Changes in motor activity are a basic response to filling of smooth muscle organs. Responses to gastric filling, for example, are thought to be regulated by neural reflexes. Here, we demonstrate a previously uncharacterized aspect of stretch-dependent responses in visceral smooth muscles that is mediated by mechanosensitive interstitial cells of Cajal. Length ramps were applied to the murine antral muscles while recording intracellular electrical activity and isometric force. Stretching muscles by an average of 27 +/- 1% of resting length resulted in 5 mN of force. Increasing length caused membrane depolarization and increased slow-wave frequency. The responses were dependent on the rate of stretch. Stretch-dependent responses were not inhibited by neuronal antagonists or nifedipine. Increases in slow-wave frequency, but not membrane depolarization, were inhibited by reducing external Ca(2+) (100 microM) and by Ni(2+) (250 microM). Responses to stretch were inhibited by indomethacin (1 microM) and were absent in cyclooxygenase II-deficient mice, suggesting that cyclooxygenase II-derived eicosanoids may mediate these responses. Dual microelectrode impalements of muscle cells within the corpus and antrum showed that stretch-induced changes in slow-wave frequency uncoupled proximal-to-distal propagation of slow waves. This uncoupling could interfere with gastric peristalsis and impede gastric emptying. Stretch of antral muscles of W/W(V) mice, which lack intramuscular interstitial cells of Cajal, did not affect membrane depolarization or slow-wave frequency. These data demonstrate a previously uncharacterized nonneural stretch reflex in gastric muscles and provide physiological evidence demonstrating a mechanosensitive role for interstitial cells of Cajal in smooth muscle tissues.