ABNORMALITIES OF RESISTANCE VESSEL STRUCTURE IN ESSENTIAL HYPERTENSION: ARE THESE IMPORTANT?

1. The relationship between essential hypertension and abnormalities of the proximal resistance vessels (small arteries) is reviewed, with particular emphasis on their structure. 2. There seems to be good evidence that the media: lumen ratio of these vessels is increased, and this may account for the increased pressor response. 3. Whether there is also growth is not clear, and it is possible that the altered structure is due to redistribution of existing cells. 4. Regardless of the basis for the altered structure, it appears that in essential hypertension the altered vascular structure is in itself sufficient to explain the increased peripheral resistance. 5. Paradoxically, the altered vascular structure does not seem to be the main determinant of blood pressure, but the altered vascular structure appears to allow it to perform its function in the most convenient fashion. 6. It is suggested that the interest in vascular structure lies in connection with therapy, for correction of blood pressure without correction of vascular structure will probably not prevent all the consequences of the disease. 7. Current therapies do not appear to be able, in the short-term, to normalize vascular structure, indicating that there is a need to find other more specific ways of correcting vascular structure.     

Structural alterations in small resistance arteries in obesity

In cardiovascular and metabolic diseases, small resistance arteries may show the presence of structural alterations. In particular, in essential hypertension, an increased media-to-lumen ratio of subcutaneous small arteries with no change in the total amount of vascular wall tissue (eutrophic remodelling) has already been described several years ago. Similar alterations have been demonstrated also in patients with diabetes mellitus and obesity; in this case, however, a more evident contribution of vascular smooth muscle cell growth (hypertrophic remodelling) is present. This review addresses the effects of obesity on small resistance artery structure. Similar to diabetic patients, obese patients show an increased media-to-lumen ratio of subcutaneous small arteries, which appears associated with hypertrophic remodelling, as demonstrated by an increase in media cross-sectional area. Endothelial dysfunction evaluated as vasodilator response to acetylcholine has also been observed. Several studies have shown that increased media-to-lumen ratio of subcutaneous small resistance arteries possesses a prognostic significance in relation to cardiovascular outcome. Appropriate antihypertensive treatment may improve microvascular alterations both in essential hypertension and in type 2 diabetes mellitus. In obesity, a pronounced weight loss may improve microvascular structure. However, further studies are needed to elucidate the effects of other pharmacological and non-pharmacological interventions in obesity.     

Pathoaetiology, epidemiology and diagnosis of hypertension

Hypertension is currently defined in terms of levels of blood pressure associated with increased cardiovascular risk. A cut-off of 140/90 mm Hg is accepted as a threshold level above which treatment should at least be considered. This would give a prevalence of hypertension of about 20% of the adult population in most developed countries. Hypertension is associated with increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. Hypertension results from the complex interaction of genetic factors and environmental influences. Many of the genetic factors remain to be discovered, but environmental influences such as salt intake, diet and alcohol form the basis of nonpharmacological methods of blood pressure reduction. Investigation of the individual hypertensive patient aims to identify possible secondary causes of hypertension and also to assess the individual's overall cardiovascular risk, which determines the need for prompt and aggressive therapy. Cardiovascular risk can be determined from (i) target organ damage to the eyes, heart and kidneys; (ii) other medical conditions associated with increased risk; and (iii) lifestyle factors such as obesity and smoking. Secondary causes of hypertension are individually rare. Screening tests should be initially simple, with more expensive and invasive tests reserved for those in whom a secondary cause is suspected or who have atypical features to their presentation. The main determinants of blood pressure are cardiac output and peripheral resistance. The typical haemodynamic finding in patients with established hypertension is of normal cardiac output and increased peripheral resistance. Treatment of hypertension should initially use nonpharmacological methods. Selection of initial drug therapy should be based upon the strength of evidence for reduction of cardiovascular mortality in controlled clinical trials, and should also take into account coexisting medical conditions that favour or limit the usefulness of any given drug. Given this approach, it would be reasonable to use a thiazide diuretic and/or a beta-blocker as first-line therapy unless there are indications to the contrary. Individual response to given drug classes is highly variable and is related to the underlying variability in the abnormal pathophysiology. There are data to suggest that the renin-angiotensin system is more important in young patients. The targeting of this system in patients under the age of 50 years with a beta-blocker (or ACE inhibitor), and the use of a thiazide diuretic (or calcium antagonist) in patients over 50 years, may enable blood pressure to be controlled more quickly.     

Basilar artery remodelling in the genetically hypertensive rat: effects of nitric oxide synthase inhibition and treatment with valsartan and enalapril

1. The structure of the basilar artery and the relationship of structure to blood pressure and ventricular hypertrophy was examined in genetically hypertensive (GH) rats, their control normotensive (N) Wistar strain, GH given the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) and GH given L-NAME and either valsartan or enalapril. 2. Systolic blood pressure (SBP; tail-cuff) was measured weekly from age 7-12 weeks. At the end of the experiment at 12 weeks, the basilar artery was fixed by perfusion and embedded in Technovit (Heraeus Kulzer GmbH, Werheim, Germany). Serial sections were cut and stained and stereological analysis applied to quantify the morphology of the vessels. Left ventricular (LV) mass was determined. 3. Both SBP and LV mass were significantly increased in GH compared with N (P < 0.001) and increased further in GH given L-NAME (P < 0.05). The GH L-NAME + valsartan and GH L-NAME + enalapril groups had significantly lower (P < 0.001) SBP and LV mass than the GH L-NAME group. 4. Basilar arteries in GH (which are frankly hypertensive, but have no apparent endothelial defect) showed hypotrophic inward remodelling compared with the N control group with no change in media to lumen ratio. 5. In the GH L-NAME group, further inward remodelling occurred and the media to lumen ratio was increased compared with N (P < 0.01) and GH (P < 0.05). Valsartan treatment in GH L-NAME rats caused eutrophic outward remodelling. Enalapril caused hypertrophic outward remodelling, suggesting that the angiotensin II-stimulated growth was not entirely suppressed with an angiotensin-converting enzyme inhibitor or that there was a bradykinin effect with enalapril. 6. In GH with an endothelial defect induced by treatment with L-NAME, the further remodelling, together with an increased media to lumen ratio and the development of a stroke-like syndrome, indicates the NOS-inhibited GH rat may be a useful model for essential hypertension (where it is known that endothelial abnormalities exist) and where stroke can develop as a consequence of the hypertension.     

Matrix Metalloproteinases are Involved in Cardiovascular Diseases

This MiniReview describes the essential biochemical and molecular aspects of matrix metalloproteinases (MMPs) and briefly discusses how they engage in different diseases, with particular emphasis on cardiovascular diseases. There is compelling scientific evidence that many MMPs, especially MMP‐2, play important roles in the development of cardiovascular diseases; inhibition of these enzymes is beneficial to many cardiovascular conditions, sometimes precluding or postponing end‐organ damage and fatal outcomes. Conducting comprehensive discussions and further studies on how MMPs participate in cardiovascular diseases is important, because inhibition of these enzymes may be an alternative or an adjuvant for current cardiovascular disease therapy.     

CARDIOVASCULAR ACTIONS OF INSULIN: ARE THEY IMPORTANT IN LONG-TERM BLOOD PRESSURE REGULATION?

1. In recent years, there has been considerable interest in the possibility that insulin may have important cardiovascular as well as metabolic actions. Perhaps the best documented cardiovascular effect of insulin is to cause peripheral vasodilation, especially in skeletal muscle. Hyperinsulinaemia also stimulates sympathetic activity and causes antinatriuresis, but these effects may be linked, at least in part, to the metabolic actions of insulin that elicit peripheral vasodilation and a tendency toward hypotension. Normal, fasting levels of insulin appear to have very little influence on peripheral vascular resistance, sympathetic activity or renal sodium excretion. 2. Decreased sensitivity of the peripheral tissues to the metabolic effects of insulin and compensatory hyperinsulinaemia have been postulated to play key roles in the pathophysiology of diseases such as hypertension and atherosclerosis. Although impaired insulin action (insulin resistance) and hyperinsulinaemia often accompany essential hypertension, especially when associated with obesity, there is currently little direct evidence for a cause and effect relationship between insulin resistance, hyperinsulinaemia and increased arterial pressure. Chronic increases in plasma insulin levels in dogs and humans have not been shown to cause hypertension, although hyperinsulinaemia raises blood pressure in rats. 3. Further research is needed to determine whether there are pathophysiological conditions or genetic factors that may predispose humans to a hypertensive effect of hyperinsulinaemia and/or insulin resistance.     

Matrix metalloproteinases and small artery remodeling

Inward eutrophic remodeling is a common structural change found in small resistance arteries that has been associated with an increased risk for life threatening cardiovascular events, the number one cause of death in industrialized societies. Because inward eutrophic remodeling is the most prevalent small artery structural change found in hypertension, hypertensive animals are the most common in vivo models used to study this particular remodeling process. In vitro, the isolated artery, pressure myograph has also been used as a model to study the mechanisms responsible for the development of small artery remodeling. Compelling recent evidence indicates that the matrix metalloproteinases (MMPs), a family of endopeptidases whose primary function is the cleavage and degradation of extracellular matrix components, are involved in vasoconstriction and the pathogenesis of hypertension. In this review we provide an overview of the known and potential roles that MMPs have on vascular remodeling, paying particular attention to their role on the inward eutrophic remodeling process of small resistance arteries that occurs in hypertension.     

Influences of maternal nutritional status on vascular function in the offspring

Fetal growth restriction leading to low birthweight is associated with increased risk of ischaemic heart disease and hypertension in later life. Increasingly, it is recognised that cardiovascular risk may also be initiated in early life when the fetus and neonate are exposed to maternal nutritional excess. This review summarises the studies in man and animals that have investigated the potential role of vascular disorders in the aetiology of atherosclerosis and hypertension arising from early life nutritional deprivation or excess. Malfunction of the arterial endothelial cell layer in the offspring has been frequently described in association with both maternal under and overnutritional states and may play a permissive role in the origin of these disorders. Also prevalent is evidence for increased stiffness of the large arteries which may contribute to systolic hypertension. Further investigation is required into the intriguing suggestion that early life nutritional imbalance may adversely influence vascular angiogenesis leading to rarefaction and increased peripheral vascular resistance.     

Nitrate and nitrite‐based therapy to attenuate cardiovascular remodelling in arterial hypertension

Hypertension is a highly prevalent disease marked by vascular and cardiac maladaptive remodelling induced mainly by renin‐angiotensin system activation followed by oxidative stress. Here, we briefly describe these damages and review the current evidence supporting a potential role for nitrate and nitrite as antihypertensive molecules that act via nitric oxide (NO) formation–dependent and NO formation–independent mechanisms and how nitrate/nitrite inhibits cardiovascular remodelling in hypertension. The renin‐angiotensin system activation and oxidative stress converge to activate proteases involved in cardiovascular remodelling in hypertension. Besides these proteases, several investigations have demonstrated that reduced endogenous NO bioavailability is a central pathological event in hypertension. In this regard, nitrate/nitrite, long considered inert products of NO, is now known as physiological molecules able to reduce blood pressure in hypertensive patients and in different experimental models of hypertension. These effects are associated with the formation of NO and other NO‐related molecules, which could induce S‐nitrosylation of target proteins. However, it remains unclear whether S‐nitrosylation is an essential mechanism for the anti‐remodelling effects of nitrate/nitrite in hypertension. Moreover, nitrate/nitrite produces antioxidant effects associated with the inhibition of signalling pathways involved in cardiovascular remodelling. Together, these findings may help to establish nitrate and nitrite as effective therapies in hypertension‐induced cardiovascular remodelling.     

Angiogenesis and hypertension: the dual role of anti-hypertensive and anti-angiogenic therapies

Essential hypertension may be a consequence of structural and functional alterations of the microvascular network growth resulting partly from abnormal regulation of vascular endothelial growth factor (VEGF), one of the most potent known angiogenic factors. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a proliferation and migration factor, is also a maintenance and protection factor for endothelial cells, whose altered regulation may cause a disturbance of vascular homeostasis. Elevated VEGF levels in hypertensive patients were shown to correlate with cardiovascular risk, early microvascular and target organ damage; accordingly treatment of hypertension significantly reduced VEGF levels. Recently and in agreement with the theory that impaired angiogenesis can contribute to increased peripheral resistance and raised blood pressure (BP), an involvement of VEGF gene promoter polymorphisms in the pathophysiology of hypertension has been hypothesized. In the last decade, anti-VEGF drugs have been used in clinical practice, especially in the oncology field. This review will summarize the present understanding of the contribution of VEGF to neoangiogenesis in hypertension and its possible role as a marker of vascular damage. Given the well established effects that antihypertensive drugs exert on the vasculature beyond BP lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on circulating VEGF levels. The biological mechanism and clinical impact of hypertensive complications during anti-angiogenic treatments will also be reviewed.     

Myocardial insulin resistance and cardiac complications of diabetes

Cardiovascular disease is a major cause of mortality and morbidity in individuals with obesity, type 2 diabetes and the metabolic syndrome. The mechanisms for this are partially understood, but include increased atherosclerosis, hypercoagulability and increased hypertension. Epidemiological data suggests however, that a component of the excess cardiovascular mortality occurs independently of underlying coronary artery disease. Indeed, diabetes is an independent risk factor for the development of heart failure and the mechanisms responsible remain to be clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver are widely recognized features of obesity and type 2 diabetes, and contribute to the pathogenesis of impaired glucose homeostasis. Insulin resistance has also been described in the vasculature, and may contribute to endothelial dysfunction and atherosclerosis. The heart is an insulin responsive organ and less is known about whether or not the heart becomes insulin resistant in diabetes and what the pathogenic consequences of this might be. This review will discuss the currently available evidence from human and animal studies, that the heart may become insulin resistant in obesity and type 2 diabetes. The potential consequences of this on cardiac structure, function and metabolism will be discussed as well as recent data from transgenic mice with perturbed cardiac insulin sensitivity that have shed interesting new insight into potential mechanisms linking cardiac insulin resistance with myocardial dysfunction in diabetes.     

Rosiglitazone plus metformin: combination therapy for Type 2 diabetes

Type 2 diabetes is a common disease associated with an increased risk of long-term complications, in particular cardiovascular disease. Intervention trials have provided evidence that strict metabolic control can substantially reduce the burden of the disease. However, in order to accomplish this, the pathogenetic defects must be tackled by appropriate therapy. Insulin resistance is a common defect in these patients and it is even more severe in those who are obese. Insulin resistance not only contributes to impaired glucose homeostasis, but also to the development of dyslipidaemia, hypertension, inflammatory response and endothelial dysfunction, thus exacerbating the cardiovascular risk. Improvement of insulin sensitivity can be obtained with metformin and thiazolidinediones. These drugs act through different mechanisms with metformin exerting a prevalent effect on the liver and glitazones improving insulin sensitivity in peripheral tissue. Because of different mechanisms, the association of the two compounds is likely to result in an additive effect. Clinical trials available indicate that the combination of the two drugs results in greater improvement in plasma glucose concentration and HbA_1c as compared to single therapy, without increasing the occurrence of specific side effects. More recently, the two compounds have been associated in the same tablet, thus providing the opportunity for a more convienient treatment that may encourage patient compliance and, at the same time, provide a tool to assess whether a more aggressive intervention on insulin resistance may produce favourable effects on the cardiovascular risk.     

Rosiglitazone plus metformin: combination therapy for Type 2 diabetes

Type 2 diabetes is a common disease associated with an increased risk of long-term complications, in particular cardiovascular disease. Intervention trials have provided evidence that strict metabolic control can substantially reduce the burden of the disease. However, in order to accomplish this, the pathogenetic defects must be tackled by appropriate therapy. Insulin resistance is a common defect in these patients and it is even more severe in those who are obese. Insulin resistance not only contributes to impaired glucose homeostasis, but also to the development of dyslipidaemia, hypertension, inflammatory response and endothelial dysfunction, thus exacerbating the cardiovascular risk. Improvement of insulin sensitivity can be obtained with metformin and thiazolidinediones. These drugs act through different mechanisms with metformin exerting a prevalent effect on the liver and glitazones improving insulin sensitivity in peripheral tissue. Because of different mechanisms, the association of the two compounds is likely to result in an additive effect. Clinical trials available indicate that the combination of the two drugs results in greater improvement in plasma glucose concentration and HbA(1c) as compared to single therapy, without increasing the occurrence of specific side effects. More recently, the two compounds have been associated in the same tablet, thus providing the opportunity for a more convenient treatment that may encourage patient compliance and, at the same time, provide a tool to assess whether a more aggressive intervention on insulin resistance may produce favourable effects on the cardiovascular risk.     

Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.     

Matrix Metalloproteinase‐2 Activity is Associated with Divergent Regulation of Calponin‐1 in Conductance and Resistance Arteries in Hypertension‐induced Early Vascular Dysfunction and Remodelling

Matrix metalloproteinase (MMP)‐2 participates in hypertension‐induced maladaptive vascular remodelling by degrading extra‐ and intracellular proteins. The consequent extracellular matrix rearrangement and phenotype switch of vascular smooth muscle cells (VSMCs) lead to increased cellular migration and proliferation. As calponin‐1 degradation by MMP‐2 may lead to VSMC proliferation during hypertension, the hypothesis of this study is that increased MMP‐2 activity contributes to early hypertension‐induced maladaptive remodelling in conductance and resistance arteries via regulation of calponin‐1. The main objective was to analyse whether MMP‐2 exerts similar effects on the structure and function of the resistance and conductance arteries during early hypertension. Two‐kidney, one‐clip (2K‐1C) hypertensive male rats and corresponding controls were treated with doxycycline (30 mg/kg/day) or water until reaching one week of hypertension. Systolic blood pressure was increased in 2K‐1C rats, and doxycycline did not reduce it. Aortas and mesenteric arteries were analysed. MMP‐2 activity and expression were increased in both arteries, and doxycycline reduced it. Significant hypertrophic remodelling and VSMC proliferation were observed in aortas but not in mesenteric arteries of 2K‐1C rats. The contractility of mesenteric arteries to phenylephrine was increased in 2K‐1C rats, and doxycycline prevented this alteration. The potency of phenylephrine to contract aortas of 2K‐1C rats was increased, and doxycycline decreased it. Whereas calponin‐1 expression was increased in 2K‐1C mesenteric arteries, calponin‐1 was reduced in aortas. Doxycycline treatment reverted changes in calponin‐1 expression. MMP‐2 contributes to hypertrophic remodelling in aortas by decreasing calponin‐1 levels, which may result in VSMC proliferation. On the other hand, MMP‐2‐dependent increased calponin‐1 in mesenteric arteries may contribute to vascular hypercontractility in 2K‐1C rats. Divergent regulation of calponin‐1 by MMP‐2 may be an important mechanism that leads to maladaptive vascular effects in hypertension.     

Mechanisms underlying beneficial health effects of tea catechins to improve insulin resistance and endothelial dysfunction

Tea is a popular beverage with a number of putative beneficial health effects. A recent large epidemiological study in Japan demonstrates that increased tea consumption is associated with decreased cardiovascular mortality (but not cancer mortality) in a dose-dependent manner. The polyphenol epigallocatechin-3-gallate (EGCG) is the most abundant tea catechin. Beneficial effects of EGCG therapy have been reported in a number of human and animal studies. Emerging evidence suggests that EGCG may improve endothelial function, hypertension, coronary heart disease, obesity, insulin resistance, as well as glucose and lipid metabolism. Studies in cultured cells and animal models suggest molecular mechanisms for EGCG to activate specific cellular signaling pathways that may play major roles in prevention and amelioration of cardiovascular and metabolic diseases. In this review, the beneficial health effects of tea and molecular mechanisms of EGCG related to cardiovascular and metabolic diseases will be discussed.     

PERIPHERAL VASCULATURE IN ESSENTIAL HYPERTENSION *

• 1 Haemodynamic evidence shows that in essential hypertension minimum vascular resistance and vascular pressor response are increased and that the vascular reserve is decreased.
• 2 The haemodynamic changes are most easily explained in terms of a generalized narrowing of the vasculature and an increase in the ratio between the thickness of the tunica media and the lumen diameter (media: lumen ratio), with no change in the functional properties of the smooth muscle itself.
• 3 Histological and in vitro studies of resistance vessels confirm these predictions. Moreover, the evidence indicates that these changes are associated mainly with remodelling (rearrangement of the same amount of material) of the vessels, rather than growth.
• 4 Although the alteration in small artery structure is usually appropriate to the actual blood pressure, the structure appears not only to be a secondary adaptation, but is also dependent on other factors, including neurohumoral factors.
• 5 The available evidence shows that normalization of the resistance vessel structure (by increasing lumen diameter and decreasing the media: lumen ratio) should be achieved not by inhibition of growth but by (reverse) remodelling. Recent evidence from clinical investigations shows that this can be achieved in essential hypertensive patients treated with the angiotensin-converting enzyme inhibitor perindopril.
• 6 The role of the resistance vasculature as a primary determinant of blood pressure remains unclear. It is suggested that the requirement for normalization of resistance vascular structure is due to a need to increase the vascular reserve.

     

CARDIOVASCULAR CONSEQUENCES OF OBESITY: ROLE OF LEPTIN

1. Several mechanisms have been implicated in the association between obesity and hypertension, including salt-sensitivity, insulin resistance and sympathetic activation. Obese animals and humans exhibit exaggerated blood pressure responses to increases in salt intake. 2. Although insulin resistance is common in obesity, it is clear that abnormal insulin action is not the sole or sufficient cause of hypertension in obesity. Obesity is associated with increased activity of the sympathetic nervous system. Sympathetic blockade has been reported to attenuate sodium retention and hypertension in experimental models of obesity. 3. The mediators responsible for salt sensitivity, insulin resistance and sympathetic activation in obesity remain unclear. 4. The novel protein hormone leptin is produced almost exclusively by adipose tissue and acts in the central nervous system through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. 5. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, renal and endocrine function. We have shown that leptin increases sympathetic nerve activity to kidney, hindlimb and adrenal gland, in addition to brown adipose tissue. 6. Despite this sympathoexcitatory action, acute systemic administration of leptin does not acutely increase arterial pressure or heart rate in anaesthetized animals. This may reflect opposing antihypertensive actions of leptin. For example, leptin increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin increases systemic insulin sensitivity, even in the absence of weight loss. 7. In conclusion, leptin may act as a mediator linking body adiposity with changes in insulin action, sympathetic neural outflow and renal sodium excretion. Alterations in leptin generation or action may, in part, underlie the sympathetic, endocrine and renal consequences of obesity.