Current Hypertension Reviews (v.9, #2)

Editorial (Hot Topic: Renin-Angiotensin System in Neuronal Disease) by Masaki Mogi, Naohisa Hosomi, Akira Nishiyama, Kousei Ohshima (85-85).

Do RAS Inhibitors Protect the Brain from Cerebral Ischemic Injury? by Naohisa Hosomi, Akira Nishiyama, Masayasu Matsumoto (86-92).
In addition to centrally regulating electrolyte homeostasis and blood pressure, angiotensin IIhas various generaleffects on the central nervous system. The existence of renin-angiotensin system components in the brain has been wellestablished. Angiotensin II and other renin-angiotensin system components are synthesized and distributed throughout thebrain. Post-ischemic oral administration of a non-hypotensive dose (1/10th of the clinical dose) of angiotensin receptorblocker (ARB) has protective effects on reducing cerebral ischemic injury and improving neurological outcomes. Braintissue angiotensin II levels transiently increase after reperfusion through the local generation of angiotensin IIand not viathe transudation of plasma angiotensin II. Systemic administration of ARBs decreases brain tissue angiotensin II in boththe intact and ischemic brain tissue via downregulation of angiotensinogen and angiotensin-converting enzyme mRNAexpression, although plasma ARB barely crosses the blood-brain barrier during systemic ARB treatment. Onlyhypotensive dose of ARB treatment opens leptomeningeal anastomoses. Therefore, systemic ARB treatment showsneuroprotective effects not through increasing collateral perfusion but decreasing brain tissue angiotensin II in a nonhypotensivedose.

RAS Inhibition Attenuates Cognitive Impairment by Reducing Blood- Brain Barrier Permeability in Hypertensive Subjects by Nicolas Pelisch, Naohisa Hosomi, Hirohito Mori, Tsutomu Masaki, Akira Nishiyama (93-98).
Recent studies have suggested that blood-brain barrier (BBB) abnormalities are present from an early stage inpatients exhibiting mild symptoms of cognitive impairment during the development of hypertension. There is alsogrowing body of evidence suggesting the potential role of the renin-angiotensin system (RAS) in the pathogenesis ofsmall-vessel disease and cognitive impairment. However, the specific contribution of the RAS to BBB disruption andcognitive impairment remains unclear. We found a significant leakage from brain microvessels in the hippocampus andimpaired cognitive functions in angiotensin II (AngII)-infused hypertensive mice, which were associated with increasedbrain AngII levels. These changes were not observed in AngII-infused AT1a receptor (-/-) mice. We also observed thatDahl salt-sensitive hypertensive rats exhibited hypertension, leakage from brain microvessels in the hippocampus, andimpaired cognitive function. In these animals, treatment with an AngII receptor blocker, olmesartan, did not alter bloodpressure, but markedly ameliorated leakage from brain microvessels and restored the cognitive decline. These datasupport the hypothesis that RAS inhibition attenuates cognitive impairment by reducing BBB injury, which is independentof blood pressure changes.

Therapeutic Approach for Neuronal Disease by Regulating Reninangiotensin System by Kousei Ohshima, Masaki Mogi, Masatsugu Horiuchi (99-107).
The renin-angiotensin system (RAS) has been postulated to regulate not only systemic hemodynamic andhydromineral homeostasis but also individualorgan function in the normal condition. On the other hand, its systemic andlocalactivationleads to hypertension and diabetes mellitus,resulting intarget end organ damage.RAS in the brain is alsowell known to be involved in the pathogenesis and progression of neuronal disease, as well as regulating blood pressure,sympathetic activity, vasopressin secretion, thirst and sodium appetite.There is increasing evidence that RAS maycontribute to neuroinflammation associated with many neuronal diseases in several animal models. Moreover, recentclinical evidence indicates that RAS blockade, including that byangiotensin converting enzyme inhibitors and angiotensinII receptor blockers, has beneficial effects in treating stroke, cognitive dysfunction, Alzheimer disease and other neuronaldiseases, suggesting the potential of RAS as a new therapeutic target in neuronal diseases. This article reviews the recentfindings ofbrain RAS involvement and thetherapeutic potential of regulating RAS in neuronal disease.

The renoprotective effects of benidipine, a calcium channel blocker (CCB) developed in Japan, are reviewedherein. Benidipine has a sustained antihypertensive effect independent of its blood concentration since it binds todihydropyridine (DHP) receptors via a ?membrane approach? (approach to the cell membrane followed by long retentionat the DHP binding site). Benidipine dilates glomerular afferent and efferent arterioles equally through inhibition of TtypeCa channels. Thus, it may cause a decrease of intraglomerular pressure and is superior to CCBs (capable of inhibitingonly L-type Ca channels) in terms of suppression of proteinuria. Additionally, benidipine suppresses worsening of renalfunction more powerfully than CCBs (suppressing only L-type Ca channels), allowing better prognosis as to renalfunction. The inhibitory effect of benidipine on T-type calcium channels results in the suppression of aldosteroneformation in the adrenal glands and of oxidative stress induced by aldosterone. Thus, the aldosterone-inhibitory andantioxidant activities of benidipine mediated by inhibition of T-type calcium channels would result in renoprotection andsuppression of disease progression in hypertensive patients with chronic kidney disease (CKD). If such patients haveproteinuria, renin-angiotensin system (RAS) inhibitors are used as first-line drugs, but benidipine, as an L-/T-type CCB, isrecommended when they require some concomitant drugs. Moreover, the superiority of RAS inhibitors has not beendemonstrated in hypertensive patients with CKD and without proteinuria. Thus, in such patients, benidipine should beconsidered as a first-line antihypertensive drug.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failurein the world. Currently there are no treatments to prevent kidney due to ADPKD. Vitamin D is traditionally known for itsrole in maintaining calcium balance and normal bone health, but it is being increasingly being recognised for a number ofother important physiological functions, including reducing blood pressure and proteinuria as well as kidney inflammationandfibrosis. Vitamin D deficiency is associated with proteinuria, increased mortality and may mediate the progression tokidney failure. Recent data from an Australian cohort study (AusDiab) reveals that vitamin D deficiency and insufficiencyare common conditions, affecting 26.6% and 42.1% of the Australian community respectively. Preclinical studies fromour 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 designof an open-label observational study of humans with ADPKD (eGFR>30 ml/min/1.73m2). All subjects will undergoscreening for vitamin D levels at the beginning of study, and those that are found to be either deficient (<50 nmol/L) orinsufficient (<75 nmol/L) will be repleted with oral cholecalciferol for 6 months. We predict that cholecalciferol willattenuate 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 asimple intervention such as vitamin D repletion, in either deficient or insufficient states, is a treatment to prevent kidneyfailure in ADPKD.

Renal artery stenosis especially that due to atherosclerotic peripheral vascular disease is increasing in thepopulation. The role of the renin angiotensin aldosterone system in the pathogenesis of renovascular hypertension iswidely accepted. There is increasing recognition of the role of the sympathetic nervous system, from both afferent andefferent signaling pathways, as a contributor to development of hypertension. In this review we briefly summarize theexperimental evidence for the respective roles of the renin angiotensin aldosterone system and the sympathetic nervoussystem 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% ofthe total), more than any other cardiovascular disease risk factor. Exercise decreases blood pressure (BP) 5-7 mmHgamong 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 isconsiderable individual variability in the BP response to exercise due to genetic and environmental factors that are poorlyunderstood. We and others have shown there is a genetic component to the BP response to exercise accounting for asignificant proportion of this variability. However, identification of specific genetic variants accounting for this variabilityis a significant challenge. This review describes new work on candidate gene and BP association studies. It also describesother important emerging work in genome wide association studies, next generation sequencing, epigenetics, and geneexpression regulation, and how this work may have future relevance to ExRx for hypertension. The ultimate goal of ourresearch is to use genetic information to personalize ExRx to optimize the effectiveness of exercise as a therapeuticmodality for the prevention, treatment, and control of hypertension. Because of the complexities surrounding work inexercise genomics, the future use of genomics in ExRx for hypertension still remains a vision of the future rather than areality of the present.

Roles of Renal Proximal Tubule Transport in the Pathogenesis of Hypertension by Shoko Horita, George Seki, Hideomi Yamada, Masashi Suzuki, Kazuhiko Koike, Toshiro Fujita (148-155).
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, thekidney plays an essential role in the regulation of blood pressure, but is also quite vulnerable to hypertensive tissuedamage. For example, most chronic kidney disease (CKD) patients have hypertension and are revealed to have highermortality than normal population. Furthermore, hypertensive renal sclerosis is emerging as the third main cause of dialysispatients. 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.

Diagnosis and Treatment of Unilateral Forms of Primary Aldosteronism by Andrea Viola, Davide Tizzani, Silvia Monticone, Valentina Crudo, Maddalena Galmozzi, Jacopo Burrello, Karine Versace, Maria Loiacono, Franco Veglio, Paolo Mulatero (156-165).
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 increasedcardiovascular risk compared to essential hypertension and by the possibility of reversing this increased risk with atargeted therapy. Surgical treatment of unilateral forms of PA (mainly aldosterone-producing adenomas) is at presentrecommended in well-selected patients because of its cost-effectiveness. Therefore, subtype differentiation of PA forms isof fundamental importance, and available guidelines recommend contrast-enhanced CT-scanning and adrenal venoussampling (AVS) as the main diagnostic tests for this purpose. In this review, we discuss the value of adrenal non-invasiveimaging and AVS, the recent advances in complementary tests and, finally, the available data on the outcome of surgicaltreatment for PA.