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Characterization of histamine‐H 3 receptors controlling non‐adrenergic non‐cholinergic contractions of the guinea‐pig isolated ileum
Author(s) -
Taylor S.J.,
Kilpatrick G.J.
Publication year - 1992
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.1476-5381.1992.tb09036.x
Subject(s) - thioperamide , medicine , hexamethonium , phentolamine , endocrinology , chemistry , contraction (grammar) , histamine , histamine h3 receptor , cholinergic , muscle contraction , receptor , propranolol , atropine , agonist , biology
1 In the presence of atropine, mepyramine and ranitidine, electric field stimulation of the guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus preparation resulted in a two component non‐adrenergic non‐cholinergic contraction. The initial contraction had a duration of approximately 1 s whereas the second contraction lasted approximately 10 s. The second contraction was completely inhibited by tetrodotoxin (0.2 × 10 −6 m ) with minimal effect on the initial contraction. Phentolamine (3 × 10 −6 m ), propranolol (3 × 10 −6 m ) and hexamethonium (10 −4 m ), did not significantly reduce either component of the contractile response. 2 The neurokinin NK 1 receptor antagonists, GR82334 and GR71251, produced concentration‐related (EC 50 = 564 and 173 n m respectively) inhibitions of the second contraction with no effect on the initial contraction. The neurokinin NK 2 receptor antagonists MEN 10207 and Ac‐Leu‐Asp‐Gln‐Trp‐Phe‐Gly‐NH 2 (R 396), 1 × 10 −9 ‐10 −5 m , were without effect on either component of the contractile response. 3 Concentration‐related inhibitions of the second contraction, with no effect on the initial contraction, were observed after inclusion of the histamine H 3 receptor agonists (R)‐α‐methylhistamine (pD 2 = 7.6), N α ‐methylhistamine (pD 2 = 7.7) and N α ,N α ‐dimethylhistamine (pD 2 = 6.3). Histamine also inhibited the second contraction (pD 2 = 6.2) in a concentration‐related manner but produced a lower maximum inhibitory effect than the other agonists tested. 4 Inclusion of the H 3 receptor antagonists, thioperamide, burimamide, impromidine and phenylbutanoylhistamine, caused parallel concentration‐related rightward shifts in the concentration‐response curve to ( R )‐α‐methylhistamine. In each case, Schild analysis of these data gave slopes not significantly different from unity. Antagonist affinity values for thioperamide (pA 2 = 8.2), burimamide (pA 2 = 7.0) and impromidine (pA 2 = 7.0) were consistent with values obtained in other assays of the H 3 receptor. However, phenylbutanoylhistamine (pA 2 = 5.8) and betahistine (p K B ≤ 4) had affinities more than ten fold lower than values obtained in other assays of the H 3 receptor. 5 Exposure of the tissues to N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (10 −6 m ) for 7–30 min followed by extensive washing, had no effect on basal contractions, but produced a rightward shift in the concentration‐response curves to ( R )‐α‐methylhistamine, N α ‐methylhistamine, N α ,N α ‐dimethylhistamine and histamine. This treatment also resulted in a decrease in the maximum inhibitory response obtainable. Apparent agonist affinity (p K D ) values of 7.01, 7.06, 6.09 and 6.13 were estimated for (R)‐α‐methylhistamine, N α ‐methylhistamine, N α ,N α ‐dimethylhistamine and histamine respectively. 6 In conclusion, pharmacological analysis has revealed that histamine H 3 receptors in the guinea‐pig ileum modulate the release of non‐adrenergic non‐cholinergic neurotransmitters, one of which is probably substance P. In addition we have identified N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline as an irreversible antagonist at H 3 receptors and have used this compound to estimate apparent affinity values of agonists at H 3 receptors in this preparation.