A method for the study of mechanisms of drug disposition in smooth muscle

Abstract

Observations on rates of dissipation of responses to various agonists, protection of receptors by residual agonist after washout, and effects of enzyme inhibitors on these processes established that relaxation of rabbit aortic strips is controlled by the concentration of agonist remaining in the environment of tissue receptors. Thus, the rate of relaxation is a valid index of overall drug inactivation. This index of drug disposition was combined with a procedure of oil immersion, which traps a fixed amount of drug in an extracellular compartment only slightly larger than the interstitial space of the tissue. Oil immersion did not detectably alter the functional capacity of the tissue and effectively separated intrinsic disposition from diffusion into the external medium. Examples are given to show that, in combination with inhibitors of specific pathways of disposition, this preparation provides a simple, quantitative, reproducible method for the study of mechanisms of drug inactivation, with the advantages that it (a) allows the study of responses and disposition in the same preparation, (b) allows analysis of the inactivation of any concentration of agonist which produces a recordable response, (c) equates disposition with termination of action, and (d) specifically follows effective drug in the environment of receptors rather than total drug in the tissue.