Desensitization of the soluble guanylyl cyclase/cGMP pathway by lipopolysaccharide in rat isolated pulmonary artery but not aorta

M S H El-Awady, S V Smirnov, M L Watson

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13 Citations (Scopus)

Abstract

Background and purpose: To investigate the function of soluble guanylyl cyclase (sGC)/3',5'-cyclic guanosine monophosphate (cGMP) pathway in lipopolysaccharide (LPS)-induced changes in vascular reactivity of rat isolated pulmonary artery and aorta. Experimental approach: Nitric oxide (NO) production, contraction responses to endothelin-1 (ET-1), relaxation responses to sodium nitroprusside (SNP), 8-pCPT-cGMP, BAY412272 and T-0156, SNP-induced cGMP production and expression of sGC(alpha 1), sGC(beta 1) and 3',5'-cyclic nucleotide phosphodiesterase-5 (PDE5) proteins were measured in LPS-treated pulmonary and aortic rings from male Wistar rats. Key results: In both vessels, LPS (10 mu g mL(-1), 20 h) increased NO production, which was inhibited by the selective inducible NOS (iNOS) inhibitor 1400W (1 mu M). In the aorta, LPS decreased ET-1-induced contractility and this decrease was inhibited by the selective sGC inhibitor ODQ (10 mu M) but not by removal of endothelium, or inhibitors of cyclooxygenase (indomethacin, 10 mM) or iNOS (1400W, 1 mM). Furthermore, aortic relaxation responses to the direct sGC activator BAY412272 were enhanced. In the pulmonary artery, SNP (1 nM to 30 mu M)-induced relaxation and cGMP production, BAY412272-induced relaxation and sGCb1 protein expression were decreased, whereas relaxation responses to the PDE5-specific inhibitor T-0156 (0.1-100 nM) were enhanced. Relaxation responses to the phosphodiesterase-resistant cGMP analogue, 8-pCPT-cGMP, and protein expression levels of sGCa1 and PDE5 were not altered in either vessel. Conclusion and implications: LPS caused a selective hypocontractility of rat aorta to ET-1 mediated mainly through NO-independent sGC activation, whereas in the pulmonary artery, the effect of sGC activation was reduced by a decreased protein expression of sGCb1 together with increased PDE5 activity.
Original languageEnglish
Pages (from-to)1164-1173
Number of pages10
JournalBritish Journal of Pharmacology
Volume155
Issue number8
DOIs
Publication statusPublished - 2008

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