Metoclopramide causes airway smooth muscle relaxation through inhibition of muscarinic M3 receptor in the rat trachea.

UNLABELLED

Although metoclopramide, often used as an antiemetic, is reported to have an anticholinesterase action, the effect on airway smooth muscle remains unclear. We investigated the effect of metoclopramide on the contraction, phosphatidylinositol response, and binding affinity of muscarinic M(3) receptors in rat trachea preparations. Male Wistar rats were anesthetized and their tracheas excised and chopped into 3-mm-wide rings, 1-mm-wide slices, or frozen 10- microm-thick sections. Contraction was induced with 0.55 microM carbachol (CCh) and, 30 min later, metoclopramide (10 microM to 1 mM) was added. The slices were incubated with (3)[H]myo-inositol, 0.55 microM CCh, and metoclopramide, and the formation of (3)[H] inositol monophosphate was measured. A radioligand binding study was conducted to examine the effects of metoclopramide using [(3)H] 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), a muscarinic M(3) receptor antagonist, in sections of the trachea. Metoclopramide concentration dependently attenuated CCh-induced contraction and inositol monophosphate accumulation, and also attenuated the binding affinity of 4-DAMP to muscarinic M(3) receptors. The 50% inhibitory concentration of metoclopramide against the binding affinity of 4-DAMP to muscarinic M(3) receptors of rat trachea was 24 micro M. These findings suggest that the attenuation by metoclopramide of CCh-induced contraction and phosphatidylinositol response may be mediated through the muscarinic M(3) receptors.

IMPLICATIONS

We investigated the effect of metoclopramide on the contraction, phosphatidylinositol response, and binding affinity of muscarinic M(3) receptors in rat trachea preparations. Our findings suggest that the attenuation by metoclopramide of carbachol-induced contraction and phosphatidylinositol response may be mediated through the muscarinic M(3) receptors.