H3-receptor activation inhibits cholinergic stimulation of acid secretion in isolated rabbit fundic glands.
We previously reported evidence for H3-receptor inhibition of cholinergic stimulation of acid secretion by isolated rabbit gastric glands. Because this inhibition was unsensitive to H2 antagonists, we postulated that the parietal cell should bear a H3-receptor. In the present study, we investigated the effects of M1-M3 muscarinic receptors antagonists on carbachol- and thioperamide-induced acid secretion (14CAP uptake) by isolated rabbit gastric glands. Furthermore, we examined whether H3-receptor ligands could affect [3H]-N-methylscopolamine binding to the isolated rabbit parietal cells. Both carbachol and thioperamide concentration-dependently stimulated 14CAP uptake in the glands with maximal responses being achieved for 100 microM and 0.1 microM, respectively. These stimulations were concentration-dependently inhibited by the H3-receptor agonists R(alpha)-methylhistamine and imetit. Maximal inhibitions did not exceed 60% for 1 microM. The muscarinic receptor antagonists, hexa-sila-difenidol p-fluoro analog (M3), pirenzepine (M1) and gallamine (M2) inhibited carbachol-induced 14CAP uptake with IC50 of 50 nM, 10 microM and >> 100 microM, respectively. Thioperamide-induced 14CAP uptake was also inhibited by hexa-sila-difenidol p-fluoro analog and pirenzepine with IC50 of 90 nM and 12 microM, respectively; whereas gallamine had no effect. [3H]-N-methylscopolamine binding to isolated parietal cells was inhibited by atropine and pFHHSiD with IC50 of 15 nM and 132 nM, respectively. Neither R(alpha)-MeHA nor thioperamide did affect this binding although a H3-receptor inhibitory effect was observed on carbachol-induced 14CAP uptake by the cells. These data support that H3-receptor activation inhibits M3-mediated cholinergic stimulation of acid secretion through mechanisms operating downstream to the receptors sites.
Bado
A
A
INSERM Unité 10, I.F.R. Biologie des Cellules Epithéliales, Hôpital Bichat, Paris.
Laigneau
J P
JP
Moizo
L
L
Cherifi
Y
Y
Lewin
M J
MJ
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018680:Cholinergic Antagonists; D005744:Gastric Acid / Q000378:metabolism*; D005748:Gastric Fundus / Q000187:drug effects* / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D019832:N-Methylscopolamine; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D011899:Ranitidine / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism
D018680:Cholinergic Antagonists; D017442:Histamine Agonists; D006633:Histamine Antagonists; D008761:Methylhistamines; D018727:Muscarinic Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C069357:alpha-methylhistamine; D011899:Ranitidine; D002217:Carbachol; C052075:thioperamide; D019832:N-Methylscopolamine