There are exceptions to the paradigm that reductions in smooth muscle tone represent reversal of activation; lowering myoplasmic calcium and inactivation of MLCK and crossbridge dephophorylation. Nitric oxide (NO) is a ubiquitous neuroendocrine, paracrine and autocrine inhibitory signal that is know to relax smooth muscle by lowering the myoplasmic calcium concentration. Urogenital smooth muscles typically have a rich inhibitory innervation which generates NO. This application proposes that NO release induces a calcium-ion and crossbridge independent active component of relaxation which accelerates the inherently slow relaxation characteristic of visceral smooth muscle. The five specific aims are to (1) characterize the calcium ion independent component of relaxation in several urogenital smooth muscle tissues, (2) test the hypothesis that increases in cGMP and activation of protein kinase G in response to NO are temporally regulated and quantitated with the active component of relaxation, (3) test the hypothesis that active relaxation is a mechanism to abolish latch and speed relaxation, (4) test the hypothesis that increases in cGMP are are temporally regulated and quantitatively correlated with changes in phosphorylation of HSP20 that inhibits force generation and (5) test the hypothesis that phosphorylation of HSP20 acts as a thin filament """"""""off switch"""""""" that prevents force generation by blocking the attachment of phosphorylated crossbridges.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK056034-01A2
Application #
6266843
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
2001-02-15
Project End
2004-12-31
Budget Start
2001-02-15
Budget End
2001-12-31
Support Year
1
Fiscal Year
2001
Total Cost
$351,500
Indirect Cost
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Murphy, Richard A; Rembold, Christopher M (2005) The latch-bridge hypothesis of smooth muscle contraction. Can J Physiol Pharmacol 83:857-64
Batts, Timothy W; Walker, John S; Murphy, Richard A et al. (2005) Absence of force suppression in rabbit bladder correlates with low expression of heat shock protein 20. BMC Physiol 5:16
Rembold, Christopher M; Wardle, Robert L; Wingard, Christopher J et al. (2004) Cooperative attachment of cross bridges predicts regulation of smooth muscle force by myosin phosphorylation. Am J Physiol Cell Physiol 287:C594-602
Wingard, C J; Nowocin, J M; Murphy, R A (2001) Cross-bridge regulation by Ca(2+)-dependent phosphorylation in amphibian smooth muscle. Am J Physiol Regul Integr Comp Physiol 281:R1769-77
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