cyclic-gmp and Coronary-Artery-Disease

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

The greater incidence of coronary artery disease in men compared to women has often suggested possible harmful effects of male sex steroids that could promote coronary atherogenesis and vasoconstriction. However, antiatherogenic and coronary vasodilator effects of testosterone have also been suggested. The interaction of testosterone (T) with its specific receptors may trigger not only long-term genomic effects, but also acute non-genomic vasodilator responses. Testosterone may activate the endothelium and stimulate the nitric oxide-cGMP and/or the hyperpolarization-mediated vascular relaxation pathway. T may also inhibit the signaling mechanisms of smooth muscle contraction such as [Ca2+]i and protein kinases. The T-induced stimulation of endothelium-dependent mechanisms of vascular relaxation and inhibition of the mechanisms of coronary smooth muscle contraction represent potential beneficial effects of T against coronary artery disease.

Topics: Calcium; Coronary Artery Disease; Cyclic GMP; Endothelial Cells; Female; Humans; Lipoproteins; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Receptors, Androgen; Testosterone

Natriuretic peptides have actions likely to ameliorate cardiac dysfunction. B-type natriuretic peptide (BNP) is indicated as treatment for decompensated cardiac failure.. To determine the utility of BNP in acute myocardial infarction (MI).. Double-blind randomised placebo-controlled trial.. Tertiary hospital coronary care unit.. 28 patients with acute MI with delayed or failed reperfusion and moderate left ventricular dysfunction.. Infusion of BNP or placebo for 60 hours after MI.. Neurohormonal activation and renal function in response to BNP infusion, secondary end points of echocardiographic measures of left ventricular function and dimension.. BNP infusion resulted in a significant rise in BNP (276 pg/l vs 86 pg/l, p = 0.001). NT-proBNP levels were suppressed by BNP infusion (p = 0.002). Atrial natriuretic peptide (ANP) and NT-proANP levels fell with a significant difference in the pattern between BNP infusion and placebo during the first 5 days (p<0.005). C-type natriuretic peptide (CNP) and NT-proCNP levels rose during the infusion with higher levels than placebo at all measurements during the first 3 days (p<0.01). Cyclic guanosine monophosphate (cGMP) was raised during the infusion period showing a peak of 23 pmol/l on day 2 (placebo 8.9 pmol/l, p = 0.002), with a correlation between BNP and cGMP levels (p<0.001). Glomerular filtration rate (GFR) fell with BNP infusion but was not significantly lower than with placebo (71.0 (5.6) vs 75.8 (5.4) ml/min/1.73 m2, p = 0.62). Patients receiving nesiritide exhibited favourable trends in left ventricular remodelling.. Nesiritide, given soon after MI, induced increments in plasma cGMP and CNP and decrements in other endogenous cardiac peptides with a neutral effect on renal function and a trend towards favourable ventricular remodelling.

Topics: Aged; Atrial Natriuretic Factor; Coronary Artery Disease; Cyclic GMP; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography, Doppler, Pulsed; Female; Follow-Up Studies; Humans; Kidney; Male; Middle Aged; Myocardial Infarction; Natriuretic Agents; Natriuretic Peptide, Brain; Peptide Fragments; Receptors, Atrial Natriuretic Factor

Topics: Adult; Aged; Animals; Coronary Artery Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Erythrocytes; Humans; Mice; Middle Aged; Nitric Oxide; Signal Transduction; Soluble Guanylyl Cyclase

Gene expression and protein expression were analyzed with quantitative polymerase chain reaction and immunoblotting, respectively. Putative allele-specific transcription factors were identified with in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed with reporter gene assays. To assess the effect of zinc finger E box-binding homeobox 1 transcription factor (ZEB1), siRNA-mediated knockdown and overexpression experiments were performed. Association of. Whole-blood. Rs7692387 is located in an intronic site that modulates

Topics: Alleles; Blood Platelets; Cell Line; Cell Movement; Coronary Artery Disease; Cyclic GMP; Genetic Loci; Genotype; HEK293 Cells; Homozygote; Humans; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Platelet Aggregation; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; RNA Interference; RNA, Messenger; RNA, Small Interfering; Sildenafil Citrate; Soluble Guanylyl Cyclase; Transcription Factors; Zinc Finger E-box-Binding Homeobox 1

Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the β1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the β1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.

Topics: Adult; Animals; Coronary Artery Disease; Cyclic GMP; Genetic Predisposition to Disease; HEK293 Cells; Humans; Immunoblotting; Immunoprecipitation; Mice; Middle Aged; Mutation, Missense; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Pyrazoles; Pyridines; Radioimmunoassay; Soluble Guanylyl Cyclase; Young Adult

Topics: Biomarkers; Clopidogrel; Coronary Artery Disease; Cyclic GMP; Humans; Nitrates; Nitric Oxide; Nitrites; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prospective Studies; Stents; Ticlopidine; Time Factors; Treatment Outcome; Vasodilation; Wales

Circulating angiogenic cells (CACs), represent a potential new therapeutic tool for the treatment of cardiovascular diseases, but their regenerative function is impaired in patients with coronary artery disease (CAD) and cardiac risk factors. The objective of this study is to assess the effect of lentiviral overexpression of endothelial nitric oxide synthase (eNOS) on the activity of CACs from patients with CAD and cardiac risk factors. In vitro and in vivo assays were employed to evaluate the regenerative capacity of the cells compared to CACs derived from healthy volunteers. Lentiviral eNOS transduction of cells from CAD patients significantly improved chemotactic migration compared with sham transduction, and increased the ability of CACs to induce angiogenic tube formation when cocultured with human umbilical vein endothelial cells (HUVECs) on Matrigel. In addition, eNOS transduction restored the ability of patient-derived CACs to enhance neovascularization and improve ischemic hind limb perfusion, approaching the efficacy of cells from healthy donors. These data indicate that CAC dysfunction seen in high-risk patients can be partially reversed by eNOS overexpression, suggesting that ex vivo gene delivery may improve the efficacy of autologous cell therapy for cardiovascular disease.

Topics: Adult; Animals; Cell Movement; Cells, Cultured; Coronary Artery Disease; Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Extremities; Female; Humans; Ischemia; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type III; Stem Cell Transplantation

The cGMP-dependent protein kinase type I (PKG I) is an essential regulator of cellular function in blood vessels throughout the body. DT-2, a peptidic inhibitor of PKG, has played a central role in determining the molecular mechanisms of vascular control involving PKG and its signaling partners. Here, we report the development of (d)-amino acid DT-2 derivatives, namely the retro-inverso ri-(d)-DT-2 and the all (d)-amino acid analog, (d)-DT-2. Both peptide analogs were potent PKG Ialpha inhibitors with K(i) values of 5.5 nM (ri-(d)-DT-2) and 0.8 nM ((d)-DT-2) as determined using a hyperbolic mixed-type inhibition model. Also, both analogs were proteolytically stable in vivo, showed elevated selectivity, and displayed enhanced membrane translocation properties. Studies on isolated arteries from the resistance vasculature demonstrated that intraluminally perfused (d)-DT-2 significantly inhibited vasodilation induced by 8-Br-cGMP. Furthermore, in vivo application of (d)-DT-2 established a uniform translocation pattern in the resistance vasculature, with exception of the brain. Thus, (d)-DT-2 caused significant increases in mean arterial blood pressure in unrestrained, awake mice. Further, mesenteric arteries isolated from (d)-DT-2 treated animals showed a markedly reduced dilator response to 8-Br-cGMP in vitro. Our results clearly demonstrate that (d)-DT-2 is a superior inhibitor of PKG Ialpha and its application in vivo leads to sustained inhibition of PKG in vascular smooth muscle cells. The discovery of (d)-DT-2 may help our understanding of how blood vessels constrict and dilate and may also aid the development of new strategies and therapeutic agents targeted to the prevention and treatment of vascular disorders such as hypertension, stroke and coronary artery disease.

Topics: Animals; Blood Pressure; Cell Line; Coronary Artery Disease; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Fluoresceins; Hypertension; Male; Mesenteric Arteries; Mice; Models, Biological; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Peptide Fragments; Protein Kinase Inhibitors; Spodoptera; Vasoconstriction; Vasodilation

Endothelial dysfunction plays an important role in the pathogenesis of hypertension. Other risk factors of atherosclerosis also affect its development. The aim of the study was to assess nitric oxide metabolites concentration (nitrites and nitrates No(x)) and endothelin (ET-1) in plasma and cyclic 3,5-guanosine monophosphate (cGMP) in 24 h-urine collection in patients with noncomplicated hypertension without risk factors of atherosclerosis and in hypertensive patients with coronary artery disease (CAD). Sixty-eight subjects were included in the study (44 men, 24 women), aged 47 +/- 76 years, allotted into four groups: I - controls (18 clinically healthy subjects); II - 12 subjects with hypertension without risk factors of atherosclerosis; III - 16 subjects with hypertension and risk factors of atherosclerosis; and IV - 22 subjects with hypertension and CAD. Plasma NO(x) concentration was determined using the Greiss method, plasma ET-1 by ELISA, and urine cGMP using the immunoenzymatic method. Plasma NO(x) concentration was 14.00 +/- 6.88 micromol/L in group I, in group II - 18.62 +/- 5.84 micromol, in group III - 9.96 +/- 4.72 micromol/L, and in group IV - 8.78 +/- 3.72 micromol/L. Statistically significant differences were between groups I and III (p < 0.05) and I and IV (p < 0.04) and groups II and III (p < 0.01) and II and IV (p < 0.01). The concentration of cGMP in 24 h urine collection was in group I - 40 +/- 24 pmol/L; in group II - 54 +/- 41 pmol/L; in group III - 38 +/- 32 pmol/L; and in group IV - 42 +/- 36 pmol/L. There were no significant differences between the groups. Plasma ET-1 concentration was 3.86 +/- 0.52 pg/mL in group I, in group II - 4.05 +/- 0.71 pg/mL, in group III - 4.22 +/- 0.79 pg/mL and in group IV - 4.38 +/- 0.75 pg/mL. Statistically significant differences were between group I and III (p < 0.05), I and IV (p < 0.03), and between group II and IV (p < 0.04). Endothelial dysfunction was not found in hypertensive patients without a family history of cardiovascular diseases and without other risk factors of atherosclerosis. Deterioration of endothelial function was observed in patients with hypertension with risk factors of atherosclerosis. It was most pronounced in those with CAD.

Topics: Aged; Atherosclerosis; Case-Control Studies; Coronary Artery Disease; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Risk Factors; Vasodilation

Chronic exposure to L-arginine results in regression of atherosclerotic lesions and reversal of endothelial dysfunction. We investigated whether chronic L-arginine supplementation induces regression of atherosclerotic lesions and reversal of endothelial dysfunction in atherogenic rhesus monkeys and the mechanism which leads to these effects. About 12 male rhesus monkeys were fed 1% cholesterol and 18 g butter for 6 months to create an experimental model of hypercholesterolaemia and atherosclerosis (Group I) and 12 monkeys were fed standard stock diet for 6 months (Group II). After, 6 months these two groups were further divided into 2 sub-groups which in addition to their respective diets were fed 2.5% L-arginine in drinking water for additional 6 months (Group III and Group IV). Systemic nitric oxide (NO) formation was assessed as plasma nitrite and cGMP formation every 3 months. Oxygen free radical (OFR) generation and malondialdehyde production as an index of lipid peroxidation were determined. Changes in isometric tension were compared in isolated ring segments of thoracic aorta from normal and hypercholesterolemic animals. Cholesterol feeding progressively reduced plasma nitrite and cGMP generation (p < 0.05). Dietary L-arginine partly restored the levels of plasma nitrite and cGMP (p < 0.05) but did not change plasma cholesterol levels. L-arginine significantly reduced aortic intimal thickening, blocked the production of carotid and coronary intimal plaques and completely preserved endothelium-dependent vasodilator function. Further, L-arginine significantly inhibited generation of the reactive oxygen species (ROS) generation and lipid peroxidation. Chronic oral supplementation with L-arginine blocks the progression of plaques via restoration of nitric oxide synthase substrate availability and reduction of vascular oxidative stress.

Topics: Animals; Arginine; Cholesterol, Dietary; Coronary Artery Disease; Cyclic GMP; Diet, Atherogenic; Endothelium, Vascular; Hypercholesterolemia; Lipid Peroxidation; Macaca mulatta; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Superoxides

We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV.. Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion.. CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway.

Topics: Amidohydrolases; Arginine; Cardiovascular Diseases; Cells, Cultured; Coronary Angiography; Coronary Artery Disease; Cyclic GMP; Cytomegalovirus Infections; Endothelium, Vascular; Female; Heart Transplantation; Humans; Male; Middle Aged; Nitric Oxide Synthase; Nitrites; Oxidative Stress; Risk Factors; Signal Transduction

Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function.. Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (P<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.. These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.

Topics: Animals; Antioxidants; Ascorbic Acid; Bradykinin; Calcimycin; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Diet, Atherogenic; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Hypercholesterolemia; Hypertension, Renovascular; Lipids; Nitric Oxide; Nitroprusside; Oxidative Stress; Renal Artery Obstruction; Renin; Substance P; Swine; Vasodilator Agents; Vitamin E

Although sarpogrelate HCl is widely used for the prevention of arterial thrombosis, its effect on atherosclerosis is unknown. Accordingly, we here investigated the effects of sarpogrelate HCl on a rabbit model of atherosclerosis. Male rabbits were fed a 0.5% cholesterol diet (HCD) (Gp 1), HCD with vitamin E (Gp 2), HCD with vitamin E and sarpogrelate (Gp 3), or HCD with sarpogrelate alone (Gp 4) for 8 weeks. The atherosclerotic area was decreased by feeding of vitamin E and sarpogrelate (16.9+/-2.0% in Gp 1 vs. 8.2+/-2.0% in Gp 3). Tone-related basal NO release was higher in Gps 3 and 4. Acetylcholine-induced relaxation tended to be improved in Gp 3. The amount of eNOS mRNA was increased in Gp 4, and aortic cyclic GMP concentration showed the same tendency. O(2)(-) release tended to be decreased in Gps 2 and 3. The matrix metalloproteinase-1 (MMP-1)-positive area was decreased, and the percentage ratio of cell numbers of smooth muscle cells/macrophages in the plaque was increased in Gp 3. The results demonstrated that sarpogrelate HCl retards the progression of atherosclerosis in rabbits, and that this effect is enhanced by concomitant administration of vitamin E. Although upregulation of eNOS may play a role as one of the underlying mechanisms, our results suggest that an additional mechanism-possibly involving the antiproliferative effects of sarpogrelate HCl on smooth muscle cells and macrophages-may also play an important role.

Topics: Acetylcholine; Animals; Antioxidants; Aorta, Thoracic; Biomarkers; Blood Proteins; Cholesterol, HDL; Coronary Artery Disease; Cyclic GMP; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypercholesterolemia; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Models, Cardiovascular; Myocardial Contraction; Myocytes, Smooth Muscle; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rabbits; RNA, Messenger; Serotonin Antagonists; Succinates; Treatment Outcome; Vasodilator Agents; Vitamin E

N(omega)-nitro-L-arginine methyl ester (l-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects of l-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice).. Wild-type and eNOS-KO mice received l-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with l-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with l-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation of L-arginine. Vascular NO and cGMP levels were not significantly reduced by l-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with l-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin II type 1 receptor antagonist) along with the suppression of vascular lesion formation.. These results provide the first direct evidence that the long-term vascular effects of l-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects of l-NAME in vivo.

Topics: Acridines; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Disease Progression; Luminescent Measurements; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidation-Reduction; Peptidyl-Dipeptidase A; Time

We examined the implications of iNOS in atherosclerosis progression using the selective inducible NO synthase (iNOS) inhibitor N:-iminoethyl-L-lysine (L-NIL) in hypercholesterolemic rabbits.. Nine rabbits were fed a 0.3% cholesterol diet for 24 weeks (Baseline group); 25 animals were maintained on the diet and treated for 12 extra weeks with L-NIL (5 mg x kg(-1) x d(-1), L-NIL group, n=8), vehicle (Saline group, n=9), or L-arginine (2.25%, L-Arg group, n=8). In abdominal aortas of Saline rabbits, the lesions (53.7+/-5.7%, Baseline) increased to 75.0+/-5.0% (P:<0.05) but remained unaltered in the L-NIL group (63. 4+/-6.6%). Similar results were obtained for the intima/media ratio in thoracic aortas. In coronary arteries, the intima/media ratio was comparable in Baseline (0.68+/-0.18) and Saline (0.96+/-0.19) rabbits but decreased to 0.34+/-0.19 (P:<0.05) in L-NIL rabbits. L-Arginine had beneficial effects only in abdominal aortas. An increased thoracic aorta collagen content was found in Saline and L-Arg but not in L-NIL rabbits. In thoracic aortas of the Saline group, acetylcholine caused modest relaxations that slightly increased by L-arginine but not by L-NIL. Relaxations to nitroglycerin were ameliorated by L-NIL.. This is the first study showing that chronic treatment with an iNOS inhibitor, L-NIL, limits progression of preexisting atherosclerosis in hypercholesterolemic rabbits. Increased intimal collagen accumulation may participate in iNOS-induced atherosclerosis progression.

Topics: Animals; Aorta, Thoracic; Arginine; Blood Cell Count; Cholesterol, Dietary; Collagen; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Enzyme Inhibitors; Hemodynamics; Hypercholesterolemia; Immunohistochemistry; Lysine; Macrophages; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rabbits; T-Lymphocytes

The increased severity of the myocardial injury produced by coronary occlusion-reperfusion in models of atherosclerosis is associated with an increase in leukocyte accumulation in the ischemic myocardium. Expression of P-selectin, an adhesion molecule involved in the interaction between leukocytes and endothelium, is increased in atherosclerotic vessels. Long-term angiotensin-converting enzyme (ACE) inhibition has been shown to reduce atherosclerotic vascular change in experimental models.. We examined changes in the size of the infarct resulting from coronary occlusion/reperfusion in normally fed and cholesterol-fed rabbits that were chronically treated with quinapril. Infarct size was significantly larger in the cholesterol-fed versus normally fed rabbits. ACE activity in the ischemic and nonischemic myocardium was significantly reduced by quinapril. Chronic quinapril administration significantly ameliorated the increased myocardial injury in cholesterol-fed rabbits. Quinapril administration markedly increased the myocardial cGMP content and reduced the myeloperoxidase activity in the border region of the ischemic myocardium in cholesterol-fed rabbits. The enhanced expression of P-selectin in myocardial tissue of cholesterol-fed rabbits was also effectively reduced by quinapril treatment. The above effects of quinapril were eliminated by blockade of bradykinin B2 receptors or inhibition of nitric oxide synthesis.. Chronic quinapril treatment ameliorated the severity of myocardial injury produced by coronary occlusion/reperfusion in cholesterol-fed rabbits, possibly because of reversal of the enhanced interaction between leukocytes and endothelium in the ischemic myocardium via a bradykinin-related pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arterial Occlusive Diseases; Coronary Artery Disease; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Hemodynamics; Isoquinolines; Leukocytes; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; P-Selectin; Peroxidase; Quinapril; Rabbits; Receptor, Bradykinin B2; Receptors, Bradykinin; Tetrahydroisoquinolines; Ventricular Fibrillation