Tolerance mechanisms of human-residential bifidobacteria against lysozyme.

We previously reported that lysozyme present in breast milk is a selection factor for bifidobacterial colonization in infant human intestines. This study is aimed at examining their underlying mechanisms. Human-residential bifidobacteria (HRB) generally exhibited higher tolerance than non-HRB to lysozymes, except B. bifidum subspecies. To assess the involvement of enzymatic activity of lysozyme, peptidoglycan (PG) was isolated and the degree of O-acetylation (O-Ac) in 19 strains, including both HRB and non-HRB, was determined. Variety in the degree of O-Ac was observed among each of the Bifidobacterium species; however, all purified PGs were found to be tolerant to lysozyme, independent of their O-Ac degree. In addition, De-O-Ac of PGs affected the sensitivity to lysozyme of only B. longum-derived PG. To examine the non-enzymatic antibacterial activity of lysozyme on bifidobacteria, lysozyme was heat-denatured. The HRB and non-HRB strains exhibited similar patterns of susceptibility to intact lysozyme as they did to heat-denatured lysozyme. In addition, strains of B. bifidum (30 strains), which showed various tolerance of lysozyme, also exhibited similar patterns of susceptibility to intact lysozyme as they did to heat-denatured lysozyme. These results suggest that bifidobacteria are resistant to the peptidoglycan-degrading property of lysozyme, and the tolerance to lysozyme among some HRB strains is due to resistance to the non-enzymatic antibacterial activity of lysozyme.

Innovative use of platinum compounds to selectively detect live microorganisms by polymerase chain reaction.

PCR cannot distinguish live microorganisms from dead ones. To circumvent this disadvantage, ethidium/propidium-monoazide (EMA/PMA) and psoralen to discriminate live from dead bacteria have been used for 2 decades. These methods require the use of numerous laborious procedures. We introduce an innovative method that uses platinum compounds, which are primarily used as catalysts in organic chemistry and partly used as anti-cancer drugs. Microorganisms are briefly exposed to platinum compounds in vivo, and these compounds penetrate dead (compromised) microorganisms but not live ones and are chelated by chromosomal DNA. The use of platinum compounds permits clear discrimination between live and dead microorganisms in water and milk (including Cronobacter sakazakii and Escherichia coli) via PCR compared with typically used PMA. This platinum-PCR method could enable the specific detection of viable coliforms in milk at a concentration of 5-10 CFU mL(-1) specified by EU/USA regulations after a 4-h process. For sample components, environmental water contains lower levels of PCR inhibitors than milk does, and milk is similar to infant formula, skim milk and blood; thus, the use of the platinum-PCR method could also prevent food poisoning due to the presence of C. sakazakii in dairy products. This method could provide outstanding rapidity for use in environmental/food/clinical tests. Platinum-PCR could also be a substitute for the typical culture-based methods currently used.

Effects of daily walking on office, home and 24-h blood pressure in hypertensive patients.

Aerobic exercise has been recommended in the management of hypertension. However, few studies have examined the effect of walking on ambulatory blood pressure (BP), and no studies have employed home BP monitoring. We investigated the effects of daily walking on office, home, and 24-h ambulatory BP in hypertensive patients. Sixty-five treated or untreated patients with essential hypertension (39 women and 26 men, 60 ± 9 years) were examined in a randomized cross-over design. The patients were asked to take a daily walk of 30-60 min to achieve 10 000 steps/d for 4 weeks, and to maintain usual activities for another 4 weeks. The number of steps taken and home BP were recorded everyday. Measurement of office and ambulatory BP, and sampling of blood and urine were performed at the end of each period. The average number of steps were 5349 ± 2267/d and 10 049 ± 3403/d in the control and walking period, respectively. Body weight and urinary sodium excretion did not change. Office, home, and 24-h BP in the walking period were lower compared to the control period by 2.6 ± 9.4/1.3 ± 4.9 mmHg (p < 0.05), 1.6 ± 6.8/1.5 ± 3.7 mmHg (p < 0.01), and 2.4 ± 7.6/1.8 ± 5.3 mmHg (p < 0.01), respectively. Average 24-h heart rate and serum triglyceride also decreased significantly. The changes in 24-h BP with walking significantly correlated with the average 24-h BP in the control period. In conclusion, daily walking lowered office, home, and 24-h BP, and improved 24-h heart rate and lipid metabolism in hypertensive patients. However, the small changes in BP may limit the value of walking as a non-pharmacologic therapy for hypertension.

The exclusive use of flow cytometry to evaluate the antibiotic-susceptibility.

BACKGROUND: Live and injured bacteria cannot be successfully discriminated using flow cytometric methods (FCM) with commercial live/dead staining agents because injured cells have intact cell membranes and are counted as live cells. We previously reported that photoactivated ethidium monoazide (EMA) directly cleaves bacterial DNA both in vivo and in vitro (Microbiol. Immunol. 51:763-775, 2007). METHODS: We report that EMA cleaves the chromosomal DNA of antibiotic-injured, but not live, Listeria monocytogenes. The combination of FCM and EMA treatment was evaluated as a rapid method to discriminate between live and antibiotic-injured L. monocytogenes. Additionally, we evaluated our methodology using blood from pediatric patients infected with other gram-negative and gram-positive bacteria. RESULTS: For antibiotic-injured, but not live, L. monocytogenes in blood, photoactivated EMA suppressed SYTO9 staining, as the SYTO9 staining of the antibiotic-injured L. monocytogenes was weak compared with that of live cells. Similarly, the rapid and clear discrimination between live and injured bacteria (gram-negative and gram-positive) was performed using the blood of pediatric patients administered antibiotics. CONCLUSIONS: The combination of FCM with EMA treatment is a rapid method for evaluating the susceptibility of live pathogens in infants with bacteremia without the need for bacterial culture. GENERAL SIGNIFICANCE: This assay is more rapid than other currently available techniques due to the elimination of the time-consuming culture step and could be used in clinical settings to rapidly determine the success of antibiotic treatment in pediatric bacteremia through the discrimination of injured (i.e., susceptible to the administered antibiotics) and live pathogens.

An advanced PCR method for the specific detection of viable total coliform bacteria in pasteurized milk.

Pasteurized milk is a complex food that contains various inhibitors of polymerase chain reaction (PCR) and may contain a large number of dead bacteria, depending on the milking conditions and environment. Ethidium monoazide bromide (EMA)-PCR is occasionally used to distinguish between viable and dead bacteria in foods other than pasteurized milk. EMA is a DNA-intercalating dye that selectively permeates the compromised cell membranes of dead bacteria and cleaves DNA. Usually, EMA-PCR techniques reduce the detection of dead bacteria by up to 3.5 logs compared with techniques that do not use EMA. However, this difference may still be insufficient to suppress the amplification of DNA from dead Gram-negative bacteria (e.g., total coliform bacteria) if they are present in pasteurized milk in large numbers. Thus, false positives may result. We developed a new method that uses real-time PCR targeting of a long DNA template (16S-23S rRNA gene, principally 2,451 bp) following EMA treatment to completely suppress the amplification of DNA of up to 7 logs (10(7) cells) of dead total coliforms. Furthermore, we found that a low dose of proteinase K (25 U/ml) removed PCR inhibitors and simultaneously increased the signal from viable coliform bacteria. In conclusion, our simple protocol specifically detects viable total coliforms in pasteurized milk at an initial count of ≥1 colony forming unit (CFU)/2.22 ml within 7.5 h of total testing time. This detection limit for viable cells complies with the requirements for the analysis of total coliforms in pasteurized milk set by the Japanese Sanitation Act (which specifies <1 CFU/2.22 ml).

Combination of angiotensin II receptor antagonist with calcium channel blocker or diuretic as antihypertensive therapy for patients with chronic kidney disease.

We compared treatment with an angiotensin II receptor antagonist (ARB) and a calcium channel blocker (CCB) combination and a fixed-dose ARB and thiazide diuretic in 18 chronic kidney disease (CKD) patients. A randomized crossover study was performed using a fixed-dose combination of losartan-hydrochlorothiazide or losartan combined with controlled-release nifedipine. Both systolic blood pressure (SBP) and diastolic blood pressures (DBPs) were lower during the nifedipine period than during the diuretic period. No significant difference was observed in urinary albumin excretion, but the estimated glomerular filtration rate was higher in the nifedipine than in the diuretic period. Serum uric acid and low-density lipoprotein cholesterol were higher in the diuretic than in the nifedipine period. A significantly low cardio-ankle vascular index, an index of arterial wall stiffness, was observed in the nifedipine period. A combination of ARB and a controlled-release nifedipine at 20-40 mg used showed a superior antihypertensive effect in CKD patients compared to a fixed-dose combination of losartan 50 mg-hydrochlorothiazide 12.5 mg in terms of blood control. The former combination is considered advantageous for maintaining renal function and artery wall elasticity without influencing uric acid or lipid metabolism.

QT dispersion and rate-corrected QT dispersion during electroconvulsive therapy in elderly patients.

BACKGROUND: Electroconvulsive therapy (ECT) induces increase of QT dispersion (QTD) and the rate-corrected QTD (QTcD), which are associated with increased risk of ventricular arrhythmias and cardiovascular mortality. The effects of electrical stimulus during ECT on QTD and QTcD in elderly patients are of considerable interest. OBJECTIVE: The purpose of this study was to clarify the differential effects of electrical stimulus caused by ECT on interbeat interval, QT interval, the rate-corrected QT (QTc) interval, QTD, and the QTcD under propofol anesthesia between younger and elderly patients with major depression. METHODS: Twenty younger psychiatric patients (aged 30-40 years) and 20 elderly patients (aged 65-75 years) scheduled for ECT were studied under propofol anesthesia. A 12-lead electrocardiogram was monitored to measure parameters. Muscle paralysis was achieved by administering 1-mg/kg succinylcholine intravenously, and the efficacy of ECT was determined by the tourniquet technique. RESULTS: The mean arterial pressure in the elderly was significantly higher than that of the younger patients from immediately to 2 minutes after electrical stimulus. The interbeat interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. There was no statistically significant difference in the QT interval between the groups. The baseline value of QTc interval was higher than the normal limits, and the QTc interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. The baseline value of QTD was higher than the normal limits, and the QTD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical stimulus. The baseline value of QTcD was higher than the normal limits, and the QTcD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical stimulus. CONCLUSIONS: The QTc interval, QTD, and QTcD may be higher than the normal limits before anesthesia in patients with major depression. The QTD and QTcD in the elderly, which are associated with increased risks of ventricular arrhythmias, are higher than those of the younger patients after electrical stimulus during ECT. Electrical stimulus may induce further increased risks of cardiac events in elderly patients.

Assessment of QT interval and QT dispersion during electroconvulsive therapy using computerized measurements.

BACKGROUND: Electroconvulsive therapy (ECT) used in the treatment of severe psychiatric disorders induces stimulation of the autonomic nervous system with initial parasympathetic outflow immediately followed by a sympathetic response. These responses induce an initial bradycardia, arrhythmias, and hypertension. QT dispersion (QTD), defined as maximal QT interval minus minimal QT interval on 12 leads of the surface electrocardiogram, reflects regional heterogeneity of ventricular repolarization. The effects of electrical stimulus due to ECT on QT interval and QTD are of considerable interest. OBJECTIVE: : This study was designed to investigate the effects of electrical stimulation caused by ECT on RR interval, QT interval, the rate-corrected QT (QTc) interval, QTD, and the rate-corrected QTD (QTcD) under general anesthesia using computerized measurements. METHODS: Thirty psychiatric patients scheduled for ECT were studied under propofol anesthesia. A 12-lead electrocardiogram was monitored to measure parameters. Muscle paralysis was achieved by administering succinylcholine 1 mg/kg intravenously, and the efficacy of ECT was determined by the tourniquet technique. RESULTS: The RR interval and QT interval decreased significantly immediately after electrical stimulus, and returned to the baseline level 1 minute after electrical stimulus. In 25 out of 30 patients, the baseline value of QTc interval was higher than the normal limits, and the QTc interval decreased significantly for 2 minutes after electrical stimulus. In 27 out of 30 patients, the baseline values of QTD and QTcD were higher than the normal limits, and the QTD and QTcD increased significantly from immediately after electrical stimulus to 5 minutes after electrical stimulus. CONCLUSIONS: The QTc interval, QTD, and QTcD, which were associated with increased risks of ventricular arrhythmias, increased significantly before anesthetic induction in patients with major depression. Electrical stimulus during ECT induced further increases of the QTD and QTcD.

Pretreatment plasma renin activity levels correlate with the blood pressure response to telmisartan in essential hypertension.

BACKGROUND: Although the therapeutic response to angiotensin II receptor blockers (ARBs) is assumed impaired in patients with low-renin hypertension, data are scarce about the association between levels of plasma renin activity (PRA) before treatment and response of ambulatory blood pressure (ABP) to ARBs in essential hypertension. METHODS: We prospectively studied 11 untreated Japanese patients with essential hypertension (3 women and 8 men, mean age: 50 +/- 9 (mean +/- SD) years). After a 4-week drug-free period, telmisartan 20-40 mg was administered orally once daily for 8 weeks. PRA levels were measured before treatment. The first ABP measurement was performed at the end of the drug-free period and the second measurement at the end of the treatment period with telmisartan. RESULTS: Telmisartan significantly decreased the 24-h ABP by 12 +/- 11 mm Hg systolic (P < 0.01) and 9 +/- 8 mm Hg diastolic (P < 0.01). Reductions in the 24-h systolic and diastolic ABPs were significantly greater in five patients with higher renin levels (> or =0.65 ng/ml/h) than in six patients with lower renin levels (<0.65 ng/ml/h) by 18 mm Hg systolic (P < 0.001) and 11 mm Hg diastolic (P < 0.05). Changes in the 24-h systolic and diastolic ABPs significantly correlated with log PRA before treatment. CONCLUSIONS: The ABP lowering effects of telmisartan were dependent on PRA levels before treatment in patients with essential hypertension. Measurement of PRA levels before treatment is thought to be useful for prediction of the ABP lowering effects of telmisartan.

Predictive significance of blood pressure values for the incidence of cardiovascular events in chronic hemodialysis patients.

We conducted a prospective study investigating the relationship between blood pressure values and the risk of cardiovascular disease in patients with end-stage renal diseases. Five hundred fifty-three patients on chronic hemodialysis were followed for 5 years, and the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and pulse pressure (PP) and the incidence of death and cardiovascular events were evaluated. There were 85 cardiovascular and 88 non-cardiovascular deaths during the 5 years. Fatal and nonfatal cardiovascular events occurred in 205 patients. Factors such as old age, diabetes and electrocardiographic findings of left ventricular hypertrophy and arrhythmia were associated with a high incidence of cardiovascular events as well as the incidence of death. With regard to blood pressure values, only PP was significantly associated with the risk of death (p=0.003). Both SBP and PP showed a significant association with the incidence of cardiovascular events (p=0.004 and p<0.001). In other words, an increase in PP by 10 mmHg corresponded to a 22% increase in cardiovascular events, and a 10 mmHg SBP increase corresponded to a 10% increase in cardiovascular events. In conclusion, PP is a better predictor of death and cardiovascular events than other blood pressure values in chronic hemodialysis patients.

Effects of functional polymorphisms related to catecholaminergic systems on changes in blood catecholamine and cardiovascular measures after alcohol ingestion in the Japanese population.

BACKGROUND: The polymorphism of human aldehyde dehyrogenase-2 (ALDH2) Glu(487)Lys is well known to be a crucial factor underlying the genetic background for alcohol sensitivity in Asian populations. Subjects with the inactive Lys(487) allele show a marked increase in blood acetaldehyde level after alcohol intake, which results in facial flushing and various cardiovascular-related symptoms. However, other polymorphisms related to catecholaminergic systems that tightly regulate the activity of the sympathetic nervous system may also influence the physiological changes after acute alcohol intake. METHODS: We investigated whether, together with the ALDH2 Gly(487)Lys and ADH1B Arg(47)His genotype, putative functionally important polymorphisms, including 9 loci in 7 human genes, were associated with changes in blood catecholamine levels and cardiovascular measures after alcohol ingestion. Forty-nine young Japanese males were subjected to blood catecholamine analysis after alcohol ingestion. Among them, 28 were also subjected to heart rate variability and blood pressure analysis. The contribution of polymorphisms to the alcohol-induced response was analyzed by multiple regression analysis. RESULTS: Among the polymorphisms examined in this study, haplotypes of the phenylethanolamine N-methyltransferase (PNMT) promoter [(-182bpG/A)_(-387bpG/A)] and catechol-O-methyltransferase (COMT) exon 4 [(Ex4 + 119bpC/G)_(Ex4 + 138bpG/A), Leu(136)Leu_Val(158)Met] are suggested to have functionally important effects on alcohol-induced cardiovascular symptoms by affecting blood catecholamine levels. The neuropeptide Y (NPY) promoter C-1450T genotype is also suggested to be involved in the individual differences in regulation of catecholamine secretion. CONCLUSIONS: This study suggested that these common polymorphisms of genes related to catecholaminergic systems, as well as those of the alcohol metabolizing system, are significant for understanding the basis of individual differences in alcohol sensitivity.

Birth weight and risk of type 2 diabetes: a systematic review.

CONTEXT: Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. OBJECTIVE: To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. DATA SOURCES AND STUDY SELECTION: Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. DATA EXTRACTION: Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. DATA SYNTHESIS: Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. CONCLUSION: In most populations studied, birth weight was inversely related to type 2 diabetes risk.

[Chronic kidney disease (CKD) as an independent risk factor for cardiovascular disease (CVD)].

Chronic kidney disease (CKD) has been shown to be an independent risk factor for cardiovascular disease (CVD) in a number of recent epidemiological studies. There are possible explanations for the independent association of CKD with CVD. Reduced renal function is associated with a high prevalence of traditional CVD risk factors, such as hypertension, diabetes, dyslipidemia, and left ventricular hypertrophy. In addition, reduced renal function may be associated with increased levels of nontraditional risk factors, such as inflammation and oxidative stress. Subjects with CKD should be considered a high-risk population for CVD and be recommended for more intensive preventive management of CVD, including active detection and strict treatment of CVD risk factors.

Effects of Bifidobacterium breve B-3 on body fat reductions in pre-obese adults: a randomized, double-blind, placebo-controlled trial.

Accumulating evidence suggests a relationship between the gut microbiota and the development of obesity, indicating the potential of probiotics as a therapeutic approach. Bifidobacterium breve B-3 has been shown to exert anti-obesity effects in high-fat diet-induced obese mice. In the present study, the anti-obesity effects of the consumption of B. breve B-3 by healthy pre-obese (25 ≤ BMI < 30) adults were investigated in a randomized, double-blind, placebo-controlled trial (trial registration: UMIN-CTR No. 000023919; preregistered on September 2, 2016). Eighty participants were randomized to receive placebo or B. breve B-3 capsules (2 × 1010 CFU/day) daily for 12 weeks. The visceral fat area significantly increased at weeks 4 and 8 in the placebo group only; no significant change was observed in the B-3 group. Body fat mass and percent body fat were significantly lower in the B-3 group than in the placebo group at weeks 8 and 12 (p<0.05, ANCOVA adjusted with baseline values). Although no significant differences were observed in blood parameters between the groups, the intake of B. breve B-3 slightly decreased triglyceride levels and improved HDL cholesterol from the baseline. No serious adverse effects were noted in either group. These results suggest that the probiotic strain B. breve B-3 has potential as a functional food ingredient to reduce body fat in healthy pre-obese individuals.

Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders.

Adrenomedullin (AM) is a vasodilator peptide that originally isolated from pheochromocytoma tissue. However, the mRNA is expressed in the normal adrenal gland, heart, kidney and blood vessels. The human AM gene is located in the short arm of chromosome 11 and is composed of 4 exons. There are 2 single nucleotide polymorphisms in introns 1 and 3, and the 3'-end of the AM gene is flanked by a microsatellite marker of cytosine-adenine repeats that is associated with an increased risk of developing hypertension and diabetic nephropathy. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of the renin-angiotensin and sympathetic nervous systems. The AM gene promoter region possessed binding site for several transcription factors, including nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2). Further, plasma AM levels are increased in patients with various cardiovascular diseases, including hypertension, heart failure and renal failure. These findings suggest that AM plays a role in the development of or response to cardiovascular disease. Indeed, experimental and clinical studies have demonstrated that systemic infusion of AM may have a therapeutic effect on myocardial infarction, heart failure and renal failure. Further, vasopeptidase inhibitors which augment the bioactivity of endogenous AM may benefit patients with hypertension and arteriosclerosis. Finally, the angiogenic and cytoprotective properties of AM may have utility in revascularization and infarcted myocardium and ischemic limbs. Because of the potential clinical benefits of AM, indications for use and optimal dosing strategies should be established.

Lower birth weight is associated with higher resting heart rate during boyhood.

There is substantial evidence that low birth weight is associated with the development of cardiovascular disease in adult life. Moreover, resting heart rate is a prognostic factor of cardiovascular morbidity and mortality. However, there are scarce data regarding the association between birth weight and resting heart rate in later life. Therefore, we investigated the association of anthropometric data at birth and hemodynamic indices including resting heart rate in Japanese boys. The data of 1,107 male students of a junior high school in Tokyo, Japan, who underwent a medical check-up in the year of admission to the school (12 or 13 years old) were used. Information on anthropometric data at birth based on "The Maternal and Child Health Handbook" was obtained from 573 students. From a standard 12-channel resting electrocardiogram, 8 cardiac cycles were used to estimate heart rate. Resting heart rate correlated positively with body mass index at the same age (r=0.100, p=0.017) and correlated negatively with birth weight (r=-0.102, p=0.015), height at birth (r=-0.125, p=0.003), and head circumference at birth (r=-0.095, p=0.025). The negative correlation of anthropometric data at birth with heart rate at the age of 12 or 13 was independent of body mass index at the same age. The mean value of resting heart rate at the age of 12 or 13 adjusted for body mass index at the same age was significantly higher in the lower tertile of birth weight than in the higher tertile of birth weight (81.7 vs. 78.5 beats/min, p=0.028). In conclusion, lower birth weight is associated with higher resting heart rate during boyhood, suggesting that elevated heart rate may be one mechanism linking small size at birth with the development of cardiovascular disease in future life.

Efonidipine reduces proteinuria and plasma aldosterone in patients with chronic glomerulonephritis.

Efonidipine, a dihydropirydine calcium channel blocker, has been shown to dilate the efferent glomerular arterioles as effectively as the afferent arterioles. The present study compared the chronic effects of efonidipine and amlodipine on proteinuria in patients with chronic glomerulonephritis. The study subjects were 21 chronic glomerulonephritis patients presenting with spot proteinuria greater than 30 mg/dL and serum creatinine concentrations of or=130/85 mmHg. Efonidipine 20-60 mg twice daily and amlodipine 2.5-7.5 mg once daily were given for 4 months each in a random crossover manner. In both periods, calcium channel blockers were titrated when the BP exceeded 130/85 mmHg. Blood sampling and urinalysis were performed at the end of each treatment period. The average blood pressure was comparable between the efonidipine and the amlodipine periods (133+/-10/86+/-5 vs. 132+/-8/86+/-5 mmHg). Urinary protein excretion was significantly less in the efonidipine period than in the amlodipine period (1.7+/-1.5 vs. 2.0+/-1.6 g/g creatinine, p=0.04). Serum albumin was significantly higher in the efonidipine period than the amlodipine period (4.0+/-0.5 vs. 3.8+/-0.5 mEq/L, p=0.03). Glomerular filtration rate was not significantly different between the two periods. Plasma aldosterone was lower in the efonidipine period than in the amlodipine period (52+/-46 vs. 72+/-48 pg/mL, p=0.009). It may be concluded that efonidipine results in a greater reduction of plasma aldosterone and proteinuria than amlodipine, and that these effects occur by a mechanism independent of blood pressure reduction. A further large-scale clinical trial will be needed in order to apply the findings of this study to the treatment of patients with renal disease.

Cardiorenal protective effects of year-long antihypertensive therapy with an angiotensin-converting enzyme inhibitor or a calcium channel blocker in spontaneously hypertensive rats.

BACKGROUND: The objective of this study was to evaluate the effect of year-long antihypertensive therapy with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor on cardiac and renal injury. METHODS: Male 15-week-old spontaneously hypertensive rats (SHR) were given either a normal diet and normal drinking water (n = 10), a diet containing 0.05% nitrendipine (n = 10), or drinking water containing 50 mg/L of quinapril (n = 10). After 12 months of antihypertensive treatment, cardiovascular organ injuries were evaluated. RESULTS: Tail-cuff blood pressure (BP) at 12 months was significantly lower in animals receiving nitrendipine or quinapril than in control animals (control, 231 +/- 2 mm Hg; nitrendipine, 194 +/- 3 mm Hg; quinapril, 191 +/- 3 mm Hg; P < .001). Furthermore, aortic thickness was reduced by nitrendipine (-19%, P < .001) or quinapril (-21%, P < .001), and cardiac ventricular weight was significantly reduced by quinapril (-18%, P < .001) but not by nitrendipine (-5%, P = not significant [NS]). Echocardiography at 12 months revealed that midwall fractional shortening was higher in the quinapril group than in the control or the nitrendipine groups (control, 9.3% +/- 0.5%; nitrendipine, 9.8% +/- 0.5%; quinapril, 10.6% +/- 0.6%; P < .05). Left ventricular hydroxyproline levels were lower in the nitrendipine group (-21%, P < .01) and the quinapril group (-36%, P < .001) than in the control animals. In control SHR, creatinine clearance began to decrease and proteinuria began to increase at 6 to 9 months. Quinapril but not nitrendipine attenuated these markers of renal impairment (creatinine clearance at 12 months: control, 4.7 +/- 0.4 mL/min/kg; nitrendipine, 5.0 +/- 0.4 mL/min/kg; quinapril, 6.1 +/- 0.4 mL/min/kg; P < .05). Histologically, the glomerular injury score was lower in the quinapril group than in the control or nitrendipine groups (control, 19 [range, 8 to 30]; nitrendipine, 18 [range, 9 to 32]; quinapril, 7 [range, 3 to 12]; P < .01). CONCLUSIONS: It is suggested that year-long antihypertensive therapy with an angiotensin-converting enzyme (ACE) inhibitor is superior to a calcium channel blocker in terms of cardiorenal protection in SHR.

Effects of valsartan on the progression of chronic renal insufficiency in patients with nondiabetic renal diseases.

The present study tested the effects of valsartan, an angiotensin II receptor blocker, on the progression of renal insufficiency in patients with nondiabetic renal diseases. The study subjects were 22 patients with nondiabetic renal diseases whose serum creatinine (Cr) ranged from 1.5 to 3.0 mg/dl. Valsartan (40-80 mg) or placebo was given once daily for 1 year each in a random crossover manner. In both periods, antihypertensive medications were titrated when the blood pressure was not lower than 140/90 mmHg. Blood sampling and urinalysis were performed bimonthly throughout the study periods. The average blood pressure was comparable between the valsartan and the placebo periods (130 +/- 9/86 +/- 6 vs. 131 +/- 8/86 +/- 6 mmHg). Serum Cr significantly increased from 1.9 +/- 0.5 to 2.3 +/- 0.8 mg/dl (p < 0.001) during the placebo period, but the change was insignificant in the valsartan period (2.1 +/- 0.6 to 2.2 +/- 0.9 mg/dl). The slope of decrease in the reciprocal of serum Cr was steeper in the placebo period than in the valsartan period (-0.064 +/- 0.070/year vs. -0.005 +/- 0.050/year, p < 0.01). During the valsartan period, urinary protein excretion was less than that during the placebo period (0.75 +/- 0.73 vs. 1.24 +/- 0.92 g/g Cr, p < 0.001). Serum K was significantly higher in the valsartan period than in the placebo period (4.6 +/- 0.5 vs. 4.4 +/- 0.5 mEq/l, p < 0.05); however, no patients discontinued taking valsartan as a result of hyperkalemia. It is possible that long-term treatment with an angiotensin II receptor blocker, valsartan, is effective at retarding the deterioration of renal function in patients with nondiabetic renal disease by a mechanism independent of blood pressure reduction.

Protective effects of an angiotensin II receptor blocker and a long-acting calcium channel blocker against cardiovascular organ injuries in hypertensive patients.

The purpose of this study is to compare the long-term effects of an angiotensin II receptor blocker (ARB) and a long-acting calcium channel blocker (CCB) on left ventricular geometry, hypertensive renal injury and a circulating marker of collagen synthesis in hypertensive patients. Patients with essential hypertension (24 men and 19 women; age, 37-79 years) were treated with a long-acting CCB, amlodipine (AML; 2.5-7.5 mg once daily) for 6 months. Then, AML was switched to an ARB, candesartan (CS; 4-12 mg once daily), in 22 patients (CS group), while AML was continued in the remaining 21 patients for another 6 months (AML group). At the end of each treatment period, ambulatory blood pressure monitoring (ABPM), echocardiography and sampling of blood and urine were performed. The average office blood pressure during the latter period was comparably controlled in the AML and the CS groups (AML: 130 +/- 8/87 +/- 7 mmHg; CS: 133 +/- 11/ 88 +/- 7 mmHg), while the average systolic blood pressure of 24-h ABPM was significantly lower in the AML than in the CS group (127 +/- 9 vs. 133 +/- 14 mmHg, p<0.05). Consequently, the left ventricular mass index was significantly decreased in the AML group (102 +/- 18 to 92 +/- 12 g/m2, p<0.05), while the change was insignificant in the CS group (103 +/- 25 to 98 +/- 21 g/m2). On the other hand, plasma procollagen I C-terminal peptide (PICP), a marker of collagen synthesis, was lowered by CS (86 +/- 21 to 70 +/- 21 ng/ml, p<0.01), but was not significantly affected by AML (80 +/- 127 to 74 +/- 91 ng/ml). CS reduced urinary albumin excretion (57 +/- 123 to 26 +/- 33 mg/g creatinine, p<0.05), but AML did not bring about significant changes (85 +/- 27 to 73 +/- 19 mg/g creatinine). The results suggested that long-acting CCBs are effective in improving left ventricular hypertrophy by controlling 24-h blood pressure, while ARBs possess protective effects against cardiovascular fibrosis and renal injury beyond their antihypertensive effects.