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Cyclic Guanosine Monophosphate and the Dependent Protein Kinase Regulate Lymphatic Contractility in Rat Thoracic Duct

Cyclic Guanosine Monophosphate and the Dependent Protein Kinase Regulate Lymphatic Contractility in Rat Thoracic Duct

Olga Yu Gasheva, Anatoliy A Gashev, David C Zawieja

J Physiol. 2013 Sep 15;591(18):4549-65.

PMID: 23836689

Abstract:

We have previously demonstrated a principal role for nitric oxide (NO) in the endothelium/shear-dependent regulation of contractility in rat thoracic duct (TD). In this study we tested the hypothesis that cyclic guanosine monophosphate (cGMP) and the dependent protein kinase (PKG) are central to the intrinsic and extrinsic flow-dependent modulation of lymphatic contractility. Lymphatic diameters and indices of pumping in isolated, cannulated and pressurized segments of rat TD were measured. The influences of increased transmural pressure (1-5 cmH2O) and imposed flow (1-5 cm H2O transaxial pressure gradients) on lymphatic function were studied before and after: (1) inhibition of guanylate cyclase (GC) with and without a NO donor; (2) application of stable cGMP analogue; and (3) inhibition of the cGMP activation of PKG. Additionally, Western blotting and immunofluorescent tissue staining were used to analyse the PKG isoforms expressed in TD. We found that the GC inhibitor ODQ induced changes in TD contractility similar to NO synthase blockade and prevented the relaxation induced by the NO donor S-nitroso-N-acetylpenicillamine. The cGMP analogue, 8-(4-Chlorophenylthio)-guanosine 3,5-cyclic monophosphate sodium salt (8pCPTcGMP), mimicked the extrinsic flow-induced relaxation in a dose-dependent manner, whereas treatment with the cGMP/PKG inhibitor, guanosine 3,5-cyclic monophosphorothioate, 8-(4-chlorophenylthio)-, Rp-isomer, triethylammonium salt (Rp-8-Br-PETcGMPS), eliminated intrinsic flow-dependent relaxation, and largely inhibited extrinsic flow-dependent relaxation. Western blotting demonstrated that both PKG-Iα and -Iβ isoforms are found in TD, with ∼10 times greater expression of the PKG-Iα protein in TD compared with the aorta and vena cava. The PKG-Iβ isoform expressed equally in TD and vena cava, both being ∼2 times higher than that in the aorta. Immunofluorescent labelling of PKG-Iα protein in the wall of rat thoracic duct confirmed its localization inside TD muscle cells. These findings demonstrate that cGMP is critical to the flow-dependent regulation of TD contractility; they also indicate an important involvement of PKG, especially PKG-Iα in these processes and identifies PKG protein as a potential therapeutic target.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP51239260	8-(4-Chlorophenylthio)-guanosine 3′,5′-cyclic monophosphate sodium salt		51239-26-0	Price
IAR42417562	Guanosine-3ʹ-5ʹ-cyclic Monophosphate, 8-(4-Chlorophenylthio)-, Triethylammonium Salt			Price

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