piperidines and Arteriosclerosis

Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia.

Topics: Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus, Type 2; Drugs, Investigational; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thiazolidinediones

Topics: Animals; Apolipoproteins B; Arteriosclerosis; Carrier Proteins; Humans; Hyperlipidemias; Indoles; Isoindoles; Lipoproteins, VLDL; Methaqualone; Piperidines

The incidence of osteoporosis and of cardiovascular disease increases in women after menopause. Although theses diseases can be prevented by estrogen replacement therapy, this treatment is associated with an increased risk of endometrial cancer and perhaps also with an increased risk of breast cancer. Thus, a therapy that could prevent postmenopausal bone loss and lower serum cholesterol concentrations without stimulating reproductive tissues would be desirable. Selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, produce beneficial estrogen-like effects on bone and lipid metabolism, while antagonizing estrogen in reproductive tissue. Both agonist and antagonist activities are mediated via high affinity interaction with the estrogen receptor (ER). Both types of ER (alpha and beta) may be involved in the mechanism by which SERMs produce tissue-selective pharmacology. This review will discuss the roles of ER alpha and ER beta in novel signal transduction pathways.

Topics: Arteriosclerosis; Estrogen Antagonists; Estrogens; Female; Humans; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Receptors, Estrogen

Endothelin-1 (ET-1) and angiotensin II may contribute to endothelial dysfunction, which is associated with increased risk of events in patients with coronary artery disease. The objective was to test whether dual ETA/ETB receptor antagonism improves endothelium-dependent vasodilatation (EDV) in atherosclerotic patients, also on treatment with angiotensin converting enzyme (ACE) inhibitor.. EDV and endothelium-independent vasodilatation were determined in 37 patients with atherosclerosis during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. The patients were then randomized to treatment with ramipril 10 mg o.d. (n=21) or placebo (n=16) for 3 months in a double-blind fashion.. Intra-arterial infusion of the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788 (both 10 nmol min(-1)) increased basal FBF by 42 +/- 4% (P <0.001) and enhanced EDV (P <0.001). Following 3 months ramipril treatment, ET receptor blockade still enhanced EDV. Acetylcholine 10 and 30 mg min(-1) increased FBF by 68 +/- 12 and 64 +/- 12 mL min(-1)/1000 mL before vs. 101 +/- 17 and 101 +/- 16 mL min(-1)/1000 mL following ET receptor blockade in the ramipril group (P <0.001).. Dual ETA/ETB receptor blockade improves endothelial function and exerts direct vasodilator effects in patients with atherosclerosis, also on treatment with ramipril suggesting that ET receptor blockade may have important therapeutic effects when added to ACE inhibition in these patients.

Topics: Acetylcholine; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Biomarkers; Double-Blind Method; Endothelin Receptor Antagonists; Endothelins; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intra-Arterial; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Ramipril; Vasodilation; Vasodilator Agents

Topics: Adult; Aged; Angina Pectoris; Arteriosclerosis; Blood Pressure; Catheterization; Clinical Trials as Topic; Coronary Circulation; Dyspnea; Fatigue; Female; Follow-Up Studies; Heart Rate; Humans; Male; Middle Aged; Myocardium; Nitroglycerin; Oxygen Consumption; Perhexiline; Physical Exertion; Piperidines; Placebos; Vasodilator Agents

Acute rejection (AR) after organ transplantation results in transplant arteriosclerosis (TA). Endothelial progenitor cells (EPCs) are involved in tissue repair and blood vessel formation but are suspected to be a cause of TA.. In this study, we introduced a syngeneic and allogeneic abdominal aortic transplant model with C57BL/6 and BALB/c mice. Syngeneic and allogeneic grafts were histopathologically analyzed after transplantation. Bone marrow-derived EPCs were injected into transplant model animals to observe their distribution and temporal concentration changes. Changes of vascular endothelial growth factor receptor 1 (VEGFR-1), phosphorylated VEGFR-1 (pVEGFR-1), VEGFR-2, pVEGFR-2, protein kinase B (Akt), pAkt, extracellular signal-regulated kinase 1 (Erk1), pErk1 levels in EPCs upon VEGF165 and the VEGFR inhibitor Vandetanib exposure were analyzed in vitro with western blotting.. In the allogeneic transplant group, two weeks after transplantation, formations of new intima layers could be observed, and its proliferation gradually increased to four and six weeks post-transplantation (p < 0.05), accompanied by significant arterial stenoses. Exogenous EPCs mainly localized to the damaged sites of the transplant arteries. In vivo, Vandetanib caused a significant dose dependent decrease of transplant hyperplasia (p < 0.05) and inhibited VEGF related proliferation, migration and adhesion of EPCs.. Vandetanib treatment can reduce arteriosclerosis induced by abdominal aorta transplantation by blocking VEGFRs in EPCs.

Topics: Animals; Aorta; Arteriosclerosis; Bone Marrow Cells; Endothelial Cells; Flow Cytometry; Graft Rejection; Graft Survival; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phosphorylation; Piperidines; Quinazolines; Signal Transduction; Stem Cells; Transplantation, Homologous; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common gamma chain. The rationally designed inhibitor of JAK3, CP-690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP-690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1(a)) or Lewis (RT1(l)) rats were heterotopically transplanted into the infra-renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP-690,550 by osmotic pumps (mean drug exposure of 110 +/- 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 +/- 0.85% vs. 0.43 +/- 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 +/- 2.4% vs. 0.38 +/- 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP-690,550-treated animals also had a significant reduction of donor-specific IgG production and of the gene expression for suppressor of cytokine signaling-3 and with unchanged levels of expression of RANTES, IP-10 and transforming growth factor-beta1. These results are the first to show that JAK3 blockade by CP-690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.

Topics: Animals; Aorta; Arteriosclerosis; Chemokine CCL5; Hyperplasia; Interferon-gamma; Janus Kinase 3; Killer Cells, Natural; Male; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transplantation, Homologous; Tunica Intima

Endothelin (ET)-1 causes vasoconstriction via ET(A) and ET(B) receptors located on vascular smooth muscle cells and vasodilatation via ET(B) receptors on endothelial cells. Studies in vitro indicate an upregulation of ET(B) receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ET(B) receptor antagonist BQ788 evoked a significant increase in FBF (31+/-13%) in the patients, whereas a 20+/-9% reduction was observed in the control subjects. The ET(A) receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102+/-25%) in the patients compared with no effect in the control subjects (-3+/-9%, P<0.001 versus patients). The ET(A) receptor antagonist BQ123 increased FBF to a similar degree in patients (39+/-11%) as in control subjects (41+/-11%). The increase in FBF evoked by selective ET(A) receptor blockade was significantly (P<0.05) less than that evoked by combined ET(A)/ET(B) receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1-mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ET(B)-mediated vasoconstriction.

Topics: Antihypertensive Agents; Arteriosclerosis; Case-Control Studies; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Forearm; Humans; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Up-Regulation; Vasodilation

The cholesteryl ester, foam cell-enriched vulnerable plaque is a principle pharmacological target for reducing athero-thrombosis. Acyl CoA:cholesterol Acyl Transferase (ACAT) catalyzes the esterification of free cholesterol in intestine, liver, adrenal and macrophages, leading in the latter cells to intracellular cholesteryl ester accumulation and foam cell formation in the arterial intima. Previous studies suggested the existence of several isoforms of ACAT with different tissue distribution and this has largely been confirmed by molecular cloning of ACAT-1 and ACAT-2. We developed a series of ACAT inhibitors that preferentially inhibited macrophage ACAT relative to hepatic or intestinal ACAT based on in vitro assays and ex vivo bioavailability studies. Four of these compounds were tested in three models of atherosclerosis at oral doses shown to give sufficient bioavailable monocyte/macrophage ACAT inhibitory activity. In fat-fed C57BL/6 mice, chow fed apo E-/- mice and KHC rabbits, the various ACAT inhibitors had either no effect or increased indices of atherosclerotic foam cell formation. Direct and indirect measurements suggest that the increase in plaque formation may have been related to inhibition of macrophage ACAT possibly leading to cytotoxic effects due to augmented free cholesterol. These results suggest that pharmacological inhibition of macrophage ACAT may not reduce, but actually aggravate, foam cell formation and progression.

Topics: Anilides; Animal Feed; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Cholesterol Esters; Diet, Atherogenic; Dietary Fats; Enzyme Inhibitors; Female; Foam Cells; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microsomes; Microsomes, Liver; Monocytes; Piperidines; Rabbits; Receptors, LDL; Sterol O-Acyltransferase; Tumor Cells, Cultured

Nuclear factor kappaB (NF-kappaB) is a transcriptional factor which may be pivotal in the pathogenesis of atherosclerosis. Endothelin-1 (ET-1) is a peptide with proatherogenic properties. We hypothesized that ET-1 may act through activation of NF-kappaB and degradation of IkappaB-alpha, the cytosolic inhibitor of NF-kappaB activation, to create an atherogenic environment. The human monocytic cell line THP-1 was stimulated with ET-1 +/- the ET antagonist, BQ788 and the proteosome inhibitor, PSI. LPS was used as a positive control. Gel shift assays for NF-kappaB activity and Western blot analysis for IkappaB-alpha were performed. Both LPS and ET-1 led to activation of NF-kappaB in nuclear extracts [3.4 +/- 0.45 (LPS) and 2.9 +/- 0.26 (ET-1) fold increase in Arbitrary Densitometric Units (ADU) compared with negative control (P < 0.005 in both cases)]. In the presence of the ETB antagonist, BQ788, NF-kappaB activation was attenuated and not different from control (1.7 +/- 0.24 fold DU compared with negative control; P = NS). In addition, both LPS and ET-1 mediated NF-kappaB activation were attenuated by preincubation with the proteosome inhibitor, PSI (1.3 +/- 0.58 and 1.1 +/- 0.3 fold increase in ADU compared with negative control respectively). Both LPS and ET-1 led to a decrease in the amount of IkappaB-alpha present in the THP-1 cytoplasmic extracts (2.1 +/- 1.5% and 54 +/- 15.7% of ADU vs negative control (P < 0.05). NF-kappaB is activated by ET-1 in human THP-1 monocytes. This data supports a role for the ETs in the development of inflammation in the vessel wall in atherosclerosis.

Topics: Antihypertensive Agents; Arteriosclerosis; Blotting, Western; Cell Line; Cell Nucleus; Cysteine Endopeptidases; Cytoplasm; Cytosol; DNA-Binding Proteins; Endothelin-1; Humans; I-kappa B Proteins; Inflammation; Macrophages; Monocytes; Multienzyme Complexes; NF-kappa B; NF-KappaB Inhibitor alpha; Oligopeptides; Peptides; Piperidines; Proteasome Endopeptidase Complex; Protein Binding

The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated.. For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required.. Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Estrogen Antagonists; Female; Organ Size; Ovariectomy; Piperidines; Rabbits; Raloxifene Hydrochloride; Uterus; Weight Gain

Vasoconstrictor responses to serotonin and norepinephrine were examined in: normal cynomolgus monkeys, atherosclerotic monkeys that were fed atherogenic diet for 3-5 years and hypercholesterolaemic but non-atherosclerotic monkeys that were fed atherogenic diet for 4-5 months. Serotonin decreased total hindlimb resistance in normal and hypercholesterolaemic monkeys, but increased total resistance in atherosclerotic monkeys. There was a greater than 10-fold increase in constrictor responses of large arteries to serotonin in atherosclerotic compared with normal and hypercholesterolaemic monkeys. In contrast, responses to norepinephrine were not increased in atherosclerotic monkeys. Thus, atherosclerosis greatly potentiates constrictor responses to serotonin in large arteries of the limb. This potentiation appears to be somewhat selective for serotonin, as it is not observed with norepinephrine.

Topics: Animals; Arteriosclerosis; Hindlimb; Hypercholesterolemia; Ketanserin; Macaca fascicularis; Methysergide; Piperidines; Serotonin; Vasoconstriction

Serotonin normally constricts most large arteries and, in most vascular beds, dilates the arterioles. In the normal limb, the net result is an increase in blood flow. In two situations potentially relevant to peripheral vascular disease, the constrictor response to serotonin is enhanced and serotonin reduces limb blood flow. Potentiation of constrictor responses to serotonin, reversed by the 5-HT2 blocker ketanserin, occurs both in the arterial collateral circulation after femoral artery ligation and in the femoral artery after intimal damage. The potentiation appears to be specific for serotonin: in neither case is the response to norepinephrine enhanced. The observations in models provide a conceptual basis for preliminary observations, which indicate that ketanserin is effective in reversing symptoms in some patients with peripheral vascular disease.

Topics: Arteriosclerosis; Humans; Ketanserin; Muscle, Smooth, Vascular; Piperidines; Regional Blood Flow; Serotonin; Serotonin Antagonists; Vascular Resistance; Vasodilation; Vasodilator Agents

Topics: Arteriosclerosis; Humans; Infusions, Parenteral; Ketanserin; Piperidines; Regional Blood Flow

A system of animal models potentially useful for the discovery and evaluation of new effective antiatherosclerotic agents is described. The models consist of a series of lipoprotein and atherosclerosis assays in rats, SEA Japanese quail and cynomolgus monkeys. SEA quail are particularly useful for detecting compounds that inhibit arterial cholesterol deposition. The use of this integrated system of models is illustrated with data on clofibrate, adamantyloxyaniline (a hypobetalipoproteinemic agent), and o,p'-DDD. Male SEA quail appear to be a quite satisfactory model for testing the effects of large numbers of compounds on atherosclerosis and are available in limited numbers to all qualified investigators in the field of atherosclerosis research for evaluation in their laboratories.

Topics: Adamantane; Aniline Compounds; Animals; Arteriosclerosis; Clofibrate; Coturnix; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Haplorhini; Humans; Hypolipidemic Agents; Macaca fascicularis; Male; Mitotane; Piperidines; Rats; Terminology as Topic

Topics: Angina Pectoris; Animals; Arteriosclerosis; Disease Models, Animal; Electrocardiography; Heart Rate; Male; Perhexiline; Piperidines; Rabbits

Topics: Adrenergic alpha-Agonists; Adult; Aged; Arteriosclerosis; Benzamides; Blood Pressure; Female; Fingers; Heart Rate; Humans; Hypotension; Indoles; Injections, Intravenous; Intermittent Claudication; Male; Middle Aged; Piperidines; Pulse; Radioisotopes; Raynaud Disease; Regional Blood Flow; Skin; Time Factors; Toes; Xenon

Topics: Adolescent; Adult; Aged; Arteriosclerosis; Coronary Disease; Diuretics; Ethacrynic Acid; Female; Furosemide; Heart Failure; Humans; Liver Cirrhosis; Male; Middle Aged; Piperidines; Pulmonary Heart Disease; Rheumatic Heart Disease; Triamterene

Topics: Adult; Aged; Ambulatory Care; Amides; Antihypertensive Agents; Arteriosclerosis; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Antihypertensive Agents; Arteries; Arteriosclerosis; Blood Pressure; Clopamide; Depression, Chemical; Diuretics; Ergot Alkaloids; Hemodynamics; Humans; Hypertension, Renal; Kidney Diseases; Kidney Function Tests; Middle Aged; Piperidines; Reserpine

Topics: Anticonvulsants; Arteriosclerosis; Blood Flow Velocity; Humans; Hyperemia; Leg; Muscles; Piperidines; Propiophenones; Regional Blood Flow; Thigh; Time Factors

Topics: Analgesia; Arteriosclerosis; Biomedical Research; Double-Blind Method; Drug Therapy; Geriatrics; Humans; Meperidine; Morphine; Myocardial Infarction; Pain; Pharmacology; Piperidines; Transplantation, Homologous

Topics: Animals; Arteriosclerosis; Atherosclerosis; Piperidines; Rabbits

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Antipyretics; Arteriosclerosis; Epinephrine; Piperidines; Rabbits