Muscarinic Cholinergic, but Not Serotoninergic Mediation of Arginine Vasopressin Response to Metoclopramide in Man

SUMMARY Y The possibility that metoclopramide (MCP) stimulates arginine vasopressin (AVP) secretion in man through a serotoninergic and/or a cholinergic muscarinic pathway was studied. Twenty normal male subjects were tested with MCP (10 mg in an i. v. bolus) alone or in the presence of the 5HT1 serotoninergic antagonist metergoline (10 mg/day p. o. in five divided doses for 4 days), the 5HT2 receptor blocker ketanserin (10 mg i. v. 5 min before MCP) (n= 10), the M1 and M2 muscarinic antagonist atropine (1.2 mg i. v. just before MCP administration) or the M1 muscarinic receptor blocker pirenzepine (40 mg i. v. 10 min before MCP) (n= 10). AVP doubled in response to MCP. The MCP‐induced AVP rise did not change after metergoline, ketanserin or pirenzepine administration, whereas it was abolished by atropine. Additional experiments were performed in order to evaluate the effect of 1.2 mg atropine, given alone, on circulating AVP levels and whether the effect of atropine on the AVP response to MCP depends on the amount of the muscarinic antagonist (dose—response study). For these purposes, atropine was given alone to the same subjects previously tested with MCP plus atropine; furthermore, eight additional male subjects were tested with MCP plus atropine given in doses ranging from 0.8 to 1–4 mg. The results of these additional studies failed to show an effect of atropine alone on AVP secretion and demonstrated a dose‐related inhibition of MCP‐induced AVP rise by increasing atropine administration from 0.8 mg to 1.2 mg. The results of the present study did not show an involvement of 5HT1 and 5HT2 serotoninergic receptors in the AVP response to MCP. On the other hand, the data indicated that atropine‐sensitive muscarinic receptors mediate the AVP response to MCP. Since atropine, but not pirenzepine, crosses the blood‐brain barrier (BBB), the present results might indicate that the AVP releasing effect of MCP is mediated by M2 receptors at places located inside and/or outside the BBB or by M1 receptors in structures located inside the BBB.