After stimulation of the longitudinal smooth muscle of the guinea-pig ileum by an optimal dose (2 x 10(-7) M) of a muscarinic agent, cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide (CD), the muscles failed to regain their normal spontaneous activity for 20 to 30 min. During the recovery period, subsequent contractions induced by either CD or 60 mM KCl were altered, particularly when only short times (15 min or less) were allowed between exposures. 2. Altered responses to CD had depressed phasic but increased tonic tensions and were characteristic of responses induced by lower doses of CD. The altered responsiveness probably represented an early phase of muscle 'densensitization'. 3. In contrast to muscarinic stimulation, the smooth muscles gave identical responses after repeated stimulation by 60 mM KCl, even when only 2 min were allowed between exposures. 4. Whereas K+ levels increased in muscles exposed to 60 mM KCl, they decreased during contractions to CD. The K+ levels remained low until the muscles recovered their normal responsiveness. 5. Increasing the extracellular K+ concentration (5 to 13 mM) hastened the recovery of the muscle responsiveness after CD, whereas lowering external K+ concentration to 1.35 mM or the addition of ouabain (5 x 10(-7) M) delayed the recovery. The results suggested that the Na+, K+-pump is rate-limiting in the recovery of the normal ionic balance of the muscles after stimulation by muscarinic agonists.
