Current Hypertension Reviews - Volume 5, Issue 4, 2009

Over the last ten years it has become clear that vascular actions of insulin extend beyond its ability to increase skeletal muscle blood flow and glucose uptake. In addition to its role in regulating glucose, protein, and fatty acid metabolism insulin exhibits distinct effects on the vascular system. In this review we will clarify the influence exerted by insulin in the maintenance of endothelial function and the relationship between insulin resistance, endothelial dysfunction and hypertension. The mechanisms by which insulin resistance leads to endothelial dysfunction are multiple and complex. Most of the abnormalities present in the insulin resistance syndrome (obesity, hyperglicemia, hypertension, dyslipidemia) are linked to endothelial dysfunction. Insulin vasodilates skeletal muscle vasculature through release of nitric oxide (NO), a mechanism that accounts for 30% of insulin overall action to stimulate glucose uptake. On the one hand, PI3-kinase-dependent insulin signalling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. On the other hand, distinct non-metabolic insulin signaling pathways (MAPK-dependent insulin signalling pathways) regulate secretion of the vasoconstrictor endothelin-1 (ET-1) from endothelium. Insulin resistance is characterized by the specific impairment of PI 3-kinase-dependent signalling that causes imbalance between NO and ET-1 production, leading to reduction of blood flow that, in turn, worsens insulin resistance. Insulin resistance is the common metabolic defect underlying type 2 diabetes, hypertension, obesity, dyslipidemia and coronary heart diseases; therefore, improving insulin sensitivity may provide an opportunity for simultaneous therapeutic strategies on metabolic and cardiovascular diseases.

Stroke is a great matter of interest especially in the industrialised countries, because of pronounced morbidity and mortality. Recurrent ischemic brain attacks are usually caused due to embolism by arrhythmic heart diseases or by occlusive disease of carotid artery (CA) due to atherosclerosis, furthering with risk factors such as hypertension, metabolic disorders, smoking, and other life-style factors. In patients with CA occlusion and reduced cerebrovascular reserve capacity (CVR), revealed by different technical modalities of CCT, MRI or PET, the EC-IC bypass can apparently prevent recurrent ischemic attacks. Some studies as well as own experiences with brain revascularisation by means of EC-IC bypass, has documented cessation of symptoms in majority of patients. Brain revascularisation should be taken into account in the proper group of patients with occlusion of CA, if sufficient anticoagulating therapy is not effective. Which of the patients with recurrent ischemic stroke based on occluded CA are proper candidates for the revascularization is not definitive. Further trials especially for redefined subgroups of patients must bring decision in this matter, as recommended by the Carotid Occlusion Surgery Study group. Unfortunately, the data published in 1985 by the EC-IC Bypass Study Group do not considered diverse subgroups of patients and their differed CVR owing to occlusion of internal carotid artery. This issue should be a matter of interest for the future.

The endothelium is a rich source of biological mediators that serve to control blood flow, temper inflammation and maintain local homeostasis. Endothelium-derived nitric oxide (NO) is the prototype of these molecules and is critical in preventing the initiation and progression of vascular disease. Consistent with a central role for NO in vascular disease, disruptions in its production and/or bioavailability have been linked to hypertension, diabetes, hypercholesterolemia, obesity, aging, and smoking. Furthermore substrate and cofactor bioavailability, NOS isoform expression profiles and oxidative stress are crucial determinants as to whether homeostatic levels of NO are maintained in blood vessels. In addition to its direct actions, NO is an important modulator of other vasoregulatory pathways such as cyclooxygenase (COX)-derived eicosanoid production and angiotensin II generation by the renin-angiotensin system. Furthermore, NO may direct the selectivity of COX-2 inhibitors; a finding relevant to controversies associated with the use of these drugs. Herein, we examine pathways that are directly or indirectly modified by alterations in NO synthesis and that are targetable for the development of novel, effective and safe agents for the treatment of cardiovascular disease.

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERa, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca2+]i, protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in pharmacokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, “hormone bioidenticals” and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in relation to the levels and effects of other sex hormones including progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to the outcome of MHT in postmenopausal CVD, as more specific modulators of sex hormone receptors become available and are used at the right dose, route of administration and timing, depending on the subject's age and preexisting cardiovascular condition.

The lack of effective hypertension management increases the risk of cardiovascular events. Issues of compliance to antihypertensive treatment are commonly seen as the main cause of not obtaining optimal blood pressure control, despite the availability of clinically well tolerated antihypertensive drug therapies. Our focus will be, therefore, on factors related to patient, physician and health care delivery process reported to influence the adherence to antihypertensive treatment and, subsequently, to affect blood pressure lowering. Research efforts within primary care settings should be accomplished to develop and to implement initiatives that improve the overall management of hypertension and ‘primarily’ prevent phenomena of insufficient adherence to treatment.

Childhood obesity is associated with a significant increased risk for several metabolic and cardiovascular complications, including hypertension. The main mechanisms implicated in the pathogenesis of high blood pressure in relation to increased body weight are insulin resistance/hyperinsulinemia, sympathetic nervous system hyperactivity and alterations in vascular structure and function. Obesity-related hypertension is associated with cardiovascular complications already during childhood and with an increased risk of coronary heart disease in adulthood. A high prevalence of the nondipping phenomenon has also been detected in obese children and adolescents and this is worrying as this condition is associated with end-organ damage. Assessing blood pressure is therefore particularly important in obese children and adolescents for an early detection of its alterations. Ambulatory blood pressure monitoring represents an important method of measuring blood pressure, particularly in the suspicion of white-coat hypertension, masked hypertension and non-dipping phenomenon. Prevention and treatment of childhood obesity represent important means in order to prevent and reduce the incidence of hypertension and the associated cardiovascular risk. Reduction in body weight is generally the first step in the management of obesity-related hypertension. However, in severe cases or in cases non responsive to lifestyle interventions, drug therapy should be considered.

Endovascular renal arterial interventions remain important treatment strategies for symptomatic renal artery stenoses causing either renovascular hypertension, renal insufficiency, or cardiac disturbance syndromes. Since endovascular intervention has not been shown to be efficacious over optimal medical therapy, it should be reserved for certain specific indications, as well as whenever medical therapy has failed. This review will discuss the current indications, patient selection methods, technique, imaging follow up, adjunctive revascularization techniques,and complications of endovascular treatment of renal artery stenoses, as well as the current trials comparing endovascular treatment to medical therapy.