The effects of aging on inhibitory neuropeptide concentrations and intrinsic inhibitory innervation of circular muscle were investigated using normal descending colon obtained at surgery. Immunoreactive vasoactive intestinal peptide, peptide histidine-methionine, met5-enkephalin, neuropeptide Y, and somatostatin were extracted from specimens of muscularis externa (patient ages: 19-84 years) and measured by radioimmunoassay. Intracellular electrical activity was recorded from strips of circular muscle (patients ages: 49-84 years) using glass microelectrodes; inhibitory junction potentials were evoked by electrical field stimulation. There were no significant differences (t tests: P greater than 0.05) between neuropeptide concentrations in patients less than 70 years old (N = 28) compared to patients greater than or equal to 70 years old (N = 12). However, the amplitude of inhibitory junction potentials declined with increasing patient age (r = -0.58, P = 0.02, N = 16), with no change in resting membrane potentials (r = 0.22; P greater than 0.05). The decline in amplitude in women (r = -0.68, P = 0.03, N = 9) preceded the decline in men (r = -0.62, P = 0.10, N = 7). Age-related decline in inhibitory junction potentials could be related to decreased: density of inhibitory nerves, release of inhibitory neurotransmitter, density of binding sites for inhibitory neurotransmitter on smooth muscle, or a combination thereof. Alternatively, this decline might represent a change in interaction of inhibitory neurotransmitter with the smooth muscle membrane, such as a change in coupling of binding site with the potassium channel, decreased number of potassium channels, or altered permeability of the potassium channel.