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Departments of 1 Clinical Pharmacology and 2 Experimental Pathology, University of Lund, S-221 85 Lund, Sweden; and 3 Salk Institute, La Jolla, California 92037
Nitric oxide (NO)-mediated
smooth muscle relaxation is mediated by cGMP through activation of
cGMP-dependent protein kinase I (cGKI). We studied the importance of
cGKI for lower urinary tract function in mice lacking the gene for cGKI
(cGKI
/) and in litter-matched wild-type mice (cGKI+/+) in vitro and
in vivo. cGKI deficiency did not result in any changes in bladder gross morphology or weight. Urethral strips from cGKI/ mice showed an
impaired relaxant response to nerve-derived NO. The cGMP analog 8-bromo-cGMP (8-BrcGMP) and the NO-donor SIN-1 relaxed the wild-type urethra (50-60%) but had only marginal effects in the
cGKI-deficient urethra. Bladder strips from cGKI/ mice
responded normally to electrical field stimulation and to carbachol but
not to 8-BrcGMP. In vivo, the cGKI-deficient mice showed bladder
hyperactivity characterized by decreased intercontraction intervals and
nonvoiding bladder contractions. Loss of cGKI abolishes
NO-cGMP-dependent relaxations of urethral smooth muscle and results in
hyperactive voiding. These data suggest that certain voiding
disturbances may be associated with impaired NO-cGKI signaling.
nitric oxide synthase; transgenic; urethra; bladder; nonadrenergic, noncholinergic
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