Current Hypertension Reviews - Volume 2, Issue 3, 2006

In the large majority of cases, the underlying cause of hypertension is unknown. In the late 1980’s, Barry Brenner and colleagues suggested that individuals with a reduced nephron endowment were more likely to develop hypertension. This was followed soon after by the report from epidemiologist, David Barker and co-workers, of a link between low birth weight and an increased risk of adult cardiovascular disease, including hypertension. It was proposed that a low birth weight was indicative of a fetus having been exposed to a suboptimal intrauterine environment and somehow being “programmed” to develop adult disease. What is the evidence for a link between these two hypotheses, and does low birth weight, associated with a decrease in nephron endowment, provide in part, a basis for essential hypertension? In the past 20 years, intensive clinical and basic research has attempted to answer these questions using a variety of approaches. In normal human populations, low birth weight has been correlated with a low nephron number and both these factors have been shown to be associated with elevated blood pressure in adulthood. Animal models, especially those employing maternal protein deficiency or glucocorticoid exposure, have in general reproduced this phenomenon with offspring born of low birth weight having a reduced nephron number and hypertension in adulthood. However, experimental evidence is accumulating that low birth weight and a reduction in nephron endowment can occur independently of one another and do not always result in adult hypertension. In particular, the timing and nature of the in utero insult, the gender of the fetus and the subsequent postnatal environment may modify the outcome significantly.

Left ventricular hypertrophy (LVH) is a common form of target organ damage associated with hypertension that increases the risk for cardiovascular morbidity and mortality. Regression of left ventricular mass (LVM) substantially reduces this risk, and antihypertensive treatment is associated with reduction in LVM. Identifying the optimal therapeutic strategy that brings effective BP reductions and superior LVM regression is therefore important for the effective management of patients with LVH. Hypertension, both mean load and variability (for example, the early morning blood pressure [BP] surge), causes LVH. LVH also results from abnormalities in neurohormonal systems (such as the renin-angiotensinaldosterone system [RAAS]), and metabolic abnormalities. Agents that block the RAAS (angiotensin receptor blockers [ARBs], angiotensin-converting enzyme inhibitors) have particular efficacy. Telmisartan is a long-acting ARB that has shown regression of LVH and improved diastolic function in several clinical trials. Compared with carvedilol, telmisartan induces more regression of LVM for the same degree of BP control, and compared with hydrochlorothiazide the regression of LVM for a given degree of BP lowering is greater. As part of the ONTARGET study that compares telmisartan, ramipril, and the combination, a substudy will assess the effects of the three therapeutic strategies on the regression of LVH

The brain pathways involved in the control of arterial blood pressure and sympathetic nerve activity are distributed throughout the central nervous system and are organized in topographically selective ensembles of premotor neurons. There is increasing evidence to support the notion that increased sympathetic nerve activity plays an important role in the pathogenesis of human and experimental hypertension. In this review, we will focus on the importance of two distinct populations of sympathetic premotor neurons, those of the rostral ventrolateral medulla and those of the paraventricular nucleus of the hypothalamus, in the genesis and maintenance of experimental hypertension. The rostral ventrolateral medulla and paraventricular nucleus of the hypothalamus contain the principal premotor neurons involved in the modulation of sympathetic vasomotor tone and arterial blood pressure. Therefore, changes in the excitatory or inhibitory neurotransmission within these two nuclei might constitute a mechanism that is essential for the development and maintenance of hypertension. The present review addresses this hypothesis.

In recent years, opinions on hypertension in the paediatric age range have been changing. Although secondary forms of childhood hypertension maintain important clinical relevance, lately much more attention has been paid to primary forms of high blood pressure in children. At present, the prevalence of primary hypertension in children is not easily defined, also because of an unsatisfactory knowledge of this phenomenon. A child with elevated blood pressure values shows a high probability of developing hypertension in adulthood. Many factors that contribute to the development and maintenance of hypertension in the adult population are already present and operating in childhood. Overweight is one of the most important of these factors. In the industrialised countries, prevalence of childhood overweight has increased markedly during the last five decades and as in adults, overweight is related to several cardiovascular risk factors in children too. For these reasons, it may be important to precisely identify the children with high blood pressure values and body weight excess that might develop cardiovascular diseases in adulthood, and thus allow activation of preventive measures and therapeutic interventions that may reduce morbidity and mortality related to cardiovascular diseases.

Acute and chronic environmental and psychosocial stress contributes to the pathogenesis and progression of cardiovascular diseases (CVD). Stress reduction via Transcendental Meditation (TM)® has been shown to lower blood pressure (BP) levels and reduce CVD risk in adults and adolescents. This article reviews recent findings indicating a beneficial BP-lowering impact of TM in hypertensive adults at rest and in pre-hypertensive adolescents at rest, during acute laboratory stress and during normal daily activity. These findings have important implications for inclusion of TM in efforts to prevent and treat cardiovascular diseases and its clinical consequences.

The renin-angiotensin system (RAS) is a pivotal regulator of the renal and cardiovascular functions playing an important role in the control of blood pressure and hydroelectrolyte balance. In the past few years the combination of classical physiopharmacological techniques with modern genomics and protein chemistry methods has lead to the identification of important novel components of the RAS: the Angiotensin (Ang) IV binding site IRAP (insulin-regulated aminopeptidase), the angiotensin-converting enzyme 2 (ACE2), and the Ang-(1-7) receptor Mas. Ang-(1-7) is one of the most interesting peptide fragments of the RAS because it has actions which are often opposite to those of Ang II. The recent identification of the Ang-(1-7) forming enzyme ACE2 and of Mas as an Ang-(1-7) receptor has added further support and more widely acceptance to a new concept of the RAS in which the system has two major arms: a vasoconstrictor/ proliferative in which the major player is Ang II and a vasodilator/anti-proliferative in which the major effector is Ang-(1-7). In this article we will briefly review these novel aspects related to the RAS with focus on the possible physiological role of the ACE2-Ang-(1-7)-Mas axis in the cardiovascular system.

The cytochrome P450 (CYP) monooxygenase system represents a major metabolic pathway of arachidonic acid in the kidney. The primary CYP monooxygenase-derived arachidonic acid metabolites (eicosanoids) in renal tubular and vascular tissues are hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs), which are further metabolized by epoxide hydrolase to dihydroxyeicosatrienoic acids (DHETs). CYP-derived eicosanoids have been shown to affect vascular tone and tubular epithelial transport, contribute to the regulation of renal function, and participate in the long-term control of blood pressure. This review will focus on the biochemistry, pharmacology, and physiological significance of the CYP-derived eicosanoids in the mammalian kidney. In addition, we will also discuss the role of these metabolites in pregnancy- and obesity-induced hypertension in animal models, and in human hypertension.

Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in etiology of hypertension. In hypertensive patients, U-II induces vasoconstriction in forearm brachial artery infusion studies. Recent studies demonstrated elevated plasma U-II concentrations in patients with hypertension, diabetes mellitus, atherosclerosis, and coronary artery disease. U-II is expressed in endothelial cells, macrophages, macrophagederived foam cells, and myointimal and medial vascular smooth muscle cells (VSMCs) of atherosclerotic human coronary arteries. UT receptors are present in VSMCs of human coronary arteries, thoracic aorta and cardiac myocytes. Lymphocytes are the most active producers of U-II, whereas monocytes and macrophages are the major cell types expressing UT receptors, with relatively little receptor expression in foam cells, lymphocytes, and platelets. U-II accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages, and stimulates cell growth and up-regulates type 1 collagen expression in human endothelial cells. U-II also activates NADPH oxidase and plasminogen activator inhibitor-1 in human VSMCs, and stimulates VSMC proliferation with synergistic effects observed when combined with oxidized LDL, reactive oxygen species and serotonin. These findings suggest that U-II plays key roles in accelerating the development of atherosclerosis, and hence coronary artery disease.

Dopamine receptors are expressed in a number of organs and tissues; the peripheral dopamine receptors influence cardiovascular and renal function by decreasing preload and afterload and by regulating fluid and electrolyte transport. Most of the knowledge on these actions of dopamine has been garnered from studies of D1-like dopamine receptors. The D3 dopamine receptor subtype, which belongs to the D2-like receptor subfamily, has been extensively studied in the neurosciences. Recently, the peripheral actions of the D3 receptor have also raised considerable interest. Previous studies showed that the D3 receptor is expressed in organs outside the central nervous system such as the kidneys and blood vessels. Activation of the D3 receptor, alone or in synergism with D1 receptor induces diuresis and natriuresis and dilates resistance vessels. The D3 receptor also interacts positively with endothelin type B receptors and negatively with the renin-angiotensin-aldosterone system. For example, the D3 receptor-mediated natriuresis can be blocked by ETB receptor antagonists and stimulation of the D3 receptor decreases AT1 receptor expression in renal proximal tubule cells and inhibits renin and aldosterone secretion. The high blood pressure observed in spontaneously hypertensive rats and D3 receptor deficient mice, may, in part, be caused by impaired D3 receptor-mediated renal sodium excretion, impaired interaction with D1 and ETB receptors and impaired inhibition of the renin-angiotensin-aldosterone system. In this review, we examine the role of the peripheral D3 receptor in the regulation of renal sodium excretion and vascular resistance, and its interaction with the renin-angiotensin system and other dopamine receptor subtypes. We also present our current understanding of the role of D3 receptor in the pathophysiology of human essential hypertension.