Current Hypertension Reviews - Volume 6, Issue 1, 2010

Leptin is a peptide hormone secreted by white adipose tissue which is primarily involved in the regulation of food intake and energy expenditure. Recent studies suggest that leptin contributes to the pathogenesis of arterial hypertension associated with the metabolic syndrome. Plasma leptin concentration is increased in obese individuals. Moreover, chronic leptin administration or transgenic overexpression increases blood pressure in experimental animals, and some studies indicate that plasma leptin is elevated in hypertensive subjects independently of body weight. The purpose of this article is to characterize the relationship between leptin and vascular nitric oxide (NO), which plays a pivotal role in the regulation of blood pressure. Acutely administered leptin stimulates endothelial NO production, which counteracts simultaneous stimulation of the sympathetic nervous system and results in no net changes in blood pressure. Unfortunately, this acute NO-mimetic effect of leptin is impaired in obesity. This “vascular leptin resistance” may contribute to blood pressure elevation due to unopposed sympathetic activity. In addition, chronic hyperleptinemia may impair endothelial function by increasing formation of reactive oxygen species which scavenge NO. Recently, important progress has been made in understanding both the mechanism of resistance to acute NO-mimetic effect of leptin and unbeneficial impact of long-lasting hyperleptinemia on endothelial function.

Microalbuminuria measurement is now widely available, but its use during and after pregnancy has not been clearly defined. This review will present a brief overview of microalbuminuria measurement and screening outside pregnancy, and discuss the diagnosis of microalbuminuria in pregnancy, the potential role of microalbuminuria in pregnancy for prediction and diagnosis of pre-eclampsia and for post partum assessment of long-term cardiovascular diseases. Several methods have been used in pregnancy for measurement of microalbuminuria. Screening is best performed by urinary spot albumin/creatinine ratio and cut-off values in the non-pregnant population are reasonable to be used in the first trimester. The roles of microalbuminuria screening in pregnancy remain unclear and further research is needed on the use of spot albumin/creatinine ratio for prediction and diagnosis of pre-eclampsia. Finally, the significance of persistent microalbuminuria beyond 6 weeks postpartum is also unclear. Microalbuminuria may represent generalized vascular disease or underlying renal disease. More research is needed into the natural history of microalbuminuria following hypertensive pregnancy, and any independent contribution of microalbuminuria to the heightened cardiovascular risk in these women.

Isolated systolic hypertension is the most common form of essential hypertension in patients over 65 years old and is not well controlled by current antihypertensive therapies. Current antihypertensive pharmacology is focused on reducing peripheral resistance and ventricular ejection. However, the increase of systolic blood pressure is mainly a consequence of large artery stiffening. This pathological process seems to be the result of medial arterial calcification (or elastocalcinosis), elastin degradation, extracellular matrix fibrosis and endothelial dysfunction. As a unifying hypothesis, we propose that initial extracellular calcification could promote extracellular matrix-cellular interactions by involving metalloproteinase matrix degradation, leading to the liberation of embedded transforming growth factor-β. This growth factor could promote a cascade of events involving vascular smooth muscle cells that adopt an osteogenic phenotype and express a different set of proteins, such as endothelin, that appear to play a central role in medial calcification and fibrosis. This review highlights the evidence supporting the hypothesis. It also presents the effects of current drugs on calcification and/or fibrosis in experimental model of isolated systolic hypertension to illustrate where we stand in our efforts to modify the process of arterial stiffening.

Hypertension is a major global public health problem. Exercise decreases blood pressure (BP) 5-7 mmHg among those with hypertension. Thus, exercise is recommended to prevent, treat, and control hypertension with a generic “one size fits all” approach. Yet, there is considerable individual variability in the BP response to exercise due to genetic and environmental factors that are not well understood. There is a significant genetic component to the BP response to exercise with heritability estimates of approximately 45% to 55%. Yet, identification of specific genetic variants accounting for this variability has proven to be a more challenging task than originally envisioned. This review describes work from our laboratory and others on candidate gene and BP association studies and how they account for some of the variability in the BP response to exercise. The ultimate goal of this work is to use genetic information to personalize exercise prescriptions to optimize the effectiveness of exercise as a therapeutic modality for the prevention, treatment, and control of hypertension. However, because of the complexities surrounding work in exercise genomics the future use of genomics in exercise prescription for hypertension is a vision of the future rather than a reality of the present.

Hypertension is a very common finding in hemodialysis patients and one of the most important risk factors for cardiovascular disease, the leading cause of morbidity and mortality in dialysis. The discontinuous nature of hemodialysis gives blood pressure a unique profile and makes the pathogenesis of hypertension complex in this population. Water and sodium retention play a pivotal role; increased activity of vasoconstrictive systems and impaired vasodilatation, hyperparathyroidism, erythropoietin, salt intake and dialysis prescription have also a role in blood pressure regulation. Aggressive treatment of hypertension must be the default approach in hemodialysis patients. The primary goal should be a strict control of body sodium content and extracellular volume by performing an optimal renal replacement therapy. If this approach proves unsuccessful, patients may benefit from antihypertensive medications. All classes of antihypertensive drugs can be used, with the sole exception of diuretics (although selected patients may advantage from furosemide therapy). Drug use, dosing, and frequency are dictated by pharmacokinetic considerations and peculiar dose adjustments must be adopted in this setting. The presence of end-stage renal disease also modifies the pharmacologic response in some cases, for example, the greater occurrence of orthostatic hypotension with alpha-blockers in a volume-depleted patient. The purpose of this review is to show the pathophysiological mechanisms, evaluate the on-going discussion about measurement techniques and recommended targets, and discuss the most appropriate management of hemodialysis-associated hypertension.

The endoplasmic reticulum (ER) is the site of synthesis and maturation of proteins, designed for secretion, and the cell membrane. Various types of stress from both inside and outside of cells disturb ER function, and unfolded or misfolded proteins accumulate in the ER. The accumulation of these abnormal proteins in the ER further disturbs ER function and cell survival can be threatened. To improve and maintain ER functions against such stress, the ER stress response pathway is activated. When the stress is too severe to maintain ER function, apoptosis pathways are activated to remove damaged cells to protect organs and the whole body. However, when a large number of cells are lost through apoptosis, disturbance of organ function is induced. Therefore, ER stress-induced apoptosis is involved in various diseases, including diabetes, ischemic diseases, atherosclerosis, and heart failure. The transcription factor CHOP/GADD153 is induced by ER stress, and is involved in ER stress-induced apoptosis. CHOP is a member of the CCAAT/enhancer binding proteins (C/EBPs), and forms heterodimers with other C/EBP family members, and binds to the CHOP-binding site of DNA, which is distinct from the C/EBP-binding site. CHOP is also involved in the process of inflammation, through the activation of pro-IL-1β. The pathological roles of CHOP therefore remain to be further investigated.

The endoplasmic reticulum (ER) is the site of lipid and protein synthesis, protein folding and maturation, and storage of free calcium in eukaryotic cells. All proteins destined for the extracellular space, plasma membrane or other intracellular compartments are folded and assembled in the ER. Disruption of the ER homeostatic mechanisms, such as perturbations in intracellular calcium homeostasis, alteration of redox status and protein glycosylation, overloading of free cholesterol, or glucose deprivation, will induce accumulation of unfolded and misfolded proteins in the ER lumen. Mammalian cells respond to these perburbations by activating the ER stress response signaling pathway, called the unfolded protein response (UPR). This cellular stress pathway is designed to cope with various environmental perturbations and ensure that protein-folding capacity is not overwhelmed. The malfolded proteins are eliminated by ERassociated protein degradation (ERAD). However, prolonged activation of the UPR ultimately triggers cell apoptosis. Recent studies have demonstrated that ER stress-induced apoptosis plays a critical role in the pathogenesis of many diseases such as diabetes, neurodegenerative diseases, inflammation, liver disease, and cardiovascular disease. This review summarizes the recent understanding of ER stress signaling in the pathogenesis of atherosclerosis.