| Natriuretic peptides (NPs) are a family of polypeptides possessing natriuretic, diuretic, vasodilative and anti-proliferation actions. In recent years, increasing attention has been paid to their inhibitory effects on heart failure, cardiac hypertrophy and restenosis of transplanted blood vessels in both basic research and clinical application. Natriuretic peptides receptor-A and B (NPR-A, B), which are membrane bound guanylate cyclase coupled to the production of 3', 5' cyclic guanosine monophophate (cGMP), mediate the biological actions of NPs, while natriuretic peptides receptor-C (NPR-C) uncoupled with cGMP acts as a clearance receptor by binding with and internalizing NPs.Vasonatrin peptide (VNP) is a new man-made member of natriuretic peptide family, It is a chimera from atrial natriuretic peptide and C-type natriuretic peptide. Recent studies have demonstrated that VNP is effective in preventing and treating hypoxic pulmonary hypertension and right ventricular hypertrophy, however the mechanism is not well understood. NPR-C plays an important role inMay, 2003the regulation of the activity of NPs. The expression of NPR-C in hypoxic heart remains controversial, and the relationship between VNP and NPR-C is still unknown. During hypoxia, ET-1 is strongly synthesized and released by endothelial cells, vascular smooth muscle cells(VSMCs), cardiac myocytes and cardiac fibroblasts. It induces strong contraction and spasm of coronary artery, and results in myocardial ischemia and even necrosis. ET-1 also promotes proliferation of VSMCs, which induces stenosis of coronary artery and more severe hypoxia. However, it is not clear whether VNP affects hypoxia-stimulated increase of ET-1. Therefore, the purpose of this study is firstly to determine the effect of VNP on the expression of NPR-C and ET-1 in chronic hypoxic rats.The human internal mammary artery (HIMA) acts as the donor for coronary artery bypass grafting. Clinical data demonstrate that the spasm of transplanted blood vessel is an important factor reducing the curative effect of coronary artery bypass grafting. It has been found that VNP has strong relaxing effect on rat aorta and pulmonary artery, but there is little report about its effect on HIMA. So the next project is to investigate the vasorelaxing effect of VNP on HIMA and reveal its underlying mechanism.Methods(1) Hypoxia on the elevation of 5,500m was mimicked with low atmospheric pressure.(2) The mRNA level of NPR-C and ET-1 in right ventricle was?9 ? May, 2003detected by the means of quantitative PCR and in situ hybridization respectively. Radioimmunoassay was used to determine the protein level of ET-1. It was also used to measure the plasma concentration of ANP and the level of cGMP in right ventricle.(3) The vasorelaxing effect of VNP on HIMA with and without endothelium was observed by perfusion in vitro. Effects of 8-Br-cGMP, HS-142-1, the selective inhibitor of NPR-A and B, methylene blue (MB), the selective inhibitor of GC, and tetraethylammonium (TEA), the selective inhibitor of Ca2+-activated K+ channel (Kca), were also investigated.(4) The effect of VNP on Kca in VSMCs from rat mesentery arteries was detected by whole-cell patch clamp technique.Results(1) Hypoxia for 7~28 d significantly increased NPR-C mRNA of right ventricle in a time dependent manner (.P<0.05). VNP (50-75 #g/kg, i.p.) significantly reduced the NPR-C mRNA level in a dose dependent manner (PO.05). The plasma concentration of ANP in hypoxic (28 d) rats was significantly higher than that in normoxic group (P<0.05), and VNP at 75 #g/kg made it more higher (P<0.01).(2) VNP at 75 #g/kg significantly inhibited the increase of ET-1 and its mRNA in hypoxic rat hearts (PO.05). Compared with the corresponding normoxic group, the level of cGMP induced by VNP was slightly increased (P>0.05).?10 ? May, 2003(3) VNP from 10-10 to 10-6 mol/L induced a concentr...
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