Functional characteristics of urinary tract smooth muscles in mice lacking cGMP protein kinase type I.
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.
Persson
K
K
Department of Clinical Pharmacology, University of Lund, S-221 85 Lund, Sweden.
Pandita
R K
RK
Aszòdi
A
A
Ahmad
M
M
Pfeifer
A
A
Fässler
R
R
Andersson
K E
KE
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000032:analysis / Q000235:genetics*; D004558:Electric Stimulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D014521:Urethra / Q000502:physiology; D001743:Urinary Bladder / Q000502:physiology*
D018679:Cholinergic Agonists; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002217:Carbachol; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP