Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP-dependent protein kinase I

1 Guanosine 3', 5'-cyclic monophosphate (cyclic GMP)-dependent kinase I (cGKI) is a major receptor for cyclic GMP in a variety of cells. Mice lacking cGKI exhibit multiple phenotypes, including severe defects in smooth muscle function. We have investigated the NO/cGMP and vasoactive intestinal polypeptide (VIP)/adenosine 3', 5'-cyclic monophosphate (cyclic AMP)signalling pathways in the gastric fundus of wild type and cGKI-deficient mice. 2 Using immunohistochemistry, similar staining patterns for NO-synthase, cyclic GMP- and VIP-immunoreactivities were found in wild type and cGKI-deficient mice. 3 In isolated, endothelin-1 (3 nM-3 mu M)-contracted, muscle strips from wild type mice, electrical field stimulation (1-16 Hz) caused a biphasic relaxation, one initial rapid, followed by a more slowly developing phase. In preparations from cGKI-deficient mice only the slowly developing relaxation was observed. 4 The responses to the NO donor, SIN-1 (10 nM-100 mu M), and to 8-Br-cyclic GMP (10 nM-100 mu M) were markedly impaired in strips from cGKI-deficient mice, whereas the responses to VIP (0.1 nM-1 mu M) and forskolin (0.1 nM-1 mu M) were similar to those in wild type mice. 5 These results suggest that cGKI plays a central role in the NO/cGMP signalling cascade producing relaxation of mouse gastric fundus smooth muscle. Relaxant agents acting via the cyclic AMP-pathway can exert their effects independently of cGKI.