Current Hypertension Reviews - Volume 9, Issue 2, 2013

In addition to centrally regulating electrolyte homeostasis and blood pressure, angiotensin IIhas various general effects on the central nervous system. The existence of renin-angiotensin system components in the brain has been well established. Angiotensin II and other renin-angiotensin system components are synthesized and distributed throughout the brain. Post-ischemic oral administration of a non-hypotensive dose (1/10th of the clinical dose) of angiotensin receptor blocker (ARB) has protective effects on reducing cerebral ischemic injury and improving neurological outcomes. Brain tissue angiotensin II levels transiently increase after reperfusion through the local generation of angiotensin IIand not via the transudation of plasma angiotensin II. Systemic administration of ARBs decreases brain tissue angiotensin II in both the intact and ischemic brain tissue via downregulation of angiotensinogen and angiotensin-converting enzyme mRNA expression, although plasma ARB barely crosses the blood-brain barrier during systemic ARB treatment. Only hypotensive dose of ARB treatment opens leptomeningeal anastomoses. Therefore, systemic ARB treatment shows neuroprotective effects not through increasing collateral perfusion but decreasing brain tissue angiotensin II in a nonhypotensive dose.

Recent studies have suggested that blood-brain barrier (BBB) abnormalities are present from an early stage in patients exhibiting mild symptoms of cognitive impairment during the development of hypertension. There is also growing body of evidence suggesting the potential role of the renin-angiotensin system (RAS) in the pathogenesis of small-vessel disease and cognitive impairment. However, the specific contribution of the RAS to BBB disruption and cognitive impairment remains unclear. We found a significant leakage from brain microvessels in the hippocampus and impaired cognitive functions in angiotensin II (AngII)-infused hypertensive mice, which were associated with increased brain AngII levels. These changes were not observed in AngII-infused AT1a receptor (-/-) mice. We also observed that Dahl salt-sensitive hypertensive rats exhibited hypertension, leakage from brain microvessels in the hippocampus, and impaired cognitive function. In these animals, treatment with an AngII receptor blocker, olmesartan, did not alter blood pressure, but markedly ameliorated leakage from brain microvessels and restored the cognitive decline. These data support the hypothesis that RAS inhibition attenuates cognitive impairment by reducing BBB injury, which is independent of blood pressure changes.

The renoprotective effects of benidipine, a calcium channel blocker (CCB) developed in Japan, are reviewed herein. Benidipine has a sustained antihypertensive effect independent of its blood concentration since it binds to dihydropyridine (DHP) receptors via a “membrane approach” (approach to the cell membrane followed by long retention at the DHP binding site). Benidipine dilates glomerular afferent and efferent arterioles equally through inhibition of Ttype Ca channels. Thus, it may cause a decrease of intraglomerular pressure and is superior to CCBs (capable of inhibiting only L-type Ca channels) in terms of suppression of proteinuria. Additionally, benidipine suppresses worsening of renal function more powerfully than CCBs (suppressing only L-type Ca channels), allowing better prognosis as to renal function. The inhibitory effect of benidipine on T-type calcium channels results in the suppression of aldosterone formation in the adrenal glands and of oxidative stress induced by aldosterone. Thus, the aldosterone-inhibitory and antioxidant activities of benidipine mediated by inhibition of T-type calcium channels would result in renoprotection and suppression of disease progression in hypertensive patients with chronic kidney disease (CKD). If such patients have proteinuria, renin-angiotensin system (RAS) inhibitors are used as first-line drugs, but benidipine, as an L-/T-type CCB, is recommended when they require some concomitant drugs. Moreover, the superiority of RAS inhibitors has not been demonstrated in hypertensive patients with CKD and without proteinuria. Thus, in such patients, benidipine should be considered as a first-line antihypertensive drug.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in the world. Currently there are no treatments to prevent kidney due to ADPKD. Vitamin D is traditionally known for its role in maintaining calcium balance and normal bone health, but it is being increasingly being recognised for a number of other important physiological functions, including reducing blood pressure and proteinuria as well as kidney inflammation andfibrosis. Vitamin D deficiency is associated with proteinuria, increased mortality and may mediate the progression to kidney failure. Recent data from an Australian cohort study (AusDiab) reveals that vitamin D deficiency and insufficiency are common conditions, affecting 26.6% and 42.1% of the Australian community respectively. Preclinical studies from our laboratory have identified that vitamin D deficiency exacerbates proteinuria and hypertension in experimental PKD, and that this is reversed by treatment with vitamin D receptor agonist. In this manuscript, we report the rational and design of an open-label observational study of humans with ADPKD (eGFR>30 ml/min/1.73m2). All subjects will undergo screening for vitamin D levels at the beginning of study, and those that are found to be either deficient (<50 nmol/L) or insufficient (<75 nmol/L) will be repleted with oral cholecalciferol for 6 months. We predict that cholecalciferol will attenuate hypertension, proteinuria and reduce the urinary excretion of a biomarker, monocyte chemoattractant protein-1 (MCP-1, a surrogate inflammatory marker of progression in ADPKD). This study will provide evidence as to whether a simple intervention such as vitamin D repletion, in either deficient or insufficient states, is a treatment to prevent kidney failure in ADPKD.

Renal artery stenosis especially that due to atherosclerotic peripheral vascular disease is increasing in the population. The role of the renin angiotensin aldosterone system in the pathogenesis of renovascular hypertension is widely accepted. There is increasing recognition of the role of the sympathetic nervous system, from both afferent and efferent signaling pathways, as a contributor to development of hypertension. In this review we briefly summarize the experimental evidence for the respective roles of the renin angiotensin aldosterone system and the sympathetic nervous system as well as their interaction in renovascular hypertension.

Hypertension is a major global public health problem, resulting in over 7.6 million deaths per year (13.5% of the total), more than any other cardiovascular disease risk factor. Exercise decreases blood pressure (BP) 5-7 mmHg among those with hypertension. Thus, the American College of Sports Medicine recommends the exercise prescription (ExRx) of 30 min or more of moderate intensity, aerobic activity on most days of the week to lower BP. Yet, there is considerable individual variability in the BP response to exercise due to genetic and environmental factors that are poorly understood. We and others have shown there is a genetic component to the BP response to exercise accounting for a significant proportion of this variability. However, identification of specific genetic variants accounting for this variability is a significant challenge. This review describes new work on candidate gene and BP association studies. It also describes other important emerging work in genome wide association studies, next generation sequencing, epigenetics, and gene expression regulation, and how this work may have future relevance to ExRx for hypertension. The ultimate goal of our research is to use genetic information to personalize ExRx to optimize the effectiveness of exercise as a therapeutic modality for the prevention, treatment, and control of hypertension. Because of the complexities surrounding work in exercise genomics, the future use of genomics in ExRx for hypertension still remains a vision of the future rather than a reality of the present.

Hypertension is a key factor of cardiovascular disease. Many organs and systems including heart, blood vessel, kidney, sympathetic nerve, and endocrine systems are involved in the regulation of blood pressure. In particular, the kidney plays an essential role in the regulation of blood pressure, but is also quite vulnerable to hypertensive tissue damage. For example, most chronic kidney disease (CKD) patients have hypertension and are revealed to have higher mortality than normal population. Furthermore, hypertensive renal sclerosis is emerging as the third main cause of dialysis patients. This mini review is to summarize the effects of angiotensin II and dopamine on renal proximal tubule transport, which may have important roles in the regulation of blood pressure.

Primary aldosteronism (PA) is now recognized as the most frequent form of secondary arterial hypertension. The importance of a correct and prompt diagnosis of PA is determined by its relevant prevalence, its increased cardiovascular risk compared to essential hypertension and by the possibility of reversing this increased risk with a targeted therapy. Surgical treatment of unilateral forms of PA (mainly aldosterone-producing adenomas) is at present recommended in well-selected patients because of its cost-effectiveness. Therefore, subtype differentiation of PA forms is of fundamental importance, and available guidelines recommend contrast-enhanced CT-scanning and adrenal venous sampling (AVS) as the main diagnostic tests for this purpose. In this review, we discuss the value of adrenal non-invasive imaging and AVS, the recent advances in complementary tests and, finally, the available data on the outcome of surgical treatment for PA.