Current Hypertension Reviews - Volume 6, Issue 4, 2010

Direct Renin Inhibitors (DRIs) are a new class of medication, and are the first which block the rate-limiting step of the renin-angiotensin-aldosterone-system (RAAS). Aliskiren, the first licensed orally active DRI, has been shown to be an effective antihypertensive agent. This review article outlines the pharmacological basis for DRI therapy, from discovery of the class to ongoing clinical trials and novel therapeutic applications of aliskiren.

Hypertension, a major cardiovascular risk factor, is the primarily cause of mortality worldwide. A large body of evidence indicates that patients with essential hypertension, and even more those with complicated hypertension, are characterized by endothelial dysfunction due to impaired nitric oxide (NO) availability secondary to oxidative stress production. Therefore, a dysfunctioning endothelium is an early marker in the development of cardiovascular events. This observation suggest that treatment strategies that improve endothelial function would exert beneficial effects in hypertensive subjects, and may also help to prevent the development of hypertension and its cardiovascular complications. Part I of the present review describes the etiology of hypertension as well as the role of NO in the physio-pathology of the endothelium whereas in Part II, we are reporting novel treatments e.g. beta-blockers, ACE inhibitors, calcium channel antagonists, NO therapies, selective inhibitors of PDE Type 5, statins and regular aerobic physical exercise to the event to improve or restore endothelial function. In the near future, large scale clinical trials are required to demonstrate that treatment of endothelial dysfunction can lead to better prognosis in patients with essential hypertension.

Terrestrial mammals, like human, must reserve water and NaCl to counter the effects of dry-environments. Their kidneys need to reabsorb as much water and sodium as possible along the proximal tubules and collecting duct. Thus, excess sodium intake tends to sodium accumulation in the body. The renal (tissue) kallikrein-kinin system (KKS) exists to prevent excessive sodium reabsorption. Renal kallikrein is secreted from the distal connecting tubule cells, which are located just distal to the major reabsorbing system. Kallikrein releases kinins, which inhibit sodium reabsorption along the collecting ducts. The kinins in the tubules are quickly destroyed by kidney-specific destroying enzymes (kininases), carboxypeptidase Y-like exopeptidase and neutral endopeptidase, which differ completely from those in plasma. Ebelactone B and poststatin were discovered as selective inhibitors of urinary kininases. Excess sodium intake causes hypertension, since sodium accumulation in the blood vessel walls increases sensitivity to hypertensive agents. Potassium, and ATP-sensitive potassium channel blockers cause renal kallikrein secretion. In bradykinin B2 receptor gene knockout mice, tissue kallikrein gene knockout mice, and kininogen-deficient rats, the knockout or deficiency does not itself induce hypertension, but these animals are salt-sensitive. Mutant kininogen-deficient (kinin-free) rats on 2% sodium intake quickly develop hypertension. Urinary kininase inhibitors reduce high blood pressure due to sodium accumulation on high sodium intake. Our ample supporting data suggest that the renal KKS prevents sodium accumulation, and that reduced levels of renal kallikrein may cause salt-sensitive hypertension.

Increased blood pressure and hypertension are a major atherosclerotic risk factor. Arterial stiffness is recognized to be reflective to the atherosclerotic states. The pulse wave velocity (PWV) is a noninvasive, simple, easy and reproducible index that can be used to assess arterial stiffness in association with blood pressure. The cardio-ankle vascular index (CAVI) has recently been developed to evaluate arterial stiffness similarly to PWV, but theoretically, this index is less influenced by blood pressure. There have been several clinical reports on the use of the CAVI in patients with hypertension. The CAVI levels are reported to be significantly and positively correlated with the ultrasonographical atherosclerotic parameters of carotid arteries, as a surrogate marker of atherosclerotic events, in hypertensive patients. Intervention studies of anti-hypertensive therapy using CAVI have shown that candesartan, olmesartan and efonidipine can improve the CAVI levels. These results suggest that the CAVI is clinically helpful for the assessment of atherosclerotic risk and the management with drug treatment in patients with hypertension. However, compared with PWV, there is not much evidence of using CAVI in a clinical setting; future research is therefore necessary.

In this review, we describe target organ damage and cardiovascular events in masked hypertension. Masked hypertension is associated with more target organ damage, including sustained hypertension, left ventricular hypertrophy, carotid atherosclerosis, microalbuminuria, silent cerebral infarct, arterial stiffness, central blood pressure and obstructive sleep apnea, than is sustained normotension. Masked hypertension represents a strong predictor of cardiovascular morbidity and mortality in diverse patient groups including diabetics and patients with prehypertension. Therefore, clinicians should pursue the diagnosis of masked hypertension in individuals at increased cardiovascular risk and follow patients with prehypertension, encouraging out-of-office monitoring of blood pressure.

Oxidative stress is characterized by the elevation of reactive oxygen species (ROS) including the superoxide anion, hydrogen peroxide and the hydroxyl radical. In almost all animal models of hypertension and humans, reducing oxidative stress with antioxidants will lower blood pressure and elevating oxidative stress increases the blood pressure. Generation of ROS in the renal vasculature is accomplished through NADPH oxidase which is expressed in macula densa and afferent arterioles (AA) and leads to enhanced arteriolar tone and reactivity which precede the onset of hypertension. The underlying mechanism is proposed to involve enhanced tubuloglomeruar feedback (TGF) through depletion of NO through interaction with superoxide anion in the juxtaglomerular apparatus (JGA) to form peroxynitrite and a number of microvascular mechanisms including abnormal elevation of intracellular calcium concentration ([Ca2+]i) which can lead to an increased vascular tone and remodeling. The Na+/Ca2+ exchanger (NCX) is critical in regulating cytosolic calcium homeostasis and our studies show that oxidative stress-induced dysregulation of cytosolic calcium homeostasis is mediated through increased Ca2+ influx through the NCX, an effect which is more pronounced in cells expressing an NCX isoform that is expressed in Salt Sensitive Dahl rat. Ca2+ influx through the NCX is preceded by elevation of intracellular Na+ (Nai) and membrane depolarization. Because of the proximity of the Na+/K+-ATPase and the NCX in the PLasmERosome, it is likely that oxidative stress-induced [Ca2+]i elevation in AA smooth muscle cells is initiated by oxidative stress-induced inhibition of the Na+/K+-ATPase which increases Nai that leads to membrane depolarization and Ca2+ influx through the NCX.

Arterial remodeling over time is a cornerstone of normal systemic aging. The age-associated arterial structural and functional changes in the intima, the media, and the adventitia are closely linked to angiotensin II (Ang II) signaling. A growing line of evidence indicates that essential elements of Ang II signaling, which encompasses milk fat globule epidermal growth factor-8, calpain-1, transforming growth factor-β1, matrix metalloproteinase-2/9, monocyte chemoattractant protein-1, nicotinamide adenine dinucleotide phosphate-oxidase, and reactive oxygen species, are upregulated within the central arterial wall in rats, nonhuman primates, and humans during aging. In vitro studies show that the elevation of Ang II signaling induces the accumulation of collagen and advanced glycated end-products, the degradation of elastin, and the increased cell cycle disorder, invasion, and hypertrophy of endothelial and vascular smooth muscle cells. Further, in vivo studies demonstrate that increased Ang II signaling accelerates arterial aging. Conversely, attenuating Ang II signaling via an inhibition of angiotensin conversing enzyme or a blockade of AT1 activation retards age-associated arterial remodeling. This review attempts to integrate complex facts of Ang II signaling within the aged central arterial wall and may shed light on new therapeutic targets for arterial aging.

Hypertension is among the common and leading causes of morbidity and mortality throughout the globe. The biological process of hypertension involves multiple physiological pathways, each of which may be affected by multiple gene products. But the mechanisms under this difference are still not full understood. In recent years, some evidence has been found supporting the involvement of epigenetic mechanisms in many cardiovascular diseases and others. We hypothesised that epigenetic mechanisms have been also involved in essential hypertension possibly by suppression of and changing the relational genes with essential hypertension.