Abstract-Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-related risk, and to guide management. The auscultatory technique with a trained observer and mercury sphygmomanometer continues to be the method of choice for measurement in the office, using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended. They have the advantage of being able to take multiple measurements. Proper training of observers, positioning of the patient, and selection of cuff size are all essential. It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a failure of blood pressure to fall during the night may be associated with increased risk. In obese patients and children, the use of an appropriate cuff size is of paramount importance.

Abstract-The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-␥ (PPAR␥) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR␥ have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPAR␥; influence the expression of PPAR␥ target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR␥ when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPAR␥ have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations. Key Words: receptors, angiotensin II Ⅲ angiotensin II Ⅲ renin-angiotensin system Ⅲ insulin resistance Ⅲ losartan A ll currently available classes of antihypertensive drugs were developed before it was widely recognized that increased blood pressure is closely associated with insulin resistance and dyslipidemia and well before public health authorities established diagnostic criteria for the metabolic syndrome. 1-3 Thus, the antihypertensive drugs in use today were designed primarily to affect cellular and biochemical mechanisms contributing to increased blood pressure and not to address the disordered carbohydrate and lipid metabolism that often accompany hypertension as part of the metabolic syndrome. Given the major impact of the metabolic syndrome on cardiovascular disease morbidity and mortality, 4 -6 the availability of antihypertensive agents that also improve insulin resistance and dyslipidemia could be of considerable clinical value.Numerous studies have demonstrated that the peroxisome proliferator-activated receptor-␥ (PPAR␥) plays an important role in regulating carbohydrate and lipid metabolism and that ligands for PPAR␥ can improve insulin sensitivity, reduce triglyceride levels, and decrease the risk for atherosclerosis. 7-15 PPAR␥ ligands also have modest antihypertensive effects related at least in part to their ability to promote peripheral vasodilation. 16 -19 Several thiazolidinedione ligands for PPAR␥ have been approved for the treatment of type 2 diabetes; however, these agents have limited capacity to reduce blood pressure and can provoke fluid retention, weight gain, edema, a...

Abstract-Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-related risk, and to guide management. The auscultatory technique with a trained observer and mercury sphygmomanometer continues to be the method of choice for measurement in the office, using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended. They have the advantage of being able to take multiple measurements. Proper training of observers, positioning of the patient, and selection of cuff size are all essential. It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a failure of blood pressure to fall during the night may be associated with increased risk. In obese patients and children, the use of an appropriate cuff size is of paramount importance. (Circulation. 2005;111:697-716.)

The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat, as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.

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Nuclear factor E2-related factor 2 (Nrf2) is a cap-n-collar basic leucine zipper (CNC-bZIP) transcription factor that is well established as a master regulator of phase II detoxification and antioxidant gene expression and is strongly expressed in tissues involved in xenobiotic metabolism including liver and kidney. Nrf2 is also abundantly expressed in adipose tissue; however, the exact function of Nrf2 in adipocyte biology is unclear. In the current study we show that targeted knock-out of Nrf2 in mice decreases adipose tissue mass, promotes formation of small adipocytes, and protects against weight gain and obesity otherwise induced by a high fat diet. In mouse embryonic fibroblasts, 3T3-L1 cells, and human subcutaneous preadipocytes, selective deficiency of Nrf2 impairs adipocyte differentiation. Fat cells play an important role in energy storage and metabolism and secrete a variety of factors that influence appetite, insulin sensitivity, inflammation, and many other pathways of biologic and clinical significance (1). Because of the significance of adipocyte biology in the pathogenesis of obesity and related metabolic, cardiovascular, and inflammatory disorders, there has been intense interest in defining the network of transcription factors that controls the expression of genes involved in fat cell development. Peroxisome proliferator-activated receptors (PPARs) 4 are ligand-activated transcription factors that belong to a nuclear hormone receptor family including related molecules that function by forming heterodimers with retinoid X receptors (2). PPAR␥ is expressed abundantly in adipose tissue and is considered to be the dominant transcriptional regulator of adipogenic differentiation (3). Accordingly, much attention has been directed at identifying factors that control PPAR␥ expression during the process of adipogenesis.CCAAT enhancer-binding proteins (C/EBPs) are leucine zipper transcription factors expressed in both white and brown adipose tissue and have been extensively studied for their roles in regulating PPAR␥ activity and adipogenesis (4, 5). C/EBP␤ and C/EBP␦ are transiently expressed at the onset of the adipose differentiation program (6, 7). This phase is then followed by induction of PPAR␥ and C/EBP␣ expression (8 -10). In addition, PPAR␥ and C/EBP␣ form a positive loop by regulating each other's expression (11,12). Although the enforced expression of C/EBP␣ in fibroblasts can trigger adipocytic differentiation, C/EBP␣ is incapable of inducing adipogenesis in the absence of PPAR␥ (13). In contrast, PPAR␥ can induce adipogenic differentiation in C/EBP␣-null cells indicating that PPAR␥ is proximal in effecting adipogenesis (14). Apart from C/EBP␤, -␦, and -␣, relatively few transcription factors have been described that bind to the Ppar␥ promoter and positively regulate Ppar␥ transcription during adipogenesis (15).The nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a member of the cap-n-collar basic leucine zipper (CNC-bZIP) family of transcription factors and has been shown to pl...

We report the construction of the first complete genetic linkage map of the laboratory rat. By testing 1171 simple sequence length polymorphisms (SSLPs), we have identified 432 markers that show polymorphisms between the SHR and BN rat strains and mapped them in a single (SHR x BN) F2 intercross. The loci define 21 large linkage groups corresponding to the 21 rat chromosomes, together with a pair of nearby markers on chromosome 9 that are not linked to the rest of the map. Because 99.5% of the markers fall into one of the 21 large linkage groups, the maps appear to cover the vast majority of the rat genome. The availability of the map should facilitate whole genome scans for genes underlying qualitative and quantitative traits relevant to mammalian physiology and pathobiology.