Hypertension is a condition associated with oxidative stress, endothelial dysfunction, and increased vascular resistance, representing probably both a cause and a consequence of elevated levels of reactive oxygen (ROS) and nitrogen (RNS) species. Mitochondria are important sites of ROS production, and a mitochondrial dysfunction, preceding endothelial dysfunction, might favor the development of hypertension. ROS production may also be induced by RNS, which inhibit the respiratory chain and may be generated through the action of a mitochondrial NO synthase. Mitochondrial uncoupling proteins are involved in both experimental and human hypertension. Finally, an excessive production of ROS may damage mitochondrial DNA, with resultant impairment in the synthesis of some components of the respiratory chain and further ROS production, a vicious cycle that may be implicated in hypertensive states.
It has been demonstrated that beta blockers are able to modify the course of the disease, through the reduction of hemodynamic in stabilization and mortality cases. The success of these drugs in the treatment of chronic heart failure is related to the sympathoadrenergic activation and to renin-angiothensin-aldosteron system. Various molecules are available at the moment. Recent research has been done on third generation beta blockers (carvedilol, nebivolol, bucindolol). These drugs have shown to possess some peculiar characteristics, in particular the ability of reducing the number of side effects which may be seen while using beta blockers of the first generations. Although it is currently difficult to give general informations based only on the pharmacologic profile, the choice of the type of drug to use in the single patient with chronic heart failure should be made considering the adequacy of the pharmacologic characteristics in each specific situation.
Since endothelial dysfunction may significantly contribute to the pathophysiology of hypertension and its complications, its modification seems to be a very attractive means to favourably affect the development of atherosclerosis and cardiovascular events in hypertensive patients. However, not all antihypertensive drugs consistently improve endothelial dysfunction. While first-generation beta-blockers showed contrasting or null effects on endothelial function, newer beta-blockers of the third generation, such as carvedilol and nebivolol, seem to be provided with specific endothelium-mediated vasodilating effects. Calcium channel blockers are generally able to increase endothelium-dependent vasodilation in several vascular beds, in patients with essential hypertension, probably through multiple mechanisms. Most studies have shown thatACE inhibitors favourably affect endothelial function mainly in the subcutaneous, epicardial and renal circulation, not only by inhibiting the effects of angiotensin II on the endothelium, but also by enhancing bradykinin-induced vasodilation, probably a hyperpolarization-related effect. On the other hand, discordant evidence is available about the effects of angiotensin II receptor type I blockers on endothelial function in patients with essential hypertension, atherosclerosis or diabetes.There are data suggesting that an increased activity of the endothelin- I system may play a role in the blunted endothelium-dependent vasorelaxation of hypertensive patients, an effect that could be contrasted by the use of endothelin-I receptor antagonists. However, to date no substantial clinical efficacy of endothelin-I receptor blockers has been shown in patients with essential hypertension. Finally, other possibly useful compounds in restoring impaired endothelial function in hypertension are some antioxidant agents such as vitamin C, folic acid, the cofactor tetrahydrobiopterin (BH4), L-arginine and the drugs of the statin class.
Abstract An important role in atherogenesis is played by oxidative stress, which may be induced by common risk factors. Mitochondria are both sources and targets of reactive oxygen species, and there is growing evidence that mitochondrial dysfunction may be a relevant intermediate mechanism by which cardiovascular risk factors lead to the formation of vascular lesions. Mitochondrial DNA is probably the most sensitive cellular target of reactive oxygen species. Damage to mitochondrial DNA correlates with the extent of atherosclerosis. Several cardiovascular risk factors are demonstrated causes of mitochondrial damage. Oxidized low density lipoprotein and hyperglycemia may induce the production of reactive oxygen species in mitochondria of macrophages and endothelial cells. Conversely, reactive oxygen species may favor the development of type 2 diabetes mellitus, mainly through the induction of insulin resistance. Similarly - in addition to being a cause of endothelial dysfunction, reactive oxygen species and subsequent mitochondrial dysfunction - hypertension may develop in the presence of mitochondrial DNA mutations. Finally, other risk factors, such as aging, hyperhomocysteinemia and cigarette smoking, are also associated with mitochondrial damage and an increased production of free radicals. So far clinical studies have been unable to demonstrate that antioxidants have any effect on human atherogenesis. Mitochondrial targeted antioxidants might provide more significant results.
Atherosclerosis (ATS) is a multifactorial disease caused by the interaction of established or emerging risk factors with multiple predisposing genes that regulate ATS-related processes. This review will discuss the current knowledge concerning the potential role of the genetic variations that could promote and/or accelerate ATS, in both animal models and humans. Allelic polymorphisms or variations of distinct genes that enhance the risk of ATS frequently occur in the general population, but only adequate gene–environment interactions will lead to the disease. The main genes so far studied are involved in the regulation of processes such as endothelial function, antioxidant potential, coagulation, inflammatory response, and lipid, protein and carbohydrate metabolism. The detection of candidate genes associated with ATS could allow, in the near future, earlier interventions in genetically susceptible individuals. Further, large-scale population studies are needed to obtain more information on the specific gene–environment and drug–gene interactions capable of influencing ATS progression.
Many experimental studies have obtained a prolonged control of blood pressure through gene treatment. This consists in the administration of genes coding for vasodilator proteins (the ‘sense’ approach), or of nucleotide sequences that are complementary to the mRNA of vasoconstrictor proteins, which are consequently synthesized in smaller amounts (the ‘antisense’ approach). Examples of the sense approach include the genes encoding endothelial nitric oxide synthase and kallikrein. Examples of the second type of approach are the antisense oligodeoxynucleotides to angiotensin-converting enzyme and endothelin-1. Also, RNA molecules, such as ribozymes and small interfering RNAs, are capable to inhibit RNA function. Whole sense genes are usually administered through viral vectors, while antisense oligonucleotides may be administered with plasmids or liposomes. Both viral and non-viral vectors have advantages and disadvantages. Despite the still persisting limitations, the possibility exists that in the future some forms of genetic treatment will be extended to the clinical setting, allowing a prolonged control of essential hypertension and its end-organ sequelae.
Progressive increase of the average lifespan pushed up the number of the elderlies in the population. The subsequent spread of degenerative conditions such as osteoarthritis has inflated the request of NSAID despite their frequent toxicity. Side effects of NSAID are sometimes severe and mainly target gastrointestinal tract, renal and platelets function. It has been estimated that around 70% of the patients treated with NSAID develop some degree of gastric damage, ranging from aspecific dyspeptic syndromes to ulcerative diseases. Drugs are now available that selectively inhibit the cyclooxygenase-2: this enzyme is involved in the synthesis of prostaglandins during the inflammatory response. These new drugs have opened new perspectives in the treatment of arthritis; they allow COX-1 to work regularly, so that those prostaglandins that are involved in the maintenance of a regular function of the gastrointestinal tract mucosa and of the platelets. Celecoxib was the firstborn of these new drugs. Differently from FANS, COXIB has got less side effects on gastrointestinal tract and platelets function. Based on the evidence of the more recent clinical experience COXIB has to be recommended; in particular celecoxib, at a schedule of 200-400 mg/die, was shown to be highly effective in the symptomatic treatment of osteoarthritis and rheumatoid arthritis.
Platelet functions are multiple, complex and not limited to haemostasis. In fact, platelets play a relevant role in vascular inflammation and atherosclerosis (ATS). In the presence of vascular lesions or inflammation, endothelial denudation or activation triggers mechanisms that render the circulating platelets adhesive for the vascular wall. Endothelial lesions expose subendothelial matrix components, such as collagen, von Willebrand factor, fibronectin and other adhesive proteins. Platelet adhesion depends on the interaction between these components and platelet receptors (mainly glycoprotein (GP) VI and GPlb-IX-V). Adhesion triggers the platelet release of inflammatory and mitogenic substances that alter the thromboresistant endothelial surface, enhance the chemoattraction of leukocytes, stimulate smooth muscle cell proliferation and contribute to matrix degradation. Finally, GPIIb-IIIa receptors are activated, leading to firm platelet aggregation and thrombus formation. Platelets participate in the formation of mural thrombi in the late stages of atherosclerotic disease, but also adhere to endothelial cells during the earlier stages of atherosclerotic plaque development. Moreover, platelets exert important functions in modulating inflammatory and immune processes. An improved comprehension of the complex platelet pathophysiology could suggest new therapeutic strategies to reduce the impact of atherosclerotic disease.
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