Uncoupling protein-1: involvement in a novel pathway for beta-adrenergic, cAMP-mediated intestinal relaxation.

The pathway for adrenergic relaxation of smooth muscle is not fully understood. As mitochondrial uncoupling protein-1 (UCP1) expression has been reported in cells within the longitudinal smooth muscle layer of organs exhibiting peristalsis, we examined whether the absence of UCP1 affects adrenergic responsiveness. Intestinal (ileal) segments were obtained from UCP1-ablated mice and from wild-type mice (C57Bl/6, 129/SvPas, and outbred NMRI). In UCP1-containing mice, isoprenaline totally inhibited contractions induced by electrical field stimulation, but in intestine from UCP1-ablated mice, a significant residual contraction remained even at a high isoprenaline concentration; the segments were threefold less sensitive to isoprenaline. Also, when contraction was induced by carbachol, there was a residual isoprenaline-insensitive contraction. Similar results were obtained with the beta(3)-selective agonist CL-316,243 and with the adenylyl cyclase stimulator forskolin. Thus the UCP1 reported to be expressed in the longitudinal muscle layer of the mouse intestine is apparently functional, and UCP1, presumably through uncoupling, may be involved in a novel pathway leading from increased cAMP levels to relaxation in organs exhibiting peristalsis.