Diuretic-induced hypokalaemia: an updated review.

Diuretic-induced hypokalaemia is a common and potentially life-threatening adverse drug reaction in clinical practice. Previous studies revealed a prevalence of 7%-56% of hypokalaemia in patients taking thiazide diuretics. The clinical manifestations of hypokalaemia due to diuretics are non-specific, varying from asymptomatic to fatal arrhythmia. Diagnosis of hypokalaemia is based on the level of serum potassium. ECG is useful in identifying the more severe consequences. A high dosage of diuretics and concomitant use of other drugs that increase the risk of potassium depletion or cardiac arrhythmias can increase the risk of cardiovascular events and mortality. Thiazide-induced potassium depletion may cause dysglycaemia. The risk of thiazide-induced hypokalaemia is higher in women and in black people. Reducing diuretic dose and potassium supplementation are the most direct and effective therapies for hypokalaemia. Combining with a potassium-sparing diuretic or blocker of the renin-angiotensin system also reduces the risk of hypokalaemia. Lowering salt intake and increasing intake of vegetables and fruits help to reduce blood pressure as well as prevent hypokalaemia.

Elevated plasma level of soluble F11 receptor/junctional adhesion molecule-A (F11R/JAM-A) in hypertension.

BACKGROUND: The F11 receptor (F11R, also known as junctional adhesion molecule A (JAM-A)) plays a role in the development of hypertension in rat. Genetic variants in the human F11R gene were demonstrated to influence systolic blood pressure. In the present study, we investigated the relationship between F11R and hypertension by examining the levels of a circulating soluble form of F11R (sF11R) in hypertensive patients. METHODS: Plasma sF11R was measured by enzyme-linked immunosorbent assay in 152 hypertensive and 166 normotensive subjects in whom seven tagging single-nucleotide polymorphisms (SNPs) in the F11R gene had been genotyped. RESULTS: Plasma sF11R levels were significantly higher in hypertensive subjects than in normotensive subjects (median (interquartile) range): 162.8 (85.5-293.2) vs. 116.5 (74.1-194.8) pg/ml, P = 0.004), which remained significantly higher after adjusting for age, sex, body mass index (BMI), and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028). In stepwise multiple logistic regression, sF11R level (log-transformed) (P = 0.040), triglycerides (log-transformed) (P = 0.024), and HOMA-IR (log-transformed) (P < 0.001) were independently associated with hypertension. Plasma sF11R level correlated with systolic and diastolic blood pressures (r = 0.15, P < 0.001, and r = 0.13, P = 0.024, respectively). In stepwise multiple linear regression, hypertension (P = 0.013) and fibrinogen levels (P = 0.027) were significant independent predictors of sF11R level. A seven-locus haplotype, present in 2.1% of the subjects, was associated with higher sF11R level (P = 0.024). CONCLUSIONS: These results further support a role of F11 receptor in the pathophysiology of human hypertension.

Elevated serum alkaline phosphatase and peripheral arterial disease in the United States National Health and Nutrition Examination Survey 1999-2004.

BACKGROUND: Alkaline phosphatase (ALP) is elevated in peripheral arterial disease (PAD). We therefore examined the relationship of PAD with ALP and other liver enzymes in the United States National Health and Nutrition Examination Survey 1999-2004. METHODS: The analysis included 5995 men and non-pregnant women aged >or=40 years with no missing data in variables of interest. PAD was defined as ankle-brachial blood pressure index (ABI) <0.90 in either leg. RESULTS: Serum alkaline phosphatase (ALP) level was associated significantly with lower ABI after adjustment for confounding factors (p=0.019). No significant association of ABI with other liver enzymes was found. Serum ALP level increased with increasing age, body mass index, C-reactive protein, monocyte count, serum uric acid, lead, cadmium, and prevalence of hypercholesterolemia, diabetes, smoking, non-alcohol drinking, and cardiovascular diseases after adjusting for age, sex, race/ethnicity, and survey years (p<0.02). The highest quartile of serum ALP was associated with an odds ratio of 1.89 (95% confidence interval [CI]: 1.25-2.85) for PAD after adjustment for confounding factors (p for trend=0.023). In subjects with normal kidney function (glomerular filtration rate >90 ml/min/1.73 m(2)), the odds ratio increased to 4.22 (95% CI 1.45-12.35) (p=0.010). CONCLUSION: Elevated serum ALP is correlated with PAD, independent of other traditional cardiovascular risk factors.

Association between plasma alkaline phosphatase and C-reactive protein in Hong Kong Chinese.

BACKGROUND: Alkaline phosphatase (ALP) is a biomarker for hepatobiliary and skeletal diseases. It is also raised in sepsis. In atherosclerotic plaques, ALP is expressed. Similar to C-reactive protein (CRP), it may be another marker of systemic inflammation. Therefore, we investigated their association in a Hong Kong Chinese population. METHODS: Plasma ALP and CRP were measured in 205 subjects (110 men, 95 women; age 55.2+/-11.6 years) in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 cohort. RESULTS: The blood levels of ALP and CRP were significantly correlated (r=0.30, p<0.001), which was due to a significant correlation in women (r=0.43, p<0.001). In a multivariate model, CRP level was related to ALP (beta=0.18, p=0.008). After adjusting for confounding factors and other liver enzymes, the relationship between ALP and CRP remained significant in women (beta=0.28, p=0.019), but in men, ALP was not an independent determinant of CRP levels. CONCLUSIONS: ALP may be another marker of systemic inflammation, especially in women. Whether it provides clinical information additional to CRP requires further study.

Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men.

BACKGROUND: Lipin 1 plays a role in abdominal obesity, insulin resistance, and hypertriglyceridemia. The gene is located at 2p25.1, a susceptibility locus for hypertension. We studied the association of tagging single-nucleotide polymorphisms (SNPs) in the lipin 1 (LPIN1) gene with hypertension and blood pressure. METHODS: Twelve tagging SNPs from the HapMap database were genotyped using Sequenom MassArray in 268 hypertensive subjects and 407 normotensive controls, of whom 268 matched the cases in age and sex. RESULTS: None of the tagging SNPs were found to be associated with hypertension after correcting for multiple testing, although carriers of the minor allele of rs10520097 had nominally lower odds for hypertension (P = 0.014). After excluding subjects who were on antihypertensive medications, the minor allele of rs10495584 was nominally associated with lower mean systolic and diastolic blood pressures in men (121.1 +/- 14.2 and 76.3 +/- 10.2 mm Hg vs. 127.4 +/- 15.2 and 80.1 +/- 10.5 mm Hg, P = 0.002 and 0.007, respectively), but not in women (P > 0.05). The association of rs10495584 with systolic blood pressure in men remained significant after correcting for multiple testing and adjustment for age, waist circumference, insulin resistance, triglyceride, and high-density lipoprotein (HDL) cholesterol (beta = -0.158, P = 0.005). An analysis of statistically similar SNPs (ssSNPs) in the regions surrounding rs10495584 suggested that its effect may be caused by its high linkage disequilibrium (LD) with the SNP, rs11524, in which the major allele forms an exonic splicing silencer sequence. CONCLUSION: Our study provides further evidence that lipin 1 may play a role in blood pressure regulation, especially in men.

Polymorphisms of the fibrinogen-beta gene are related to 2-hour glucose level after oral glucose tolerance test in Hong Kong Chinese.

Fibrinogen, an acute phase protein, is an important inflammatory marker that is associated with cardiovascular diseases. We studied the association of three common human fibrinogen-beta gene (FGB) variants, -455G>A, -249C>T, and -148C>T with glycemic parameters in 265 non-diabetic Hong Kong Chinese subjects. Both FGB variants, -455G>A and -148C>T were in complete linkage disequilibrium and were associated with higher levels of plasma fibrinogen and 2-h glucose after a 75-g oral glucose load (p<0.01). Carriers of FGB AC-haplotype, comprising the two nucleotide variants at positions -455 and -249, had higher fibrinogen level (2.64 +/- 0.65 vs 2.42 +/- 0.52 g/L, p=0.002) and 2-h glucose after a 75-g oral glucose load (5.87 +/- 1.14 vs 5.47 +/- 1.22 g/L, p=0.006). The associations were significant in men, but not women. In stepwise multiple regression analysis, AC-haplotype was independently associated with plasma fibrinogen level and 2-h glucose (p=0.002 and 0.010 respectively). This suggests that fibrinogen may play a role in the development of impaired glucose tolerance.

Prevalence, treatment, and control of diagnosed diabetes in the U.S. National Health and Nutrition Examination Survey 1999-2004.

PURPOSE: This study aimed to examine the trends in prevalence, treatment, and control of diagnosed diabetes in United States adults 20 years of age or older. METHODS: Data from the National Health and Nutrition Examination Survey 1999-2004 were used. Glycemic, blood pressure, and total cholesterol target levels were defined as having glycosylated hemoglobin <7.0%, blood pressure <130/80 mm Hg, and total cholesterol <200 mg/dL, respectively. RESULTS: The prevalence of diagnosed diabetes was 7.8% in 2003-2004 and increased significantly in people aged 40-59 years, women, non-Hispanic whites, and obese people in the period 1999-2004. Although there was no significant change in the pattern of antidiabetic treatment, the age-adjusted percentage of people with diagnosed diabetes achieving glycemic and blood pressure target levels increased from 35.8% to 57.1% (p = 0.002) and from 35.7% to 48.3% (p = 0.04), respectively. However, there were only insignificant increases in percentages of those persons achieving total cholesterol target level (from 48.8% to 50.4%) and those achieving all 3 target levels (from 7.5% to 13.2%). CONCLUSIONS: In 1999-2004, the prevalence of diagnosed diabetes increased significantly in some subgroups of the population. However, the increases in percentages of people with diabetes achieving glycemic and blood pressure targets are encouraging, although there is room for improvement.

The role of urotensin II in the metabolic syndrome.

Urotensin II is a potent vasoconstrictive peptide that mediates both endothelium-independent vasoconstriction and endothelium-dependent vasodilatation. Its plasma level correlates positively with body weight and is raised in diabetes, renal failure, hypertension, and other cardiovascular diseases including congestive heart failure and carotid atherosclerosis. It can inhibit glucose-induced insulin secretion, and genetic variants in urotensin II gene are associated with insulin resistance and type 2 diabetes. Urotensin II also affects lipid metabolism in fish and food intake in mice. Recent studies have also demonstrated a role of urotensin II in inflammation and endothelial dysfunction. These findings suggest a close relationship between urotensin II and at least some components of the metabolic syndrome, including hypertension, insulin resistance, hyperglycemia, and inflammation.

Prevalence of the metabolic syndrome in the United States National Health and Nutrition Examination Survey 1999-2002 according to different defining criteria.

The authors studied the prevalence of the metabolic syndrome in the 1999-2002 National Health and Nutrition Examination Survey (NHANES) according to the World Health Organization, National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. There was 92.9% agreement between the NCEP and IDF definitions. The IDF prevalence was higher (p = 0.001) due to more men fulfilling its criteria than the NCEP's (39.9 +/- 1.7% vs. 33.6 +/- 1.6%; p = 0.007). If central obesity were not a prerequisite, the IDF prevalence would increase slightly to 40.3 +/- 1.1%. Subjects categorized as having the metabolic syndrome under IDF but not NCEP tended to be men, younger, and leaner. Their prevalence of self-reported coronary heart disease was not significantly different from that of other metabolic syndrome patients. Whether waist circumference is a prerequisite does not affect the diagnosis of the metabolic syndrome in the United States. The IDF definition identifies additional individuals at risk for cardiovascular disease.

Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance.

We studied single nucleotide polymorphisms (SNPs) and haplotypes in the urotensin-II (UTS2) and urotensin-II receptor gene (UTS2R) in Hong Kong Chinese (224 hypertensive and 306 normotensive unrelated subjects) and their relation to hypertension and the metabolic syndrome. For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function. For UTS2R, the AC haplotype (-11640A and -8515C) was associated with higher 2 h plasma glucose after a 75 g oral glucose load. Therefore, U-II and its receptor may play a role in insulin resistance.

Treatment and control of diabetes mellitus in the United States National Health and Nutrition Examination Survey, 1999-2002.

Control of glycemia and other risk factors in people with diabetes has a critical bearing on clinical outcome. Using data from the US National Health and Nutrition Examination Survey 1999-2002, the authors compared the characteristics and control among diabetic subjects in different antidiabetic treatment groups. Among diagnosed diabetic subjects (n=827), 18.3%, 15.2%, 56.6%, and 9.6% used diet therapy alone, insulin therapy alone, oral antidiabetic drugs alone, or both insulin and oral antidiabetic drugs, respectively. The pattern of antidiabetic treatment differed by age and race/ethnicity, but not sex and status of the cardiometabolic syndrome. Only a minority of patients had satisfactory control of glycemia (38.8%), low-density lipoprotein cholesterol (35.0%), and blood pressure (42.5%). Patients taking only insulin had the poorest glycemic control (15.2%), while patients using diet treatment alone (65.9%) had the best glycemic control. There is a need to improve glycemic control. Better patient education, intensive lifestyle changes, and newer therapies need to be explored.

Adrenomedullin gene expression and levels in the cardiovascular system after treatment with lipopolysaccharide.

To study the effect of septicaemia, the temporal changes in tissue adrenomedullin (AM) and preproAM mRNA levels were studied in the heart and blood vessels after lipopolysaccharide (LPS) injection. Radioimmunoassay and solution hybridization-RNase protection assays were used to follow the changes in AM and its mRNA levels respectively after intraperitoneal injection of 10 mg/kg LPS in rats. The preproAM mRNA levels increased at 1 h in the right atrium after LPS injection, while the AM contents decreased at 1 h in the left atrium. The preproAM mRNA levels increased at 3 and 6 h in the left ventricle, whereas it increased at 6 h in the right ventricles after LPS injection. There was an increase in preproAM mRNA levels at 1 and 3 h in the mesenteric artery, while AM levels were increased at 1, 3 and 6 h. However, there were no such changes in the thoracic aorta. There were also increases in tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 in the heart, and in the mesenteric artery (TNF-alpha and IL-1beta) and in thoracic aorta (IL-1beta and IL-6). The present results suggest that the biosynthesis and secretion of AM may be increased in cardiovascular tissues of rats injected with LPS, and that AM may play multiple roles in inflammation.

Differential induction of adrenomedullin, interleukins and tumour necrosis factor-alpha by lipopolysaccharide in rat tissues in vivo.

The aim of the present study was to determine the temporal changes in tissue adrenomedullin (AM) and cytokine contents and cytokine and preproAM mRNA levels in the kidney, liver, adrenal gland and spleen of lipopolysaccharide (LPS)-treated rats. Rats were injected with LPS (10 mg/kg, i.p.). Radioimmunoassay and solution hybridization-RNase protection assays were used to follow the changes in AM and its mRNA levels, respectively; ELISA and reverse transcription-polymerase chain reaction were used to follow the changes in cytokines and their mRNA levels, respectively. In the kidney, the preproAM mRNA levels were increased 1 and 3 h after LPS treatment, whereas AM levels were decreased at 3 h. Interleukin (IL)-6 and IL-1beta levels were increased at 3 and 6 h, respectively. The preproAM mRNA levels were elevated in the liver 3 h after LPS injection. Concentrations of tumour necrosis factor (TNF)-alpha and IL-1beta were increased at l and 6 h, respectively. There were no changes in the levels of either preproAM mRNA or AM in the adrenal gland and the spleen. In the spleen, TNF-alpha levels were elevated at 1 and 3 h after LPS injection and IL-1beta was elevated at 1 and 6 h after LPS injection, whereas in the adrenal gland IL-1beta was elevated at 6 h after injection. The mRNA levels of the three cytokines were elevated at all three time intervals examined in the kidney, liver, adrenal gland and spleen, with the exception that TNF-alpha mRNA was not elevated in the adrenal gland at 6 h after LPS injection and IL-1beta mRNA was not elevated in the spleen at 3 and 6 h. The plasma concentrations of TNF-alpha were increased at 1 and 3 h after LPS injection, whereas plasma concentration of IL-1beta and IL-6 were elevated at 3 and 6 h for both. The present results suggest that the biosynthesis and secretion of AM may be differentially regulated in various tissues of rats injected with LPS and that AM may interact with cytokines during inflammation.

Adrenomedullin is both proinflammatory and antiinflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line.

Adrenomedullin (ADM) is a potent vasorelaxant peptide that plays important roles in cardiovascular homeostasis and inflammatory response. ADM derived from macrophages is one of the major sources of ADM that is produced in the inflammatory process. To assess the functions of ADM in inflammation, we studied the temporal changes in ADM production and its effect on secretion of macrophage migration inhibitory factor (MIF) and cytokine response of NR8383 rat macrophages activated by lipopolysaccharide (LPS). NR8383 cells were stimulated by LPS in the absence and presence of exogenous ADM, and the concentrations of ADM, MIF, and proinflammatory cytokines (IL-6, TNF-alpha, and IL-1beta) in the culture media and gene expressions of the cells were measured. We confirmed that the secretion and mRNA expression of ADM in the macrophages were markedly increased by LPS. ADM increased initial secretion of MIF and IL-1beta from both nonstimulated and LPS-stimulated cells, and it also increased basal and LPS-induced IL-6 secretion of the cells by 2- to 15-fold. However, it reduced secretion of TNF-alpha from LPS-stimulated cells by 34-56%. Our results suggest that ADM modulates MIF secretion and cytokine production and plays important roles in both the initiation and propagation of the inflammatory response.

Adrenomedullin: its role in the cardiovascular system.

Adrenomedullin is a 52-amino acid peptide that was first isolated from human pheochromocytoma. Subsequently, it was found to be distributed widely in the body, including throughout the cardiovascular system. It belongs to a family of peptides that include calcitonin gene-related peptide and amylin. Adrenomedullin causes vasorelaxation and influences vascular proliferation and interacts closely with nitric oxide, and it may have a role in the pathophysiology of hypertension, ischemic heart disease, and cardiac and renal failure. Nonpeptide agonists or antagonists of adrenomedullin may have potential therapeutic application. The role of adrenomedullin in septicemic shock also merits further investigation.

Plasma concentration of urotensin II is raised in hypertension.

OBJECTIVES: Urotensin II is the most potent vasoconstrictor known. Its role in hypertension has not been investigated. Here, we studied the plasma levels in hypertensive and normotensive human subjects. DESIGN: A cross-sectional case-control study. SETTING: Hypertension clinic and research clinic of a university teaching hospital. PARTICIPANTS: Sixty-two hypertensive outpatient subjects (52% male, aged 57 +/- 13 years) and 62 normotensive controls (45% male, aged 54 +/- 13 years) recruited from the general population. MAIN OUTCOME MEASURES: Plasma urotensin II levels measured by radioimmunoassay, systolic and diastolic blood pressure. RESULTS: Plasma urotensin II was 8.8 +/- 0.9 pmol/l in normotensive controls and 13.6 +/- 1.4 pmol/l in hypertensive subjects (P = 0.005). In multiple regression analysis, systolic blood pressure was related to plasma urotensin II (beta = 0.31, P < 0.001) and age (beta = 0.28, P = 0.001), accounting for 10 and 8%, respectively, of the variance in systolic blood pressure. There was no significant correlation with gender, renal function or diabetes. CONCLUSIONS: Plasma urotensin II was raised in hypertensive patients compared to normotensive controls, and was directly related to systolic blood pressure. Our findings raise the possibility that urotensin II may have an aetiological role in hypertension and its complications.