentrations of 0.1 mM and above.