cyclic-gmp and Graft-Occlusion--Vascular

Restenosis following endovascular interventions is the main limitation of their long-term success. The incidence of restenosis varies according to the method (stenting, endarterectomy) and the treated vascular region, but the pathomechanism and risk factors are similar. The current article reviews of the author's previous studies in this field. In clinical studies, we compared the restenosis rate after carotid artery stenting and carotid endarterectomy. We also analyzed the complement activation profile after these interventions. In another study, we investigated the role of two polymorphisms of the estrogen receptor alpha in the occurrence of carotid restenosis after either carotid artery stenting or carotid endarterectomy. In an animal model of carotid endarterectomy, we studied the role of the nitrite-oxide-cyclic guanosine monophosphate signaling and the effect of the phosphodiesterase-5 inhibitor therapy in neointimal hyperplasia. Our results suggest that higher incidence of restenosis following carotid endarterectomy can be correlated with the more highly expressed complement activation after this type of carotid intervention. Polymorphisms in the estrogen receptor alpha gene could contribute to the restenosis formation, especially in women. Neointimal hyperplasia can be attenuated by increased cyclic guanosine monophosphate signaling.

Topics: Animals; Carotid Arteries; Complement Activation; Cyclic GMP; Endarterectomy, Carotid; Estrogen Receptor alpha; Female; Graft Occlusion, Vascular; Humans; Hyperplasia; Incidence; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Polymorphism, Genetic; Rats; Retrospective Studies; Signal Transduction; Stents; Tunica Intima; Vascular Patency

Dipyridamole is a potential pharmacological agent to prevent vascular stenosis because of its antiproliferative properties. The mechanisms by which dipyridamole inhibits the growth of vascular smooth muscle cells, especially venous smooth muscle cells, are unclear. In the present study, dipyridamole transiently but significantly increased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in human venous and arterial smooth muscle cells in a time- and dose-dependent manner. Peak concentrations of both cyclic nucleotides were achieved at 15-30 min. and correlated with inhibition of proliferation in both cell types. The antiproliferative effects of dipyridamole observed at 48 hr were similar whether drug exposure was only 15 min. or sustained for 48 hr. Specific competitive inhibitors of protein kinases A and G attenuated the antiproliferative effects of subsaturating concentrations of dipyridamole, with the effects of protein kinase inhibition being particularly pronounced in venous smooth muscle cells. Flow cytometry analysis showed that dipyridamole caused an enrichment of cells in G(0)/G(1) and a corresponding reduction of cells in S phase. These data indicate that a transient increase in cGMP and cAMP is sufficient to induce downstream kinase activation and subsequent cell cycle arrest, and that protein kinase G may be more important than protein kinase A in mediating the growth inhibitory effect of dipyridamole in venous protein kinase.

Topics: Aorta; Cell Cycle; Cell Proliferation; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dipyridamole; Enzyme Inhibitors; Graft Occlusion, Vascular; Humans; L-Lactate Dehydrogenase; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Saphenous Vein; Thionucleotides

Because pathologic mechanisms for transplant vasculopathy are still uncertain, we tested the hypothesis that endothelial function, in terms of the release of endothelium-derived relaxing factor (EDRF), is impaired in patients with evidence of angiographic transplant vasculopathy.. The long-term prognosis after heart transplantation is mainly determined by the development of transplant vasculopathy.. The study included 23 patients undergoing diagnostic cardiac catheterization approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of transplant vasculopathy. Coronary flow velocity (by intravascular Doppler echocardiography) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary bolus injections (1 ml) of the endothelium-dependent dilator substance P (20 pmol) and the endothelium-independent dilators nitroglycerin (0.1 mg) and papaverine (8 mg). Substances were injected through the lumen of the Doppler catheter, which was placed into the midportion of the left anterior descending artery.. Increases in blood flow velocity in response to substance P were significantly less in patients with than in patients without evidence of transplant vasculopathy. In addition, flow-mediated dilation of epicardial coronary arteries in response to papaverine was abolished in patients with such evidence. Vasodilation of epicardial coronary arteries in response to nitroglycerin and increases in flow velocity in response to papaverine were similar in both groups.. These results suggest that transplant vasculopathy in heart transplant patients is associated with endothelial dysfunction (that is, impaired EDRF-mediated vasodilation). Furthermore, responsiveness of epicardial arteries to increased flow appears to be abolished in patients with evidence of transplant vasculopathy. These abnormal vascular functions may contribute to the pathogenesis of transplant vasculopathy and its vascular complications.

Topics: Adult; Analysis of Variance; Blood Flow Velocity; Blood Platelets; Cardiac Catheterization; Coronary Angiography; Coronary Circulation; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; Female; Graft Occlusion, Vascular; Heart Transplantation; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Nitroglycerin; Papaverine; Substance P; Vasodilation

The aim was to examine the capacity of the human saphenous vein (native and surgically prepared) and the internal mammary artery to generate cyclic GMP, the second messenger that mediates smooth muscle relaxation following production of nitric oxide.. 209 vessel segments were used from 22 patients undergoing coronary revascularisation. Isolated vessel segments were stimulated with a range of endothelium dependent and endothelium independent agonists and flash frozen for radioimmunoassay for cyclic GMP.. Control/basal levels of cyclic GMP were significantly higher in the internal mammary artery than either native or distended saphenous vein. Endothelium dependent agonist stimulation with acetylcholine, bradykinin, or substance P induced significant increases in cyclic GMP in internal mammary artery and native saphenous vein, whereas distended veins showed non-significant changes in response to agonist stimulation. Endothelium removal abolished agonist stimulated increases in cyclic GMP. Glyceryl trinitrate and sodium nitroprusside elicited significant further increases in cyclic GMP in native vein and internal mammary artery. All values obtained were significantly greater in arterial than in venous tissue.. Differences in basal and stimulated cyclic GMP activity in arteries and veins have been shown. This could represent an additional protective mechanism against constrictor influences in arterial bypass grafts, which may explain their documented better long term performance.

Topics: Acetylcholine; Bradykinin; Coronary Artery Bypass; Culture Techniques; Cyclic GMP; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Mammary Arteries; Nitroglycerin; Saphenous Vein; Substance P; Vascular Patency