Current Hypertension Reviews - Volume 2, Issue 1, 2006

The prevalence and incidence of dementias are expected to increase in the future. Accordingly, the identification of causes of dementia and of possible risk factors is very important. A large body of evidence has shown that hypertension is a risk factor for vascular dementia. Recently, it has been demonstrated that hypertension could affect the course of Alzheimer disease. A strong relationship between hypertension and cognitive decline (CD) or dementia has been reported by several observational studies, especially in untreated subjects. The risk increases with increasing blood pressure (BP). However, this relationship is not linear, since BP may decrease to normal or low levels before dementia becomes clinically manifest. There may also be an association between BP variability in hypertensive patients and impaired cognition. Recent studies, using the 24-hour non-invasive monitoring, have shown that both short-term and longterm BP variability are associated to CD. This variability may reflect central nervous system dysregulation or occult injury to prefrontal autonomic centers. Trials with antihypertensive drugs focusing on CD and dementia have shown that active treatment may be beneficial, although the optimal BP levels have not yet defined. Future studies, comparing the different effect of antihypertensive drugs are expected to further clarify this topic.

Microalbuminuria, i.e., abnormal urinary excretion of albumin detectable by sensitive, low cost, and widely available tests, can be found in up to one third of non diabetic patients with primary hypertension. Microalbuminuria has been shown to predict an increased probability of suffering a cardiovascular event or death. The pathogenetic mechanisms leading to the development of microalbuminuria are not yet fully known: blood pressure load and increased systemic vascular permeability, possibly due to early endothelial damage, seem to play a major role. Increased urinary albumin excretion has been associated with several unfavorable metabolic and non metabolic risk factors and sub-clinical organ damage, such as left ventricular hypertrophy and carotid atherosclerosis. Microalbuminuria itself has recently been recognized as a sign of hypertensive target organ damage and since it reflects the influence of so many clinically relevant parameters, it can rightly be considered an integrated marker of cardiovascular risk, a unique feature among the several available prognostic predictors for stratifying risk in hypertensive patients. While microalbuminuria has proven to be a forerunner of overt renal damage in the presence of diabetes mellitus, conflicting clinical evidence makes this hypothesis tempting at the moment, but speculative in non diabetic hypertensives. Effective antihypertensive treatment, especially with drugs counteracting the renin angiotensin system, has been found to reduce urinary albumin excretion. More recently, regression from microalbuminuria to normoalbuminuria has been associated with an amelioration of cardiovascular outcome, regardless of achieved blood pressure levels and type of drug. This evidence emphasizes the usefulness of evaluating urinary albumin excretion not only to assess cardiovascular risk, but also to monitor the efficacy of treatment in clinical practice.

Aldosterone is a key cardiovascular hormone. Recent studies have illustrated its role in cardiac fibrosis and left ventricular hypertrophy as well as in impaired vascular reactivity. Moreover, many of these actions have been shown to be independent of its known effects on blood pressure. In a clinical setting, the benefits of aldosterone blockade in cardiovascular disease have been adequately demonstrated in recent large, randomised clinical trials. Aldosterone blockade was once limited by dose-related side effects, however, the introduction of a new, more selective, aldosterone receptor antagonist (eplerenone) has led to an increase in its use as a therapeutic strategy in cardiovascular disease. The role of aldosterone in hypertension has also been recently re-evaluated. As a result more widespread screening of hypertensive subjects using the aldosterone to renin ratio (ARR), the prevalence of Primary Aldosteronism (PA) is now estimated, albeit controversially, to be at least 10%. It is now accepted that screening for PA should be more widespread and not limited to those with hypokalaemia. Moreover, whilst there remains debate over the exact labelling of individuals with hypertension and raised ARR it is clear that such subjects have aldosterone levels inappropriate for the prevailing renin ('aldosterone-associated hypertension'). It is important that such individuals are identified since they can be offered more targeted treatment with selective aldosterone blockade or even surgery to control or normalise blood pressure.

Primary aldosteronism (PA) is one of the potentially curable forms of hypertension. The hypertension is secondary to aldosterone action in the kidney, reabsorbing sodium and water that increases the intravascular volume and blood pressure. PA was previously believed to account for less than 1% of hypertensive patients when hypokalemia is used as screening method. However, recent studies using the plasma aldosterone to renin activity ratio (ARR) as screening test have demonstrated a high prevalence of PA in hypertensive populations. This prevalence vary depending on the severity of hypertensive disease being higher in stages 2 (8.55%) and 3 (13.5%) of the disease. Only a small proportion of PA patients (between 9 and 37%) are hypokalemic. The diagnosis of PA is advocated to confirm the autonomy of aldosterone secretion from the renin-angiotensin system and to differentiate the clinical subtypes of the disease. The most common subtypes of PA are idiopathic aldosteronism and aldosterone-producing adenoma. Other causes are glucocorticoid-remediable aldosteronism, unilateral or primary adrenal hyperplasia and adrenal carcinoma. This article reviews the new data about prevalence, diagnosis criteria and describes the clinical, biochemical and genetic characteristics of the different subtypes of the disease.

Self- measurement of blood pressure (BP) at home has gained increasing importance for the diagnostic and therapeutic evaluation of hypertensive patients. In comparison with clinic BP, self-measurement of BP with automated devices has several advantages: (1) higher reproducibility; (2) elimination of the "white coat effect" and observer bias; and (3) improvement of both compliance and BP control. Furthermore, there is evidence that home BP better correlates with target-organ damage and prognosis and provides a more accurate evaluation of treatment effect. On the other hand, it has great potential advantages of lower equipment and staff cost compared with ambulatory BP. These features of home BP have led various medical organizations to recognize its clinical usefulness in the diagnosis of white coat hypertension and in evaluating response to antihypertensive medication, particularly in the primary care setting. We aim here to present a critical review of the uses, strengths and weaknesses of the technique of home BP monitoring for the assessment of hypertension in the clinical practice.

The Metabolic or Insulin Resistance Syndrome is a cluster of cardiovascular risk factors, such as type 2 diabetes mellitus, hypertension, central obesity, dyslipidaemia, and other disorders, which have been proposed to be secondary to insulin resistance. A number of possible mechanisms linking insulin resistance and compensatory hyperinsulinemia with hypertension have been described, such as renal sodium reabsorption enhancement, sympathetic nervous system activation, or blunted insulin-mediated vasodilatation due to endothelial dysfunction. PPARγ agonists or thiazolidine-diones (TZDs) are a class of oral antihyperglycemic agents that act through improvement of insulin sensitivity. Apart from their action on glycemic control, in several studies TZDs have been also reported to exert beneficial effects on other parameters of the metabolic syndrome. This review summarizes the literature data on the effect of troglitazone, pioglitazone and rosiglitazone on blood pressure (BP), which derive from animal and human studies that were either specifically designed to determine the effect of TZDs on BP or just examined BP levels among other parameters. In addition, it presents in vitro and in vivo evidence about various TZDs actions on the cardiovascular system that could positively influence BP, representing therefore possible mechanisms of this BP amelioration.

Smooth muscle cells as well as non-excitable cells express multiple cationic channels with variable selectivity for Ca2+, K+, Na+. Several of these channels are sensors of Ca2+ store depletion, G-protein-coupled receptor activation, membrane stretch, intracellular pH, oxidative stress, phospholipid signals and other factors. A novel family of such channels is represented by highly conserved heterotetramer homologues of Drosophila TRP (transient receptor potential). Direct evidence exists for roles of TRPC1, TRPC4/5, TRPC6, TRPV, TRPP in store-operated Ca2+- gating in various tissues, including epithelial cell Ca2+ transport, thus controlling renal and intestinal homeostasis of divalent cations. Mice deficient in TRPV5 display phenotypic defects amongst which hypercalciuria and impaired bone mineral density. Polycystin 2 (PC2), encoded by the PKD2 gene, is an epithelial transmembrane protein whose mutation is associated to autosomal dominant polycystic kidney disease (ADPKD). PC2 behaves as a TRP-type Ca2+-permeable nonselective cation channel located on the cilia of tubular epithelial cells. Recent studies indicate that a PC1-PC2 channel complex is an obligatory novel signaling pathway implicated in the transduction of environmental signals into cellular events. TRPrelated ion channels may also play a role in the pathogenesis of arterial hypertension through direct effects on vascular smooth muscle contraction, renal perfusion/hemodynamics, and the total body balance of divalent cations.

Vascular contraction is modulated, in part, by the cytoplasmic Ca2+ concentration in smooth muscle cells (SMCs). Ca2+ influx through voltage gated Ca2+ channels (VGCC) is governed by membrane potential. In turn, membrane potential is determined by the relative conductance of the membrane to various ions. Increase in Cl- conductance depolarizes SMCs to activate VGCC. K+ channel activation or inhibition can favor hyperpolarization or depolarization, respectively, to modulate VGCC activity. The importance of the kidney in the determination of extracellular volume and blood pressure has motivated study of renal SMC channel architecture. VGCC mediated Ca2+ entry has been consistently found in the preglomerular microcirculation. In contrast, the route of Ca2+ entry in the postglomerular microcirculation varies with cortical location. Juxtamedullary efferent arterioles and descending vasa recta express VGCC while superficial efferent arterioles may not. The subtypes of K+ channel that govern membrane potential also varies along the renal microvascular circuit. Exploration of rodent models have tended to confirm an increase in VGCC activity in hypertension. Alterations in K+ channels and gap junction - connexin proteins also occur but are subtype specific. This review summarizes current knowledge of renal SMC channel architecture and its alteration in hypertension.

Immune dysfunction has been reported in patients with hypertension and in spontaneously hypertensive rats. Increased circulating levels of ouabain were observed in experimental models and in human hypertension. Despite the correlation between immunologic depression and hypertension, the mechanisms involved are unclear. This review examines evidences of immune dysfunction in hypertension and presents observations suggesting that ouabain is capable of inducing lymphocyte changes related to some of the immune disturbances observed. Defects in thymocytes, mature lymphocyte subsets, lymphocyte proliferation, cytokines balance and increased immunoglobulin production, were reported in animal models and/or hypertensive patients. Ouabain potentiates the effects of glucocorticoids on thymocytes, inducing plasma membrane depolarization, loss of mitochondrial membrane potential, changes in CD69 levels, increased intracellular calcium and apoptosis of thymocyte subsets. The activation of mature lymphocytes is inhibited by ouabain following different stimuli and these cells display changes in c-myc, CD69 and CD25 levels, plasma membrane polarization and mitochondrial membrane potential. These cells underwent apoptosis, suggesting an exacerbation of the process of activation induced cell death. Levels of cytokines such as IL-1, IL-2, IL-6, TNF, and GM-CSF are modified by ouabain. Some of the ouabain effects may result from a mechanism different from the traditional inhibition of the Na+/K+ ATPase.