IN VIVO OBSERVATIONS ON THE NATURE OF ATROPINE TACHYPHYLAXIS EXHIBITED BY INTESTINAL SMOOTH MUSCLE

¹ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan

It has been observed that frequently repeated administrations of atropine produce rapidly diminishing effects on intestinal motility in the dog. An investigation of this phenomenon was undertaken, utilizing balloon recording techniques in trained unanesthetized dogs with intestinal fistulas.

Atropine tachyphylaxis may be demonstrated at any level of the intestinal tract, and the pattern it assumes may be varied by manipulation of doses, routes of administration, and time intervals. Tolerance development is not dependent upon connections with the central nervous system, although extrinsically denervated intestine exhibits greater sensitivity to atropine's depressant effect and/or less capacity for atropine-refractory activity than does normally innervated intestine.

Studies with other drugs which depress intestinal motility indicate that only those drugs possessing "muscarinicblocking" activity are capable of exhibiting tachyphylaxis in the intestine, and potency in the former respect parallels capacity for the latter. Close chemical similarity to atropine is not a prerequisite, but all drugs exhibiting tachyphylaxis shows crossed tolerance with atropine.

Attempts to alter the development of tolerance by administration of higher doses of atropine, atropine hydrolysis products, posterior pituitary, corticotropin, epinephrine, methacholine, or tetraethylammonium were unsuccessful, but some of these agents altered intestinal functioning in other interesting ways.

Cholinergic blockade in the intestine was found to persist long after the inhibitory response to a dose of atropine had terminated. The duration of the tolerant state paralleled the duration of cholinergic blockade, both being dependent on the size of the initial dose. By very gradual administration of the drug, complete resistance to atropine could be achieved, independent of any inhibitory effect on intestinal motility.