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

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. Using immunohistochemistry, similar staining patterns for NO-synthase, cyclic GMP- and VIP-immunoreactivities were found in wild type and cGKI-deficient mice. In isolated, endothelin-1 (3 nM–3 μM)-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. The responses to the NO donor, SIN-1 (10 nM–100 μM), and to 8-Br-cyclic GMP (10 nM–100 μM) were markedly impaired in strips from cGKI-deficient mice, whereas the responses to VIP (0.1 nM–1 μM) and forskolin (0.1 nM–1 μM) were similar to those in wild type mice. 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. British Journal of Pharmacology (2000) 129, 395–401; doi:10.1038/sj.bjp.0703061