Abstract
This study determined how closely the contractile physiology of the pig gastroesophageal junction follows the human. We obtained human tissue from organ transplant donors and pig tissue from a slaughterhouse. Total, M-2 and M-3 receptor density was determined by subtype specific immunoprecipitation. Total and M-2 are higher in pig than human. M-3 receptors are 2 fold higher in human than pig sling and over 2 fold lower in human than pig clasp fibers. The methoctramine and darifenacin potency to inhibit bethanechol contractions, calculated by classic Schild analysis, indicates that both M-2 and M-3 receptors cause contraction which violates the assumption of one receptor causing the effect. An analysis method relating dual occupation of M-2 andM-3 receptors to the contractile response was developed based on the published Ka values of M-2 and M-3 receptors for bethanechol of 170 μM and 110 μM respectively, and mass-action binding which, at equilibrium, gives receptor occupation = [A][R] / ([A] + Ka), where [A] denotes the agonist concentration, [R] is the receptor concentration and Ka is the agonist dissociation constant (reciprocal of affinity). Three dimensional plots for M-2 and M-3 occupation and contractile response are shown in the figure. Although the M-3 receptor subtype density is different between human and pig, the physiology of the contractile response is similar. This indicates that the pig may be a good model for human gastroesophageal junction physiology. Muscarinic receptor density (fMol/mg solubile protein)
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