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- Hedlund, Petter, et al.
(författare)
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Erectile dysfunction in cyclic CMP-dependent kinase I-deficient mice
- 2000
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences; 1999. - 0027-8424 .- 1091-6490. ; 97:5, s. 2349-2354
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Tidskriftsartikel (refereegranskat)abstract
- The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.Penile erection is produced by an increased blood flow to the corpus cavernosum (CC), made possible by opening of penile resistance vessels (helicine arteries), relaxation of the CC cells, and occlusion of the venous outflow (1). The erectile response in several animal models depends on nitric oxide (NO), produced by nerves as well as vascular endothelium (1, 2–4). NO activates soluble guanylate cyclase, which leads to the production of cyclic GMP (cGMP). cGMP signals via three different receptors in eukaryotic cells, including ion channels, phosphodiesterases, and protein kinases (5). At present, however, the molecular targets that are activated by cGMP and finally execute the relaxation of penile smooth muscle are not known. In addition, two different cGMP-dependent protein kinases (cGKI and cGKII) have been identified in mammals (6, 7). cGKII is expressed in the small intestine, brain, and cartilage (8–10), whereas high levels of cGKI are found in vascular and intestinal smooth muscle, platelets, Purkinje cells of the cerebellum, and CC cells (11, 12). Inactivation of cGKI in mice abolished both NO/cGMP-dependent relaxation of vascular and intestinal smooth muscle and inhibition of platelet aggregation, causing hypertension, intestinal dysmotility, and abnormal hemostasis (13). In the present study, we investigated the function of cGKI in erectile tissue and the capability of cGKI-deficient mice to reproduce. Furthermore, we analyzed whether a cross-talk exists between the cGMP and cyclic AMP (cAMP) signaling cascades in smooth muscle (5, 14), i.e., whether cAMP can cause relaxation via cGKI.
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| 3. |
- Ny, L, et al.
(författare)
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Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP-dependent protein kinase I
- 2000
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Ingår i: British Journal of Pharmacology. - : Wiley-Blackwell. - 0007-1188 .- 1476-5381. ; 129:2, s. 395-401
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Tidskriftsartikel (refereegranskat)abstract
- 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 microM)-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 microM), and to 8-Br-cyclic GMP (10 nM - 100 microM) were markedly impaired in strips from cGKI-deficient mice, whereas the responses to VIP (0.1 nM - 1 microM) and forskolin (0.1 nM - 1 microM) 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.
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