oxadiazoles and Hypercholesterolemia

Regional differences in the profile and treatment strategies of patients with cardiometabolic diseases have been studied in several different countries. The Cardio-Vascular and metabolic treatments in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry was designed to evaluate patient profiles and medical management of cardiometabolic diseases in routine clinical care settings across Canada. Primary objectives were to (1) evaluate regional variability of patient profiles with cardiometabolic disease(s) and (2) assess treatment differences of patients treated for type 2 diabetes (T2D), hypercholesterolemia (HCh), and hypertension (HTN) across Canada.. CV-CARE is a multi-center, observational, prospective registry that enrolled Canadian patients treated with metformin-extended release (MetER) for T2D, colesevelam (C) for HCh, azilsartan (AZI) for mild-to-moderate essential HTN and azilsartan/chlorthalidone (AZI/CHL) for severe, essential HTN. Patient characteristics and treatments were assessed at baseline.. The registry enrolled 6960 patients, with a total of 4194 patients making up the primary analysis population [MetER (n=995); C (n=1639); AZI (n=1364); AZI/CHL (n=498)]. First-line use of MetER was more common in British Columbia (BC; 45.5%) compared to Ontario (ON; 29.8%), and Quebec (QC; 12.9%). C treatment for HCh was used as monotherapy most readily in BC (68.7%) compared with QC (59.7%) and ON (35.8%). Dual action of low-density lipoprotein cholesterol and hemoglobin A1c reduction was the predominant reason for C add-on therapy (46.8%), with highest usage seen in ON (62.9%). AZI treatment for HTN was most frequently used in BC (43.8%), and AZI/CHL was most commonly used in ON (12.0%). First-line use of AZI was more common in QC (50%) vs. ON (34.9%) and BC (24.1%). The primary reason for switching to AZI and AZI/CHL from prior treatment was lack of efficacy across provinces.. This is the first regional description of the CV-CARE cohort. Significant variations in both baseline profile and treatments were observed which could have an impact on long-term outcomes.

Topics: Aged; Anticholesteremic Agents; Antihypertensive Agents; Benzimidazoles; Canada; Chlorthalidone; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertension; Hypoglycemic Agents; Male; Metformin; Middle Aged; Oxadiazoles

The CV-CARE registry provides RWE in Canadian routine clinical practice.. In a real-world Canadian setting, MetER, C, AZI, AZI/CHL, and TXC show improvement of the cardiometabolic profile of T2D, HCh, and HTN patients.

Topics: Aged; Anticholesteremic Agents; Antihypertensive Agents; Benzimidazoles; Canada; Cardiovascular Diseases; Chlorthalidone; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Female; Humans; Hypercholesterolemia; Hypertension; Hypoglycemic Agents; Male; Metabolic Syndrome; Metformin; Middle Aged; Oxadiazoles; Prospective Studies; Registries; Treatment Outcome

1. The present study evaluated the effect of diabetes, hypercholesterolaemia and their combination on the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to relaxation of rat isolated aortic rings and the potential contribution of oxidant stress to the disturbance of endothelial function. 2. Thoracic aortic rings from control, diabetic, hypercholesterolaemic and diabetic plus hypercholesterolaemic rats were suspended in organ baths for tension recording. Generation of superoxide by the aorta was measured using lucigenin-enhanced chemiluminescence. 3. The maximal response to acetylcholine (ACh) was significantly reduced in diabetic or hypercholesterolaemic rats compared with control rats. In rats with diabetes plus hypercholesterolaemia, both the sensitivity and maximal response to ACh was impaired. In control rats, the response to ACh was abolished by the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) or inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, in rats with diabetes, hypercholesterolaemia or both, relaxation to ACh was resistant to inhibition by L-NNA or ODQ, but abolished by additional inhibition of K(Ca) channels with charybdotoxin plus apamin. 4. The generation of superoxide was not significantly enhanced in aortic rings from either diabetic or hypercholesterolaemic rats, but was significantly increased in aortic rings from rats with diabetes plus hypercholesterolaemia. 5. These results suggest that when diabetes and hypercholesterolaemia impair endothelium-dependent relaxation, due to a diminished contribution from NO, a compensatory contribution of EDHF to endothelium-dependent relaxation of the aorta is revealed. The attenuation of NO-mediated relaxation, at least in the presence of both diabetes and hypercholesterolaemia, is associated with enhanced superoxide generation.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Apamin; Biological Factors; Blood Glucose; Body Weight; Charybdotoxin; Cholesterol; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanylate Cyclase; Hypercholesterolemia; Indomethacin; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Oxadiazoles; Oxidative Stress; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Superoxides; Vasodilation; Vasodilator Agents

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.

Topics: Acetophenones; Allopurinol; Animals; Carbachol; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hypercholesterolemia; In Vitro Techniques; Male; Muscle Relaxation; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Onium Compounds; Oxadiazoles; Penis; Phosphodiesterase Inhibitors; Piperazines; Purines; Quinoxalines; Rabbits; Rotenone; Sildenafil Citrate; Sulfones; Superoxides; Uncoupling Agents; Xanthine Oxidase

Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal smooth muscle response. NO relaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca(2+)) store refilling via the sarco/endoplasmic reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta.. A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The residual relaxation to NO was still less in HC and, in both normal and HC aorta, was abolished by concomitant administration of the SERCA inhibitor cyclopiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxation in either normal or HC aorta. SERCA activity measured by (45)Ca(2+) uptake was markedly decreased in HC, although SERCA2 protein expression did not change significantly.. These data suggest that NO-induced relaxation but not that to SNP is partially mediated by cGMP-independent Ca(2+) uptake into sarco/endoplasmic reticulum and that reduced sarco/endoplasmic reticulum Ca(2+) pump function can account for the impaired response to NO in HC.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Calcium; Calcium-Transporting ATPases; Cells, Cultured; Dose-Response Relationship, Drug; Endothelium, Vascular; Ethylenediamines; Free Radical Scavengers; Hypercholesterolemia; In Vitro Techniques; Indoles; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Organometallic Compounds; Oxadiazoles; Quinoxalines; Rabbits; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Superoxide Dismutase; Thapsigargin; Vasodilation

We studied the effects of CAS1609, a nitric oxide donor, on leukocyte-endothelial interactions during the early stages of hypercholesterolemia in rat mesenteric microcirculation. Rats were randomly divided into four groups: (a) rats fed control diet, (b) rats fed control diet while receiving CAS1609, (c) rats fed a high-cholesterol (HC) diet and given C93-4845 (an inactive control compound), and (d) rats fed an HC diet and given CAS1609. Both HC groups developed significantly elevated plasma cholesterol levels compared with rats fed the control diet. Intravital microscopy of mesenteric venules revealed a significant increase in leukocyte rolling and adherence in the untreated HC rats compared with control rats (P < .01). This was significantly attenuated in the HC rats given CAS1609. The HC rats given C93-4845 also developed aortic endothelial dysfunction (ie, impaired relaxation to acetylcholine or ADP) that was significantly prevented by CAS1609 infusion (P < .02). Immunohistochemical staining of ileum demonstrated significantly enhanced localization of P-selectin and intercellular adhesion molecule-1 (ICAM-1) on venular endothelium in the untreated HC rats compared with control rats (P < .01). However, P-selectin and ICAM-1 expression were significantly attenuated in HC rats given CAS1609 (P < .05 and P < .01, respectively). Thus, hypercholesterolemia induces microvascular dysfunction characterized by loss of endothelium-derived nitric oxide, increased rolling and adherence of leukocytes, and increased expression of P-selectin and ICAM-1. Infusion of CAS1609 significantly attenuated these changes due to hypercholesterolemia. Our data suggest that nitric oxide plays a significant role in the prevention of the early endothelial dysfunction observed in hypercholesterolemia.

Topics: Animals; Cell Adhesion; Cholesterol, Dietary; Endothelium, Vascular; Hypercholesterolemia; Ileum; Intercellular Adhesion Molecule-1; Leukocytes; Male; Microcirculation; Nitric Oxide; Oxadiazoles; P-Selectin; Rats; Rats, Sprague-Dawley; Vasodilator Agents