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 n M –3 μ 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. The responses to the NO donor, SIN‐1 (10 n M –100 μ M ), and to 8‐Br‐cyclic GMP (10 n M –100 μ M ) were markedly impaired in strips from cGKI‐deficient mice, whereas the responses to VIP (0.1 n M –1 μ M ) and forskolin (0.1 n M –1 μ M ) 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