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Background Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. Methods We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from Findings We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0–5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91–0·98]) compared with those without type 2 diabetes (0·89 [0·87–0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated. Interpretation Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted. Funding British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.

Findings 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4?2 years (IQR 3?0?5?0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0?99 [95% CI 0?95?1?04] for ACEIs; 0?96 [0?92?1?01] for ARBs; 0?98 [0?89?1?07] for 13 blockers; 1?01 [0?95?1?07] for thiazides), with the exception of calcium channel blockers (1?06 [1?01?1?11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1?00 [95% CI 0?93?1?09] for ACEIs; 0?99 [0?92?1?06] for ARBs; 0?99 [0?89?1?11] for 13 blockers; 1?04 [0?96?1?13] for calcium channel blockers; 1?00 [0?90?1?10] for thiazides). Summary Background Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. Methods We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), 13 blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). Findings 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4 & middot;2 years (IQR 3 & middot;0 & ndash;5 & middot;0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0 & middot;99 [95% CI 0 & middot;95 & ndash;1 & middot;04] for ACEIs; 0 & middot;96 [0 & middot;92 & ndash;1 & middot;01] for ARBs; 0 & middot;98 [0 & middot;89 & ndash;1 & middot;07] for 13 blockers; 1 & middot;01 [0 & middot;95 & ndash;1 & middot;07] for thiazides), with the exception of calcium channel blockers (1 & middot;06 [1 & middot;01 & ndash;1 & middot;11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1 & middot;00 [95% CI 0 & middot;93 & ndash;1 & middot;09] for ACEIs; 0 & middot;99 [0 & middot;92 & ndash;1 & middot;06] for ARBs; 0 & middot;99 [0 & middot;89 & ndash;1 & middot;11] for 13 blockers; 1 & middot;04 [0 & middot;96 & ndash;1 & middot;13] for calcium channel blockers; 1 & middot;00 [0 & middot;90 & ndash;1 & middot;10] for thiazides). Interpretation We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers.

Clinic physicians' awareness of the Japanese hypertension guideline (JSH 2000) and compliance with its recommendations were assessed to derive policy implications for effective blood pressure control. Data were obtained from two postal questionnaire surveys conducted in 2000 and 2004, and subjects were 896 and 1425 clinic physicians, respectively, who were engaged in general internal medicine. Recognition rates of JSH 2000 were 63.1% (n = 822) before its announcement in 2000 and 94.4% (n = 1400) in 2004. Rates of access, familiarity and utilisation of JSH 2000 were 87.0, 81.6 and 68.9%, respectively (n = 1400) in 2004. As for major management strategies for low-risk hypertension: in 2000, for patients with 140-149/90-94 mmHg, 81.5% of 812 respondents performed lifestyle modification, and 11.2% prescribed medicines, whereas for patients with 150-159/95-99 mmHg, 71.7% of 807 respondents prescribed medicines, and 24.3% conducted lifestyle modification; in 2004, 90.0% of 1384 respondents conducted lifestyle modification, 22.6% prescribed medicines, 2.5% referred patients to other facilities, and 6.4% did nothing. In 2004, 68.9% of 1388 respondents agreed with the new definition of hypertension, whereas 17.1% preferred 160/95 mmHg. Respondents' age (P0.05) and a percentage of hypertensives in daily patient load (P0.0005) significantly associated with the choice of the old criteria. In conclusion, JSH 2000 achieved a substantial improvement in clinic physicians' awareness and their compliance to its recommendations on low-risk hypertension management. One of the strategies for further enhancement in their compliance with JSH 2004 would be its dissemination to those who are old and/or do not see hypertensive patients so frequently.

The objective of this Phase III double-blind parallel-group controlled study was to examine the superiority of amlodipine 10 mg once daily (the amlodipine 10 mg group) to amlodipine 5 mg once daily (the amlodipine 5 mg group) in 305 Japanese outpatients with essential hypertension whose systolic blood pressure (SBP) had not reached the therapeutic target levels (

To investigate possible associations between diabetic microangiopathy and genetic polymorphisms in factors relevant to arterial thrombosis.We conducted a case-control study on a total of 280 patients with Type 2 diabetes, comparing those without retinopathy or nephropathy (n = 92) and those with microangiopathies (n = 188), for the association of polymorphisms in four candidate genes, paraoxonase 1 (PON1), plasminogen activator inhibitor-1, fibrinogen, and platelet glycoprotein Ibalpha.There were no differences between the two study groups in gender distribution, age at diagnosis of diabetes (47.9 +/- 8.4 and 49.0 +/- 11.4 years, respectively), or duration of diabetes (14.9 +/- 4.5 and 14.5 +/- 8.4 years, respectively). Among the gene polymorphisms tested, the 192Gln/Arg polymorphism of PON1 was associated with the prevalence of retinopathy [odds ratio (OR) = 3.13, 95% confidence interval (CI) = 1.42-6.89, P = 0.0046, Gln/Gln vs. Gln/Arg and Arg/Arg]. This polymorphism was also associated with nephropathy (OR = 3.01, 95% CI = 1.30-6.98, P = 0.0103). There were no differences between the three PON1 genotypes (Gln/Gln, Gln/Arg, and Arg/Arg) with regard to the present disease status. Logistic regression analysis for the adjustment of other risk factors revealed that genotypes with PON1 192Arg were an independent predictor of retinopathy. No associations were found between microangiopathies and the other polymorphisms evaluated (plasminogen activator inhibitor-1, fibrinogen, and platelet glycoprotein Ibalpha).This study suggests that the presence of the 192Arg-allele in the PON1 gene is a genetic risk factor for microangiopathy in Type 2 diabetes mellitus.

The Japanese society of hypertension organized guidelines subcommittee for guidelines for the management of hypertension by request of Japanese physicians and people in the Ministry of Health and Welfare in 1998. Professor Masatoshi Fujishima in the School of Medicine, Kyushu University became a chairman in the committee. He had proceeded the preparation smoothly, and in July, 2000 the new guideline for the management of hypertension was published. The Japanese new guideline for the management of hypertension is slightly different from those in other countries, such as JNC-VI or the WHO/ISH guideline. The Japanese new guideline was prepared under the consideration of characteristics of hypertension in Japan, Japanese life style and recent trends in the management of hypertension in Japan. It is desired that Japanese physicians treat hypertensive patients according to this new guideline, and questionable parts in the guideline should be corrected to make it more useful and valuable. Especially the parts peculiar to the Japanese guideline should be ascertained by further studies in Japan.

Continuous angiotensin-converting enzyme (ACE) inhibitor therapy does not necessarily produce significant decreases in plasma aldosterone levels (aldosterone escape). We examined the role of aldosterone escape in 75 essential hypertensive patients treated with an ACE inhibitor (enalapril maleate [34 patients], imidapril hydrochloride [24 patients] or trandolapril [17 patients]) for 40 weeks. With treatment, blood pressure decreased and plasma renin activity increased, while plasma aldosterone concentrations did not change. Aldosterone escape was observed in 38 of the 75 patients and in 17 of 37 patients with left ventricular hypertrophy before treatment. Left ventricular mass index did not change in patients with aldosterone escape but decreased significantly in patients without aldosterone escape. The present study demonstrated a high incidence of aldosterone escape in patients with essential hypertension despite the use of ACE inhibitors. The results also suggest that aldosterone escape may reverse the beneficial effects of an ACE inhibitor on left ventricular hypertrophy.

Insulin resistance is associated with advanced and moderate chronic renal failure (CRF). However, insulin resistance in chronic glomerulonephritis (CGN) before onset of frank renal dysfunction is not fully evaluated. We attempted to investigate the association of insulin resistance with mild renal dysfunction and with abnormal calcium homeostasis.Eighteen young, lean non-diabetic male patients with biopsy-proven CGN (age 30 +/- 7 years, body mass index 23.0 +/- 2.5 kg/m2) were enrolled. Insulin sensitivity was estimated by the glucose infusion rate (M value) during euglycemic hyperinsulinemic clamping for 60 to 120 min. Calcium-related parameters including intracellular calcium concentrations ([Ca2+]i) in platelets were also measured. Renal function was normal or slightly impaired (serum creatinine, 1.0 +/- 0.2 mg/dl; glomerular filtration rate (GFR), 68 to 131 ml/min/1.48 m2). We divided subjects into an insulin-sensitive (IS) group (M value7.3 mg/kg/min, the overall mean) and an insulin-resistant (IR) group (M value7.3 mg/kg/min).During a 75 g oral glucose tolerance test, the plasma glucose concentration at 120 min after glucose loading and the immunoreactive insulin concentration at 60 min were significantly higher in the IR group. GFR was notably lower in the IR group than in the IS group (p = 0.0003), and was significantly correlated with insulin sensitivity (p0.02, r = 0.58). The basal [Ca2+]i was significantly higher in the IR than in the IS group (39 +/- 9 vs. 30 +/- 9 nM, p0.05).Mild renal dysfunction and elevated basal [Ca2+]i are associated with insulin resistance in CGN.

The relative importance of hypertension in the progression of renal failure is well understood. Recently, several studies have provided evidence that antihypertensive therapy enhances renal survival. However, the specific antihypertensive drug regimens that are most effective in generating such long-term effects remain controversial.Forty-nine hypertensive IgA nephropathy (IgAN) patients (39 +/- 7 years old, serum creatinine 1.1 +/- 0.2 mg/dl) with proteinuria received antihypertensive therapy with angiotensin-converting enzyme inhibitors (ACEi: 2.5-10 mg of benazapril daily) and calcium channel blockers (CCBs: 2.5-10 mg amlodipine daily) for 3 years. The patients' blood pressures in group one were controlled below 140/85 mmHg by increases in their first drug dose or by addition of the second drug in group 1. Blood pressures for patients in group 2 were controlled using the same two options, except to levels below 130/70 mmHg. Patients within the two groups were selected and controlled with regard to sex, age, and serum creatinine. The renal protective effects of each protocol were evaluated in terms of reductions in creatinine clearance. After 3 years of the above outlined blood pressure control regimens, the reductions in creatinine clearance were compared.Creatinine clearances decreased in group 1 patients (from 85.7 +/- 2.4 ml/min to 72.9 +/- 2.4 ml/min, p0.05). On the other hand, creatinine clearance remained essentially unchanged for patients in group 2 (from 87.2 +/-4.7 ml/min to 85.9 +/- 5.9 ml/min). Although creatinine clearance in both groups was almost the same at the start of study, there was a significant difference between them by the conclusion of the study (p0.05). Proteinuria and hematuria did not change significantly throughout the study and there were no significant differences in these respects between these two corresponding groups. There were no significant differences between the groups with reference to side-effects or complications.These data provide evidence that reducing blood pressure has protective renal effects in cases of mild renal insufficiency with hypertension in IgA nephropathy.

A 35-year-old man was brought into the emergency room of Keio University Hospital by ambulance because of a sudden onset of coma. His Glasgow Coma Scale was 3 and his blood pressure 150/100 mmHg. CT scanning revealed a subcortical hemorrhage 8 cm in diameter. His respiration deteriorated rapidly, and an emergency craniotomy was performed for hematoma removal and cerebral decompression. Postoperatively the patient remained in a deep coma (GCS = 3) requiring respiratory support. The family presented an organ donor card previously signed by the patient, and brain death was confirmed in accordance with Japan's transplant law. As a result of two tests conducted six hours apart brain death was confirmed on the 5th postoperative day. With the family's consent, the donor's heart, kidneys and skin were removed for organ transplantation to be performed in other institutions. An autopsy was performed after the removal of the organs and skin. An extensive subgaleal hemorrhage was found in the left cerebral hemisphere, and microscopic examination revealed extensive necrosis with karyolysis of neuronal cells, but no viable neuronal cells were found in the cerebrum. The brain stem was marked by edema, hemorrhage, infarction necrosis and neuronal cell loss. The cerebellum was swollen and congested and showed autolysis of the granular layer. These findings suggested brain death syndrome with respirator brain. Other autopsy findings included a huge pheochromocytoma in the right adrenal gland, bilateral bronchopneumonia, liver congestion and fatty metamorphosis with four cavernous hemangiomas, and mild chronic lymphocytic thyroiditis. This patient was the second brain-dead organ donor and the first brain-dead patient to undergo postmortem examination in Japan.

The localization of inositol trisphosphate (IP(3)) receptor isoforms, types 1-3, in the kidney and their role in the regulation of the intracellular calcium concentration - [Ca(2+)](i) - are discussed.Immunohistological studies with isoform-specific antibodies were performed to reveal the localization of IP(3) receptor isoforms. To examine the role of IP(3) receptor type 1 in the glomeruli, the responses of [Ca(2+)](i) to hormonal stimuli were examined in IP(3) receptor type 1 knockout mice.In the immunohistological study, type 1 receptor was present in arteries, afferent arterioles, and mesangial cells. Double staining with antibodies against aquaporin 2 and IP(3) type 2 receptor revealed that type 2 receptor was localized mainly in the intercalated cells. The type 3 receptor showed characteristic intracellular localization in the collecting duct cells of the cortex to the outer medulla. Immunostaining of type 3 receptor was most intense in the cytoplasm on the basolateral membrane side and was not seen on the apical side. The responses of [Ca(2+)](i) to angiotensin II and endothelin in the glomeruli were markedly attenuated in IP(3) receptor type 1 knockout mice.The three isoforms of the IP(3) receptor showed distinctive localization in the kidney, and the type 1 receptor plays a major role in the regulation of [Ca(2+)](i) in the glomeruli. The physiological significance of the cell-specific localization, however, remains to be determined.

Platelets might be involved in the pathogenesis of diabetic microangiopathy. Wide interindividual variations in the density of a platelet collagen receptor (alpha2beta1 integrin or glycoprotein Ia/IIa) are reportedly associated with polymorphism(s) in the gene encoding the alpha subunit of the receptor, including a Bgl II polymorphism in intron 7. The aim of the present study was to determine the relationship between the Bgl II polymorphism and the susceptibility to diabetic microangiopathy. A case-control study comparing 227 patients with type II diabetes mellitus (119 with versus 108 without diabetic retinopathy) as well as 169 nondiabetic subjects demonstrated that genotypes with Bgl II (+) allele had a significant increase in the risk for retinopathy. The odds ratio for Bgl II (+/+) to Bgl II (-/-) was 3.41 (95% CI, 1.49-7.78, P =.0036) when analysis was confined to those with a disease duration of diabetes of 10 years or more. The present study suggests that the presence of a Bg II (+) allele is a genetic risk factor for diabetic retinopathy. (Blood. 2000;95:1560-1564)

The effect of pravastatin on renal function in hypertensive patients with mild renal dysfunction and hyperlipidemia was examined. A total of 57 subjects given dihydropyridine calcium blockers were randomly assigned to placebo (n = 25) and pravastatin groups (n = 32). The period of study was 6 months. In the placebo group, lipid metabolism did not change throughout the study period, but the serum creatinine concentration (Scr) increased from a baseline of 1.6+/-0.07 mg/dl to 2.1+/-0.2 mg/dl in the 6th month of study and blood urea nitrogen (BUN) increased from 26.2+/-1.1 mg/dl to 32.4+/-30.1 mg/dl. In the pravastatin group, the serum total cholesterol decreased from a baseline of 251.4+/-7.3 mg/dl to 218.2+/-6.5 mg/dl in the 6th month of study, while Scr (1.3+/-0.07 mg/dl vs. 1.3 +/-0.09 mg/dl) and BNU (20.5+/-1.2 mg/dl vs. 21.0+/-1.4 mg/dl) did not change. The change in Scr in the placebo group was significantly different from that in the pravastatin group (F = 3.75, p = 0.05). The slope of the change in 1/Scr was 0.02+/-0.07 dl x mg(-1) x month(-1) in placebo group and -0.01+/-0.03 dl x mg(-1) month(-1) in pravastatin group (P0.05). The results indicate that pravastatin attenuates the deterioration of renal function in patients with mild renal dysfunction, together with an improvement of lipid metabolism.

Recent clinical studies have established an important role of angiotensin converting enzyme inhibitors (ACE-I) as a tool for renal protection. Although angiotensin receptor antagonists (AII-A) share the common property with ACE-I with regard to blockade of angiotensin activity via angiotensin type 1 receptors (AT1), AII-A is also reported to stimulate AT2 that plausibly activates nitric oxide production within renal medulla and augments synthesis of vasodilatory P450-metabolites in renal afferent arterioles. In contrast, AII-A is reported to have no effect on bradykinin activity. Results obtained in experimental animals indicate that AII-A effectively prevents the progression of renal injury. Several clinical studies are in progress, and the preliminary results suggest that AII-A has potent renal protective action in a variety of renal disorders.

Pharmacological blockade of the renin-angiotensin system has been found to be a safe and efficacious way to treat hypertension and congestive heart failure. The success of the angiotensin converting enzyme inhibitors has led to interest in alternative ways to block the renin-angiotensin system. Angiotensin II receptor antagonists are a new class of anti-hypertensive drugs that provide a specific blockade of the effects of angiotensin II. Losartan potassium, the first compound of this class, has recently been approved in Japan. It seems likely that the angiotensin receptor antagonists will be suitable to first-line therapy and use of this class for treatment of hypertension will dramatically increase in Japan because of the excellent clinical and laboratory safety profiles.

Vitamin D dependency rickets type I (VDDR-I) is an autosomal recessive disorder in which 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-hydroxylase) activity in renal proximal tubules is deficient. VDDR-I is recognized throughout the world, but occurs more frequently in a subset of the French-Canadian population. We and others have recently cloned the human 1alpha-hydroxylase cDNA and gene, making it possible to screen for mutations. The first VDDR-I mutations were reported in one American and four Japanese patients. In this study, we screened for 1alpha-hydroxylase mutations in French-Canadian patients with VDDR-I.The nine exons of the 1alpha-hydroxylase gene were amplified by polymerase chain reaction (PCR) from genomic DNA of four unrelated French-Canadian patients with VDDR-I and their parents, and sequenced.Three of the patients were homozygous for a single base-pair deletion (G) at position 262 in the cDNA that lies in exon 2, and causes a premature termination codon upstream from the putative ferredoxin- and heme-binding domains. The fourth patient was homozygous for a 7-bp insertion (CCCCCCA) at position 1323 of the cDNA that lies in exon 8, and causes a premature termination upstream from the putative heme-binding domain. In each family, obligate carriers have one copy of the mutant allele. These mutations, which could be detected by PCR-restriction fragment length polymorphism and polyacrylamide gel electrophoresis of the PCR products, were not found in 25 normal French-Canadians.We describe two novel 1alpha-hydroxylase mutations that are consistent with loss of function in four French-Canadian patients with VDDR-I and suggest that the 1alpha-hydroxylase mutations arise from more than one founder in this population.

Over the past few decades, numerous randomized controlled studies of the treatment of hypertension have been conducted in Western countries to determine whether blood pressure reduction reduces the risk of stroke and myocardial infarction. Diuretics and beta blockers, because they have been shown in clinical trials to reduce cardiovascular morbidity and mortality, are the preferred drugs of first choice. No direct evidence yet supports the theoretical advantages of calcium channel blockers and ACE inhibitors over diuretics and beta blockers. Because East Asian nations differ culturally from Western countries, it is very difficult to conduct a randomized trials, thus, there were no reports of large, long-term, randomized placebo-controlled clinical trials of hypertension.

An etiologic agent directly linked to the development of IgA nephropathy (IgAN) has not been identified, despite the fact that various causes, including viral infections, have been implicated in the pathogenesis of this disease. Human immunodeficiency virus (HIV) infection has been linked with the development of IgAN in several clinical studies, and retroviral infection may be associated with the pathogenesis of IgAN in some patients. The incidence of IgAN has been found to possess distinct geographical distributions, and familial genetic clustering. To determine if retroviral infection is associated with IgAN in a large population of patients, genomic DNA from peripheral blood mononuclear cells from 90 patients seronegative for HIV and human T-cell leukemia virus type 1 (HTLV-1) (37 IgAN, 33 other glomerulonephritis, and 20 healthy controls) was evaluated by nested PCR using a pan-lentivirus-specific primer set (PLSPS), targeting the consensus sequence of the lentiviral pol gene. In 37.8% (14 of 37) of the patients with IgAN, the PCR products migrated in parallel with bands produced by PCR of simian immunodeficiency virus (SIV) infected cells. No products of the expected size were detected in the other patient groups (p0.0001, Chi-square). These results suggest that exposure to retroviral infection is more common in patients with IgAN, compared with patients with other proliferative glomerulonephritides, or patients without renal disease. These data demonstrate a possible association of IgAN with infection with non-HIV, non-HTLV-1 retrovirus.

The effects of calcium channel blockers (CCBs) and angiotensin converting enzyme (ACE) inhibitors on blood pressure and the progression of renal dysfunction were compared in hypertensive patients with polycystic kidney disease (PKD). Twenty-six patients with PKD and hypertension who had been treated with other antihypertensive agents, such as diuretics, beta-blockers, or alpha-methyldopa, were followed up for two years, during which their blood pressure and renal function were monitored. Patients were divided into two groups classified according to the type of antihypertensive agents given. Group 1 (n = 14) received CCBs, while group 2 (n = 12) received ACE inhibitors. No significant differences were found in their blood pressure control and serum creatinine levels throughout the study. The creatinine clearances were decreased in both groups. However, the decreases in creatinine clearance were smaller (p < 0.05) in the group treated with CCBs. In addition, two patients in group 2 showed rapid increases in serum creatinine. Our data suggest that CCBs reduced blood pressure effectively and preserved renal function in PKD patients at least as well as ACE inhibitors.

1. To reveal the mechanism responsible for the increase in blood pressure (BP) response to high salt intake in salt-sensitive essential hypertensives, pressor responses to angiotensin II and norepinephrine on high and low salt diet, influence of high salt intake on calcium metabolism and insulin sensitivity were studied in essential hypertensive and in normotensive subjects with or without family history of hypertension. 2. Pressor responses to angiotensin II and norepinephrine were significantly increased in salt-sensitive essential hypertensives irrespective of high or low salt diet. 3. In normotensive subjects with positive family history, high salt diet elevated BP in association with an increase in urinary calcium excretion. This observation, however, was not shared by the normotensive subjects with negative family history of hypertension. In the normotensive subjects with positive family history of hypertension, the cytosolic calcium concentration in platelets was significantly higher than in those with negative family history. A significant correlation between the cytosolic calcium concentration and elevation of BP was also observed. 4. In normotensive subjects with family history of hypertension, insulin sensitivity was decreased and correlated negatively with the cytosolic calcium concentration. 5. These results suggest that in salt-sensitive essential hypertensives increased pressor responses to angiotensin and norepinephrine and elevation of BP as well as insulin resistance may result from inherited abnormalities of intracellular calcium metabolism.

To assess the value of using imidapril hydrochloride (ACE/TA-6366), a long-acting angiotensin converting enzyme (ACE) inhibitor developed in Japan, to treat patients with essential hypertension.A double-blind, comparative, phase III study was carried out using enalapril maleate as a control, with a 4-week observation period and a 12-week treatment period. Both drugs were started at a dose of 5 mg once a day, increasing to 10 mg in patients whose antihypertensive response was insufficient after 4 weeks. The study included 231 outpatients aged 30-74 years; of these, 108 in the imidapril group and 115 in the enalapril group were assessed. There were no differences in background factors between groups.An adequate antihypertensive effect was observed in 71.3% (77/108) in the imidapril group in in 66.1% (76/115) in the enalapril group, with no significant difference between groups. The pulse rate was unchanged in both groups. The drug had no adverse effects in 86.1% (93/108) of the imidapril group and 79.1% (91/115) of the enalapril group, with no significant difference between groups. Adverse drug effects were observed din 5.6% (6/108) of the imidapril group and 12.2% (14/115) of the enalapril group. Cough was the most frequent side effect, reported in 0.9% (1/108) of the imidapril group and 7.0% (8/115) of the enalapril group. Other side effects were reported in 4.6% (5/108) of the imidapril group and 5.2% (6/115) of the enalapril group. Abnormal laboratory values were observed in 3.7% (4/108) of the imidapril group and 0.9% (1/115) of the enalapril group.Imidapril showed excellent clinical efficacy and safety compared to enalapril. The low incidence of cough is of particular interest.

The clinical efficacy and safety of bevantolol hydrochloride, a newly developed beta-blocker, used in combination with other types of antihypertensive agents, were evaluated in patients with severe hypertension by multicenter open-label trials. A total of 28 patients were studied at 20 medical centers. Four patients (14.3%) were excluded for some reasons, and the remaining 24 patients (22 outpatients and 2 inpatients) were analyzed. Following the initiation of therapy, blood pressure decreased from 181 +/- 15 (SD)/114 +/- 3 mmHg to 170 +/- 17/102 +/- 8 mmHg (p0.01) on the 14th day of the therapy and gradually lowered further thereafter. At the end of the trial (8th week), blood pressure was stabilized at the level of 160 +/- 14/96 +/- 10 mmHg. The antihypertensive efficacy rated by the changes in mean blood pressure was 79.2% (19/24). Pulse rate decreased slightly but significantly from 75 +/- 10 beats/min to 70 +/- 7 (p0.05) on the 14th day of the therapy and stabilized at the similar level thereafter. As abnormal laboratory data were detected in 3 patients and 1 patient complained of a mild headache, the safety ratio was 83.3% (20/24 patients). When the usefulness was assessed in terms of antihypertensive efficacy and safety profiles, bevantolol hydrochloride was considered useful in 75.0% of the patients studied. In conclusion, bevantolol hydrochloride, used in combination with other classes of antihypertensive agents, appears to be an excellent drug for the management of patients with severe hypertension.

The effects of a new dihydropyridine calcium channel blocker, amlodipine, on blood pressure (BP) and renal function were studied in spontaneously hypertensive rats (SHR). These effects were compared with those of an angiotensin-converting enzyme (ACE) inhibitor, enalapril. In addition, the effects of amlodipine on BP and renal function were studied in hypertensive patients with renal impairment. In five of six nephrectomised salt-loaded SHR, increases in BP, urinary excretion of protein and serum creatinine were attenuated by the administration of 2 mg/kg/day of amlodipine. The progression of renal histological damage was also markedly decreased. The protective effects of amlodipine against renal damage were similar to those of enalapril. However, the mechanisms of action of these two agents seem to differ as, unlike enalapril, amlodipine did not significantly dilate the efferent arteriole in hydronephrotic perfused rat kidney. In a clinical study, 2.5-5 mg/day of amlodipine was administered once a day for 8-10 weeks to 39 hypertensive patients with renal impairment (serum creatinineor = 1.5 mg/dl to5 mg/dl) or renal parenchymal disease (serum creatinine5 mg/dl). A significant reduction in BP (reduction of mean BPor = 13 mm Hg) was observed in 28 patients (80%). Headache was experienced as a side-effect in one of 35 patients (2.9%). With respect to the influence of amlodipine on renal function, mean values of blood urea nitrogen and serum creatinine were unchanged for the total group whereas a slight elevation of serum creatinine was observed in four of 35 patients (11.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

The goals of these preliminary studies were to evaluate the effects of a new angiotensin II receptor antagonist, TCV 116, on the daytime blood pressure profile in hospital inpatients with essential hypertension, and to evaluate the clinical efficacy and safety of this agent in outpatients with essential hypertension.In study 1, daytime blood pressure changes were studied in 28 inpatients with mild to moderate essential hypertension (systolic blood pressureor = 150 mmHg, diastolic blood pressureor = 90 mmHg). In study 2, 55 outpatients with essential hypertension (systolic blood pressureor = 160 mmHg, diastolic blood pressureor = 95 mmHg) were enrolled in a dose-finding study.In study 1, after a 1-week placebo run-in period, blood pressure and the pulse rate were measured every 2 h except at night. TCV 116 monotherapy was started at 1 mg/day and increased stepwise at 3- to 5-day intervals to 2, 4 and 8 mg/day until a predetermined reduction in blood pressure was achieved. The daytime profiles of blood pressure and the pulse rate were again monitored at the end of the treatment period. In study 2, after a 4-week placebo run-in period, TCV 116 alone was administered for 2 weeks at 1 mg/day. The dose was then increased to 2 mg/day and stepwise at 2-week intervals to 4 and 8 mg/day until a predetermined reduction in blood pressure was achieved. The total treatment period was 8-12 weeks.In study 1, a sufficient reduction in blood pressure was achieved in 19 of 28 patients (68%), with blood pressure significantly reduced at all measurement points, compared with the placebo run-in period. No differences were seen in the pulse rate. The only adverse reaction reported was a rash in one patient. In study 2, a sufficient reduction in blood pressure was achieved in 42 out of 55 patients (76%). The cumulative efficacy rate increased dose-dependently (15% at 1 mg/day, 38% at 2 mg/day, 60% at 4 mg/day and 76% at 8 mg/day). No differences were seen in the pulse rate. Adverse reactions were reported in three out of 55 patients (5.5%). No dry cough was reported by any of the patients.TCV 116, an angiotensin II receptor antagonist, has potential as an antihypertensive agent. A dose of 4-8 mg once per day appears to be appropriate for the treatment of patients with mild to moderate essential hypertension.

We investigated the relation between home blood pressure (BP) and body weight in 38 young normotensive men (mean age, 16 years) whose parents were normotensive (PNT group) and 34 age- and sex-matched normotensive men, one or both of whose parents were hypertensive (PHT group). Although causal BP measurements were similar in both groups, home systolic BP was significantly higher in the PHT group (123 +/- 1 mm Hg) than in the PNT group (116 +/- 1 mm Hg). Body weight was significantly greater in the PHT group (66.0 +/- 1.4 v 61.8 +/- 1.3 kg, P.05) and body mass index (BMI) was not significantly higher in the PHT group (22.4 +/- 0.5 v 21.3 +/- 0.5 kg/m2, P = .09). Body weight (r = 0.38) and BMI (r = 0.42) were significantly correlated with home systolic BP in the PHT group. There were no differences in serum lipid or uric acid concentrations between the two groups. Our results showed that young normotensive subjects with a genetic predisposition to hypertension weighed more and had higher home systolic BPs compared with subjects without a family history of hypertension. Our observations further indicated a close relationship between a family history of hypertension and increased body weight, even in young normotensive men.

A 32-year-old Japanese male presented with abundant proteinuria, and renal biopsy revealed diffuse subendothelial and mesangial deposits in the glomeruli without hypercellularity or mesangial interposition. There was no clinical or laboratory evidence of systemic conditions such as collagen-vascular disease, paraproteinemia, or infection. Treatment with corticosteroid was ineffective and the patient eventually went into end-stage renal failure. To our knowledge, this is the first report of an idiopathic progressive glomerulopathy characterized by diffuse, global subendothelial and mesangial deposits, which suggests to us a novel insight into glomerular subendothelial/mesangial deposition.

Hypertension is more common in hypothyroidic patients than in euthyroid controls in older age groups. Treatment of the thyroid deficiency alone lowers blood pressure in most patients. Hemodynamically, cardiac output is reduced and total peripheral resistance is elevated. The latter probably is secondary to an increase of sympathetic nervous tone and a relative increase in alpha-adrenergic response. In hyperthyroidism, elevation of diastolic blood pressure is uncommon. Systolic hypertension is more common in younger age groups. Treatment of the hyperthyroidism alone lowers systolic blood pressure in most patients. An increase in cardiac output and a decrease in total peripheral resistance accompany the hyperthyroidism. Potentiation of catecholamine action by an excess of thyroid hormone has been invoked as an explanation, because thyroid hormone excess is accompanied by increased beta-adrenergic receptors in some tissue, including heart.

Recent prospective study of intravenous magnesium sulphate administration into patients with acute myocardial infarction revealed the improvement of survival rate of these patients. This study was designed to determine the effect of intravenous administration of magnesium on the renin-angiotensin-aldosterone (RAA) system. MgSO4 (0.72% in 3.24% glucose solution) at 5 mEq/hr was infused intravenously into six healthy normotensive men for six hours. MgSO4 infusion increased plasma renin activity (PRA) at 60 minutes (4.1 +/- 1.4 ng/ml/hr vs 2.7 +/- 0.8 ng/ml/hr, p0.05) and decreased plasma aldosterone concentration (PAC) at 180 minutes (40 +/- 8 pg/ml vs 60 +/- 12 pg/ml, p0.05). The maximum level of serum magnesium reached 2.32 +/- 0.09 mEq/L, from the control value of 1.58 +/- 0.07 mEq/L, at -3 hours. Analysis of both serum levels and urinary excretion of electrolytes revealed significant increases in urinary excretion of calcium and magnesium, whereas no significant changes in other electrolytes in serum or urinary excretion were found. To clarify the mechanism by which magnesium increased PRA and suppressed PAC, either prostaglandin synthesis inhibitor, indomethacin (75 mg/day), or a calcium channel blocker, diltiazem (90 mg/day), was administered. Indomethacin completely blocked the increase in PRA but did not induce any changes in PAC. Diltiazem inhibited the decrease in PAC but did not induce any changes in PRA. These data indicate that magnesium stimulates renin release through the elevation of prostaglandins and suppresses aldosterone production through the intracellular calcium mobilization. From these results it is suggested that a favorable effect of magnesium administration to patients with myocardial infarction relates to the alterations of the RAA system.

Despite the usefulness of angiotensin converting enzyme (ACE; EC 3.4.15.1) inhibitors for patients with renal insufficiency, some hesitation has been exercised in applying ACE inhibitors to the treatment of such patients because most ACE inhibitors are excreted mainly into the urine. In this context, development of an ACE inhibitor which is excreted into the bile has been sought. The pharmacokinetic properties of the novel ACE inhibitor, temocapril hydrochloride (temocapril HCl; CS-622), were investigated in six healthy volunteers. This drug is excreted mainly into the bile in animal studies. Temocapril HCl was given in a single dose of 0.5, 1.0, and 2.0 mg, and 36, 44, and 38 per cent of the administered drug was excreted in the feces and 17, 19, and 24 per cent in the urine as the de-esterified active diacid form (the diacid metabolite) within 48 h, respectively. The plasma ACE activity was markedly inhibited. No abnormal clinical findings suggestive of side-effects were observed. Thus, from the pharmacokinetic standpoint, temocapril HCl is expected to be a useful drug for patients with renal dysfunction.

The kidney is the principal organ in the body that mediates the excretion of water and minerals, and also functions as an endocrine organ in producing hormones, enzymes (e.g., renin), and vasoactive molecules (e.g., prostaglandins). Circulating catecholamines and autonomic innervation of the kidney can influence those important functional responses as well as vascular constriction via renal adrenergic receptors. The adrenergic receptors are members of a large family of G protein-coupled receptors. Recent advance of molecular cloning has revealed a growing heterogeneity of adrenergic receptor subtypes. They share a common topographical motif consisting of seven putative transmembrane regions, where. They are thought to be essential for ligand binding. Multiple subtypes of adrenergic receptors may exist in the kidney. Defining the precise role of renal adrenergic receptors in disease states, particularly hypertension, will certainly require the application of new tools of biochemistry and molecular biology.

It has been suggested that the mineralocorticoid action of glycyrrhizin is caused by a defect in the conversion of cortisol to cortisone through inhibition of the enzyme 11β-dehydrogenase (11β-DH). We investigated the functional significance of the inhibition of this enzyme as a mechanism of the mineralocorticoid action of glycyrrhizin. Eighteen healthy volunteers were divided into three groups of six and treated as follows: (1) 225 mg glycyrrhizin/day, (2) 0·1 mg 9α-fluorocortisol (FC)/day and (3) 225 mg glycyrrhizin and 1·5 mg dexamethasone/day, all of which were given for 7 days. The administration of glycyrrhizin or FC induced a similar mineralocorticoid effect; specifically, suppression of plasma renin activity, hypokalaemia and kaliuresis. During the concomitant administration of glycyrrhizin and dexamethasone, however, these mineralocorticoid effects were significantly attenuated. During the administration of glycyrrhizin, urinary excretion of cortisol increased without change in the plasma levels of cortisol, while both plasma level and urinary excretion of cortisone decreased. Changes in cortisol metabolism were not observed during the administration of FC. These results demonstrated the functional significance of the inhibition of 11β-DH in the mineralocorticoid activity of glycyrrhizin in man. Journal of Endocrinology (1992) 135, 147–152