1,721,006 research outputs found
The classification of calcium antagonists and their selection in the treatment of hypertension. A reappraisal
No full textCalcium antagonists have become one of the most important advances in the treatment of hypertension since their introduction over 20 years ago. The increase in the number of available calcium antagonists (as new formulations of preexisting drugs or new chemical entities) over recent years has contributed to an ever-changing scenario regarding their appropriate use compared with other antihypertensive agents. As a consequence of this evolving situation, several authors have proposed a 3-generation classification of calcium antagonists currently, or soon to be, marketed in several counties. The classification system is based among other variables, on chemical structure, tissue selectivity, administration frequency and duration of action. In this article, this classification is reviewed and updated on the basis of new information that is available. In addition, factors which influence the selection of calcium antagonists in the treatment of hypertension in specific patient populations are discussed. As well as pharmacodynamic and pharmacokinetic considerations, these factors also include previous experience with particular drugs in specific patient populations, cost of treatment and drug interactions. Among the dihydropyridine calcium antagonists, the first generation compounds have been clearly superseded and are not recommended for use in hypertensive patients. Whilst the second generation agents represent an adequate treatment, third generation calcium antagonists possess distinct advantages. Definitive confirmation of the role of calcium antagonists in hypertension lies in several ongoing large multicentre trials
Endothelial dysfunction, hypertension and atherosclerosis: A review of the effects of lacidipine
No full textLacidipine, a third generation dihydropyridine calcium antagonist, has demonstrated pronounced anti-atherosclerotic activity in preclinical studies. The drug can act at several stages within the atherosclerotic process, utilising its anti-hypertensive and antioxidant properties to protect hypertensive animals against mortality and vascular damage, to reduce cholesterol levels from the vessel wall of hypercholesterolaemic animals, and to reduce the progression of existing atherosclerotic lesions. The clinical benefit of lacidipine in atherosclerosis has recently been confirmed in humans in a large, multicentre, comparative, 4-year clinical trial involving patients with mild to moderate hypertension. The European Lacidipine Study on Atherosclerosis (ELSA) showed that lacidipine was able to slow the progression of atherosclerosis, measured as carotid intimato-media thickness, by 40% compared with atenolol (p = 0.0073). Although further comparative trials are needed, based on the results of ELSA, lacidipine is likely to become a promising therapeutic agent for atherosclerosis
Maintenance of vascular integrity: Role of nitric oxide and other bradykinin mediators
Full text linkIn the blood-vessel wall, the endothelium plays a key functional role by generating several substances that modulate vascular smooth muscle tone, as well as growth, and platelet function. This review focuses on the role of the endothelial L-arginine/nitric oxide signal transduction pathway in the maintenance of vascular integrity. Functional alterations of this pathway may be important in cardiovascular disease, because depressed activity of this protective mechanism leads to impaired relaxation and is also associated with reduced antithrombotic properties of the endothelial layer. Many of the beneficial effects of ACE inhibitor therapy may be mediated through their ability to enhance the physiological roles of nitric oxide
Tetrahydrobiopterin and endothelial nitric oxide synthase activity
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SIRT1, p66Shc, and set7/9 in vascular hyperglycemic memory: Bringing all the strands together
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High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells
No full textBACKGROUND: Hyperglycemia is a primary cause of premature vascular disease. Endothelial cell dysfunction characterized by diminished endothelium-dependent relaxations is likely to be involved. Little is known about the molecular mechanisms of hyperglycemia-induced endothelial dysfunction. METHODS AND RESULTS: This study was designed to determine the effect of hyperglycemia on the L-arginine/nitric oxide (NO) pathway. Expression of endothelial nitric oxide synthase (eNOS) mRNA and production of NO were studied in human aortic endothelial cells exposed to control levels (5.5 mmol/L) and high levels (22.2 mmol/L) of glucose for 5 days. We examined the effect of glucose on NO release by measuring changes in nitrite (NO2-) levels by Griess reaction. Superoxide anion (O2-) production was also examined by the ferrocytochrome c assay. NOS mRNA and protein expression, which were evaluated by reverse transcription-polymerase chain reaction and Western blotting, were approximately twofold greater in endothelial cells exposed to high glucose. Elevated glucose levels increased NO2- production by only 40% but increased the release of O2- by more than threefold. CONCLUSIONS: The present study demonstrates that prolonged exposure to high glucose increases eNOS gene expression, protein expression, and NO release. However, upregulation of eNOS and NO release is associated with a marked concomitant increase of O2- production. These results provide the molecular basis for understanding how chronic exposure to elevated glucose leads to an imbalance between NO and O2-. This may explain impaired endothelial function and be important for diabetic vascular disease
Statins blunt thrombin-induced down-regulation of endothelial nitric oxide synthase expression in human endothelial cells
No full textThrombin plays a pivotal role in the pathophysiology of acute coronary syndromes by mediating thrombus formation and endothelium-dependent vasomotor dysfunction. In human endothelial cells, prolonged incubation with thrombin downregulates endothelial nitric oxide synthase (eNOS) expression via activation of Rho. Statins are effective in patients with acute coronary syndromes. These beneficial effects are attributed to their pleiotropic effects and also to an improved lipid profile. We hypothesized that statins may prevent the down-regulation of eNOS induced by thrombin in human endothelial cells. Human umbilical vein endothelial cells were used. Expression and activity of eNOS protein were evaluated by Western blotting and L-citrulline assay, respectively. Rho A membrane translocation was evaluated by Wesern blotting after fractionation. Stimulation of human umbilical vein endothelial cells with thrombin (4U/mL, 24h) significantly decreased eNOS expression. The addition of simvastatin significantly prevented thrombin-induced down-regulation of eNOS expression in a concentration-dependent manner (100nmol/L to 10 mu mol/L). Cerivastatin (10 mu mol/L) also reversed the down-regulation of eNOS by thrombin. Both simvastatin and cerivastatin-blocked thrombin-induced decrease in NOS activity. Stimulation with thrombin (4U/mL, 10min) significantly increased the membrane translocation of Rho A. Simvastatin (10 mu mol/L) and cerivastatin (10 mu mol/L) significantly decreased thrombin-induced membrane translocation of Rho A. Therefore, statins blunt thrombin-induced down-regulation of eNOS expression in human endothelial cells. This finding provides a novel mechanism of the pleiotropic effects of statins, which may be beneficial for patients with acute coronary syndromes
Nebivolol induces NO-mediated relaxations of rat small mesenteric but not of large elastic arteries
No full textNebivolol is a newer beta(1)-selective adrenergic receptor antagonist, which unlike classic beta-blockers, lowers systemic vascular resistance by direct vasodilator effects possibly involving NO. This study was designed to determine the effects of nebivolol on small arteries, which contribute to the most parr of systemic vascular resistance. Mesenteric arteries, isolated from 9-week-old Wistar-Kyoto (WKY) rats, were studied under perfused and pressurized conditions using a video dimension analyzer. Aortic rings from the same animals were suspended in organ chambers, and isometric tension was measured. Experiments were performed during contraction to prostaglandin F-2 alpha. In small arteries, nebivolol (10(-9) to 3 x 10(-5) M) induced concentration-dependent relaxations (maximum, 55 +/- 8%). The relaxations were less pronounced as compared with those to acetylcholine (maximum, 99 +/- 2%; p < 0.05), but were significantly greater than those to atenolol (maximum, 2 +/- 0%; p < 0.05). Nebivolol-induced responses were markedly reduced by the NO-synthase inhibitor N-omega-nitro-L-arginine methylester(L-NAME; 10(-4) M; maximum, 11 +/- 2%; p < 0.05). This inhibition could be entirely reversed by pretreatment with l-arginine (10(-3) M; maximum, 46 +/- 7%), a precursor of NO. In contrast to mesenteric arteries, nebivolol did not affect vascular tension of precontracted aortas. These findings indicate that nebivolol induces NO-mediated relaxations in small arteries but not large elastic vessels and therefore, independent of its antihypertensive action, might be effective in protecting the microcirculation in various cardiovascular disease states
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