Current Hypertension Reports

Siragy, Helmy

doi: 10.1007/s11906-010-0124-4pmid: 20524089

Hollenberg, Norman

doi: 10.1007/s11906-010-0128-0pmid: N/A

Bradford, Chastity N.; Ely, Debra R.; Raizada, Mohan K.

doi: 10.1007/s11906-010-0122-6pmid: 20556668

A decade has passed since the discovery of angiotensin-converting enzyme 2 (ACE2), a component of the ACE2–angiotensin (Ang)-(1-7)–Mas counterregulatory axis of the renin angiotensin system (RAS). ACE2 is considered an endogenous regulator of the vasoconstrictive, proliferative, fibrotic, and proinflammatory effects of the ACE–Ang II–angiotensin II type 1 receptor (AT1R) axis. Both animal and clinical studies have emerged to define a role for ACE2 in pulmonary arterial hypertension (PAH). There is scientific evidence supporting the concept that ACE2 maintains the RAS balance and plays a protective role in PAH. The activation of pulmonary ACE2 could influence the pathogenesis of PAH and serve as a novel therapeutic target in PAH. Current therapeutic strategies and interventions have limited success, and PAH remains a fatal disease. Thus, more research that establishes the novel therapeutic potential and defines the mechanism of the ACE2–Ang-(1-7)–Mas counterregulatory axis in PAH is needed.

Jansen, Pieter; Danser, Jan; Spiering, Wilko; Meiracker, Anton

doi: 10.1007/s11906-010-0123-5pmid: 20532698

Obesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiotensin system, leading to renal sodium and water retention, links obesity with hypertension. There is also evidence for the release of factors by visceral adipose tissue promoting excessive aldosterone production, and a more central role of aldosterone in obesity hypertension is emerging. Randomized studies evaluating the effect of different classes of antihypertensive agents in obesity hypertension are scarce, short-lasting, and small. Considering the emerging role of aldosterone in the pathogenesis of obesity hypertension, mineralocorticoid receptor antagonism may play a more central role in the pharmacologic treatment of obesity hypertension in the near future.

Rehman, Asia; Schiffrin, Ernesto

doi: 10.1007/s11906-010-0117-3pmid: 20514556

Hypertension is associated with structural and functional alterations in the vasculature that lead to hemodynamic disturbances and target organ damage. The benefit of reducing blood pressure on risk reduction is well established. Antihypertensive drugs partially correct hypertensive vascular changes by a number of mechanisms, but their influence may vary in different vascular beds. Recently, combinations of drugs with complementary or synergistic effects have shown favorable effects on the vasculature; these combinations may contribute to risk reduction and improve outcomes in the future. Clinical trial evidence has shown an improvement in morbidity and mortality indicators that could be related to vascular effects of antihypertensive drugs, but this effect needs to be proven in future long-term prospective studies involving simultaneous evaluation of small-artery and large-artery properties.

Laffer, Cheryl; Elijovich, Fernando

doi: 10.1007/s11906-010-0125-3pmid: 20524088

It is currently accepted that hypertension, atherosclerosis, and diabetes are disorders with subtle or overt activation of inflammatory mediators. Therefore, it has become increasingly important to ascertain whether current antihypertensive drug families have proinflammatory or anti-inflammatory actions that modify the outcomes of their hemodynamic effects on blood pressure. We review the current state of knowledge about the effects of the major classes of available antihypertensive agents on inflammation and speculate on the possible contribution of these effects to observations in clinical trials. We suggest that a strategy of drug development specifically addressing inflammation in hypertension may provide increased benefit in terms of target organ damage, and we describe some examples of these promising developments.

Ko, Seung-Hyun; Cao, Wenhong; Liu, Zhenqi

doi: 10.1007/s11906-010-0114-6pmid: 20582734

Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes.

Tirosh, Amir; Garg, Rajesh; Adler, Gail

doi: 10.1007/s11906-010-0126-2pmid: 20563672

Key components of the metabolic syndrome (MetS), ie, obesity and insulin resistance, are associated with increased aldosterone production and mineralocorticoid receptor (MR) activation. Both MetS and hyperaldosteronism are proinflammatory and pro-oxidative states associated with cardiovascular disease. This review discusses emerging data that MR activation may contribute to abnormalities seen in MetS. In view of these data, MR antagonists may be beneficial in MetS, not only by controlling hypertension but also by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level. Clinical trials have demonstrated benefits of MR antagonists in heart failure, hypertension, and diabetic nephropathy, but additional trials are needed to demonstrate the clinical significance of MR blockade in MetS.

Elliott, William

doi: 10.1007/s11906-010-0120-8pmid: 20524091

There are many theories about why selective inhibitors of the second isoform of cyclooxygenase (COX-2) increase cardiovascular risk. Although torcetrapib raises blood pressure and cardiovascular risk, it has been difficult to prove such a link for COX-2 inhibitors in randomized clinical trials. This review shows a significant correlation in placebo-controlled trials between the five agents’ elevations in blood pressures and their rate ratios for cardiovascular events. A larger body of evidence arises from randomized clinical trial comparisons of selective versus nonselective inhibitors of COX-2, but these results are heterogeneous for naproxen versus other traditional agents. The best current trial evidence comes from the centrally adjudicated placebo-controlled trials of celecoxib for colonic polyps: If the blood pressure did not rise at 1 or 3 years after randomization, cardiovascular risk did not significantly increase. Many more data will become available in 2013, after the only prospective clinical trial involving cardiovascular end points is completed.

Félétou, Michel; Köhler, Ralf; Vanhoutte, Paul

doi: 10.1007/s11906-010-0118-2pmid: 20532699

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage.