cyclic-gmp and Coronary-Restenosis

Endogenous nitric oxide (NO), and possibly NO-releasing drugs, can both inhibit and promote vascular proliferative disorders, such as atherosclerosis and restenosis. The cell types and signaling pathways that mediate these opposing effects are controversial. It is widely assumed that the NO-mediated synthesis of the second messenger cGMP and the activation of cGMP-dependent protein kinase type I (cGKI) inhibits the proliferation of vascular smooth muscle cells and, thus, vascular remodeling. However, recent data from transgenic mouse models challenge this view. Here, we propose that cGMP signaling through cGKI might promote vasculoproliferative processes and their clinical complications. This new concept has important implications for the use of cGMP-elevating drugs in humans and might help to identify novel therapeutic strategies for vascular proliferative diseases.

Topics: Animals; Coronary Artery Disease; Coronary Restenosis; Cyclic GMP; Humans; Intracellular Signaling Peptides and Proteins; Mice; Muscle, Smooth, Vascular; Nitric Oxide

Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the pathogenesis of atherosclerosis and restenosis. This study investigated piperazinedione derived compound TW-01-mediated inhibitory effects on VSMC proliferation and intimal hyperplasia.. Cell proliferation was determined using [(3)H]-thymidine incorporation and MTT assay; cell cycle distribution was measured using flow cytometry; proteins and mRNA expression were determined using western blotting and RT-PCR analyses; DNA binding activity of nuclear factor-κB (NF-κB), as measured using enzyme-linked immunosorbent assays (ELISA); in vivo effects of TW-01 were determined using balloon angioplasty in the rat.. TW-01 significantly inhibited cell proliferation. At the concentrations used, no cytotoxic effects were observed. Three predominant signaling pathways were inhibited by TW-01: (a) extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) activation and its downstream effectors of c-fos, c-jun, and c-myc; (b) DNA binding activity of nuclear factor-κB (NF-κB); and, (c) Akt/protein kinase B (PKB) and cell cycle progression. Furthermore, TW-01 also inhibited Ras activation, a shared upstream event of each of these signaling cascades. In vascular injury studies, oral administration of TW-01 significantly suppressed intimal hyperplasia induced by balloon angioplasty.. The present study suggests that TW-01 might be a potential candidate for atherosclerosis treatment.

Topics: Angioplasty, Balloon; Animals; Carotid Artery, Common; Cell Proliferation; Cell Survival; Cells, Cultured; Coronary Restenosis; Cyclic AMP; Cyclic GMP; Diketopiperazines; Human Umbilical Vein Endothelial Cells; Humans; Hyperplasia; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Smooth Muscle; NF-kappa B; Pyridines; ras Proteins; Rats, Wistar; Tunica Intima

To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA).. Porcine coronary arteries were treated with PTCA and immediately afterwards locally treated for 5 minutes, with a selective cytosolic guanylate cyclase inhibitor, 1 H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ) + SIN-1 or only SIN-1 using a drug delivery-balloon. Arteries were angiographically depicted, morphologically evaluated and analyzed after one and eight weeks for actin, myosin and intermediate filaments (IF) and nitric oxide synthase (NOS) contents.. Luminal diameter after PCI in arteries treated with SIN-1 alone and corrected for age-growth was significantly larger as compared to ODQ + SIN-1 or to controls (p < 0.01). IF/actin ratio after one week in SIN-1 treated segments was not different compared to untreated segments, but was significantly reduced compared to ODQ + SIN-1 treated vessels (p < 0.05). Expression of endothelial NADPH diaphorase activity was significantly lower in untreated segments and in SIN-1 treated segments compared to controls and SIN-1 + ODQ treated arteries (p < 0.01). Restenosis index (p < 0.01) and intimal hyperplasia (p < 0.01) were significantly reduced while the residual lumen was increased (p < 0.01) in SIN-1 segments compared to controls and ODQ + SIN-1 treated vessels.. After PTCA local delivery of high concentrations of the NO donor SIN-1 for 5 minutes inhibited injury induced neointimal hyperplasia. This favorable effect was abolished by inhibition of guanylyl cyclase indicating mediation of a cyclic guanosine 3',5'-monophosphate (cGMP)-dependent pathway. The momentary events at the time of injury play crucial role in the ensuring development of intimal hyperplasia.

Topics: Actins; Analysis of Variance; Angioplasty, Balloon, Coronary; Animals; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Cyclic GMP; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Guanylate Cyclase; Hyperplasia; Intermediate Filaments; Molsidomine; Myosins; NAD(P)H Dehydrogenase (Quinone); NADP; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxadiazoles; Quinoxalines; Signal Transduction; Sus scrofa; Time Factors; Tunica Intima

A single and local administration of L-arginine after balloon angioplasty enhances nitric oxide (NO) generation and inhibits lesion formation in animals.. The present study assessed the effect of increasing NO to inhibit restenosis after percutaneous transluminal coronary angioplasty (PTCA) in humans by local and systemic administration of L-arginine, a precursor of NO in humans.. L-arginine was administered to 34 consecutive patients with angina pectoris or old myocardial infarction via a cardiac catheter (500 mg/4 min) before PTCA, and via a peripheral vein (30 g/4 hr, for 5 days) after PTCA. Patients were treated between December 1998 and December 2000. Plasma concentrations of L-arginine, NO (as nitrite + nitrate) and cyclic guanosine monophosphate (cGMP) were measured before and after L-arginine administration. The control group consisted of 90 patients who underwent PTCA successfully without L-arginine administration in the period between July 1996 and November 1998. Baseline clinical and angiographic characteristics were compared between the two groups. All patients were followed by coronary angiography for 3 months after PTCA. Quantitative coronary angiography and restenosis rate were studied.. Baseline clinical and angiographic characteristics were not different between the two study groups. Despite a significant elevation in plasma L-arginine concentration after L-arginine administration, NO and cGMP did not increase significantly. After PTCA, the difference in restenosis rates between L-arginine and control subjects (34% vs 44%) was not significantly different.. Short-term administration of high dose L-arginine did not significantly change the restenosis rate after PTCA.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Arginine; Coronary Restenosis; Cyclic GMP; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Myocardial Infarction; Nitric Oxide