Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 6, Issue 4, 2006

Arterial hypertension is an important cause of morbidity and mortality because arterial hypertension is not only an abnormal increase of arterial pressure, it is also accompanied by a number of concomitant disorders. More than a "silent killer", high blood pressure is a "time bomb" because patients who can feel great and have high blood pressure are exposed to stroke, myocardial infarction, heart failure and kidney failure. Prevalence of arterial hypertension in the world in adult population was about 26.6% in men and 26.1% in women in 2000, that corresponds to 1 million individuals with considerable disparities between developed countries and other countries, especially for the complications, due both to diagnostic failure and absence of therapy. Projections estimate that this number would increase by 60% in 2025, mainly due to the increase in food intake that should dramatically increase the prevalence of diabetes, metabolic syndrome and obesity, three important causes of arterial hypertension in developed countries and in emergent countries with an expected increase of respectively 25% and 80% of arterial hypertension in 2025. Arterial hypertension is a frequent disease that induces an important amount of research activity and a constant flow of knowledge and findings. Although the understanding of the factors involved in the pathophysiology of arterial hypertension has increased, which include neuro-endocrine factors, vascular and endothelial functions, autocrine and paracrine functions, interrelationships between target organ functions, metabolic disorders, genetic factors, primary (essential) hypertension remains a blanket that recovers our ignorance. Although important progress have been made in the treatment in arterial hypertension these last years in western countries, and although we have very efficient compounds to reach the goals of pressure values, the best statistics show that only about 50% of the known hypertensive are correctly treated. Moreover, even in patients correctly treated, the risk of complications remains higher than in normotensive patients showing the reduction of arterial pressure is only a part of the treatment. Thus, the challenge for the next years is not only the improvement of our means to reach the goal of "normal" pressure in hypertensive patients, it is also the prevention of target organs from deterioration due to the disease which does nor resume in an elevated pressure. This important objective will be reached only if our knowledge of pathophysiology of the disease(s) increases. With the assistance of the writers who have helped to produce this issue, it is possible to examine the most relevant aspects of arterial hypertension in a detailed and, I hope, a clear and accessible manner. The papers published in this issue try to provide pathophysiological informations that may be useful for the comprehension of arterial hypertension and its complications, and that also could be useful for the development of new therapeutic interventions that are not only pharmalogical.

Hypertension is defined as either an elevation of systolic blood pressure (SBP) to ≥ 140 mmHg and/or elevation of diastolic blood pressure (DBP) to ≥ 90 mmHg for adults. Hypertension is a frequent, age-related disorder and a major risk factor for stroke, coronary heart disease, heart failure and renal failure. The relation between BP and cardiovascular disease (CVD) mortality and morbidity is strong, direct and continuous over a wide range such that BP values must be viewed as a continuum in which a high BP means an increased cardiovascular risk and worse prognosis. Thus, the paradigm has shifted from hypertension to BP-related diseases. The magnitude of the burden of hypertension and high BP in both developed and developing countries contributes to prediction of worldwide epidemic of CVD. Effective strategy emphasizes focusing on SBP, identifying high-risk patients and targeting reductions in multiple risk factors, including end-organ damages. Recent studies have focused on six modifiable risk factors, namely cigarette smoking, lipids abnormalities, diabetes, BP levels, obesity, and stress. Three protective factors have also been individualized, namely the Mediterranean regimen, regular physical activity and regular, moderate alcohol consumption. Besides health promoting lifestyle modifications, the major classes of antihypertensive agents, namely diuretics, β-blockers, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, are suitable for the initiation and maintenance of therapy, and there is a frequent need to use at least two drugs in combination in order to achieve optimal BP. It is important to point out the fact that most clinical trials are of short duration and their significance must be confirmed on longterm outcomes.

More than one-fourth of individuals in the Eastern populations are hypertensive. Both large (conductance) arteries and small (resistance) arterioles are involved in the physiopathology of hypertension. Large arteries from hypertensive subjects are stiffer and thicker than in normotensive matched controls. Stiffer arterial walls are responsible for higher pulse wave velocity and earlier reflection wave in hypertensives leads to increased systolic pressure and pulse pressure and finally to increased left ventricular after-load. Evidence for these pathophysiological mechanisms arises from studies of pulsatile arterial hemodynamics, as highlighted recently by the role of PWV and wave reflections as independent factors in cardiovascular risk in hypertension. Resistance arterioles (200-30 μm) are characterized by the presence of a myogenic tone able to protect the capillary bed against abnormally high blood pressure and to control the local tissue blood flow. Several types of alterations of resistance vessels are characteristics of chronic hypertension. -reduced lumen diameter in relation with exaggerated vasoconstriction, - hypertrophy of the vascular wall resulting in decreased lumen size and increased wall-to-lumen ratio, - rarefaction of microvessels i.e. arterioles and capillaries. Experimental and clinical results allowed to evidence that antihypertensive drugs might reverse the structural changes of the large and resistance arteries. Through modification in the timing of wave reflections, it is also possible to reduce the disproportionate increase in systolic blood pressure and the associated cardiovascular risk. Some recent trials are aiming to reduce or reverse microvascular network rarefaction. This could be a promising way not only to normalize arterial blood pressure but also to reduce target organs complications.

Left ventricular hypertrophy (LVH), defined as an increase in left ventricular mass, is one the aspect of the cardiac phenotype observed during hypertension and other conditions associated with a chronic increase in LV afterload. Since myocardial hypertrophy helps to normalize LV wall stress and the load of the constituting myocytes, LVH has long been considered to be a beneficial adaptive mechanism. However, LVH is also an independent risk factor for the occurrence of clinical events, including death. During the past 25 years, basic cardiac research has allowed to better understand the reasons for such a negative outcome. During the eighties, the other phenotypic characteristics of the hypertrophied LV have been established, showing a number of tissular, cellular and molecular alterations, the adaptive nature of which was clearly questionable. Since the beginning of the nineties, research has moved to the field of the mechanisms responsible for such changes and has allowed to identify a large number of triggers, initiators, signal transduction pathways and networks, effectors and counter-effectors responsible for LVH and the other phenotypic aspects of LV remodeling. Some of them referred to as "adaptive" are beneficial and participate to LV adaptation to the chronically increased afterload. However, in the context of hypertension most of them referred to as "maladaptive" are clearly detrimental and can be regarded, as at least in part, as responsible for the poor prognosis. The goal of the present article is to summarize the main actors of this hypertension-associated LV remodeling putting emphasis on those constituting potential targets for the development of new therapies aimed at preventing detrimental LV remodeling resulting from chronic hypertension.

Arterial hypertension is a major coronary risk factor due to an increase prevalence of coronary atherosclerosis. On the other hand, many arguments are suggestive of symptomatic or silent episodes of "myocardial ischemia" in hypertensive patients without coronary artery stenosis. Several pathophysiological processes that are implicated in coronary vascular changes are detrimental for the oxygen demand/supply equilibrium and adaptation of coronary circulation and coronary blood flow to an increase in myocardial oxygen demand. First, apart from coronary atherosclerosis, epicardial vessels are altered by vessel wall remodelling and structure changes. Second, structural alterations of the coronary arterioles due to medial hypertrophy and perivascular fibrosis limit the functional area of the vessels which are also compressed by a higher intramyocardial pressure, resulting in a reduction of coronary flow reserve. Third, the increase in intercapillary distance due to myocardial hypertrophy increases the distance of oxygen diffusion to cardiac myocyte mitochondria, the site of ATP synthesis. Fourth, the endothelium-dependent nitric-oxide dilation of coronary vessels is depressed, thus impairing the adaptation of coronary circulation to changes in myocardial oxygen demand. All these changes do not depend on myocardial hypertrophy, although myocardial hypertrophy aggravates the disorders. Antihypertensive therapy may have beneficial effects by reducing myocardial mass and arterial pressure, by restoring a normal vascular structure and architecture, and by improving coronary vasomotion.

High blood pressure is the most prevalent modifiable risk factor for stroke. Observational and interventional studies have shown that lowering blood pressure with drugs, even in normotensive high-risk patients, may achieve effective primary stroke prevention. Uncertainties remain concerning the optimal blood pressure target, especially in older people with low diastolic blood pressures. Data from The Perindopril Protection Against Recurrent Stroke Study and other placebo-controlled trials showed that secondary prevention of stroke can also be provided by blood pressure lowering medication, even in normotensive subjects. Possible differences in the preventive potential of the various available antihypertensive agents remain to be documented, both for the primary and secondary prevention of stroke. Much uncertainty remains concerning the optimal blood pressure management in the context of acute stroke. Some trials currently evaluate the effect of lowering blood pressure on subsequent outcome, such as mortality and dependence, whereas others assess the effect of increasing blood pressure. Conflicting results have been obtained from small trials. These are possibly explained by differences in inclusion criteria or follow-up duration, or by a U-shaped relationship between systolic blood pressure at admission and outcome. This review focuses on the preventive trials that led to implement the current guidelines concerning blood pressure management in relation to the risk of stroke. It briefly describes ongoing trials that test new strategies to improve the management of acute stroke.

Hypertension may cause renal vascular lesions and glomerular damage, constituting hypertensive nephrosclerosis. This ultimately may lead to end-stage renal failure, mainly in African-American subjects. Such a situation is exceedingly rare in Caucasian patients with non-malignant hypertension. The direct effect of pressure is well evidenced experimentally in the 2 kidneys-one clip Goldblatt model: only in the unclipped kidney which is exposed to high blood pressure, vascular lesions develop in interlobular arteries and afferent arterioles, followed by glomerular sclerosis. The pressureinduced glomerular damage is limited by an autoregulation based on vasoconstriction of the afferent arteriole. The efficiency of this autoregulation is largely under genetic influence. A deficient autoregulation with vasodilated afferent arterioles leads to more early and severe glomerular damage. Conversely, afferent arteriolar vasodilatation, with glomerular hyperfiltration, may precede any increase in blood pressure. This occurs mainly when sodium excretion is limited, due to any congenital functional defect, or a reduced number of nephrons. Hypertension occurs secondarily, and appears as the hemodynamic counterpart necessary to maintain the sodium balance. In this case, the same primary renal abnormality causes both hypertension and glomerulosclerosis. This is believed to be a frequent cause of hypertension-associated glomerulosclerosis. Whatever the sequence of events, reducing blood pressure is the best way to limit kidney damage. Antihypertensive drugs have, however some actions on renal circulation independent of blood pressure. Calcium channel blockers blunt the autoregulation of afferent arterioles. On the contrary, drugs which inhibit the renin angiotensin system reduce glomerular capillary pressure, and have a beneficial effect on the progression of renal failure.

Hypertension is a frequent condition in obese subjects and in subjects with diabetes and other components of the metabolic syndrome. The pathophysiology of the increase in blood pressure (BP) is multifactorial. Three targets, heart, vessels and the kidneys, are involved in BP regulation. Insulin, leptin and some adipocytokins, whose plasma levels are often increased in these subjects, are likely to play a major role. They act through various mechanisms, some of them contributing to rise BP and others to lower BP. An imbalance between these opposite effects, as evidenced in insulin resistance state, may account for elevated BP. Because hypertension is a major determinant for cardiovascular complications and also for microangiopathic complications in patients with diabetes, tight BP control is mandatory to prevent these complications. Weight loss and lifestyle changes are the cornerstone of hypertensive management, but pharmacological anti-hypertensive treatments are often required to achieve this goal. Drugs with favourable metabolic effects, including for some of them a demonstrated effect in diabetes prevention, should be preferably chosen.