Munemichi Inaba

Insulin levels during fasting and the glucose tolerance test and Homa's index predict subsequent development of hypertension.

Objective To determine whether there is a longitudinal relationship between hypertension and hyperinsulinemia and to find the most useful parameter(s) for predicting the subsequent development of hypertension. Subjects and methods The oral glucose (75 g) tolerance test (OGTT) was performed in 313 patients, who were divided into three groups according to glucose tolerance based on the WHO criteria: normal, borderline and diabetes mellitus. The fasting insulin (IRI) levels, ΣIRI (the sum of the insulin levels 0, 30, 60 and 120 min after the OGTT), insulinogenic index and Homas index, a candidate for the simple assessment of insulin sensitivity, of the normotensive and hypertensive subjects in each subgroup were compared. In addition, 145 normotensive subjects were followed up for over 3 years and observed for the development of hypertension. Results Hypertensive diabetic subjects had not only higher fasting IRI levels and ΣIRI values, but they also had higher Homas indices than normotensive diabetics. Normotensive subjects with normal glucose tolerance (n = 20) did not develop hypertension. However, 16 out of 94 patients with borderline glucose tolerance and five out of 31 diabetics became hypertensive. The incidence of hypertension in the group with fasting IRI ≥ 15, ΣIRI ≥ 150 or Homas index ≥ 4 was between 5 and 9 times higher than that in the group with fasting IRI < 10, ΣIRI < 100 or Homas index < 2. This difference was still significant when multivariate analysis, including various factors such as age, body mass index (BMI) and sex, was performed. Conclusions These results suggest that higher plasma IRI levels and/or insulin resistance are closely related to the pathogenesis of hypertension in patients with diabetes mellitus. Homas index, fasting and ΣIRI may be useful predictors of the subsequent development of hypertension.

Predictive power of home blood pressure and clinic blood pressure in hypertensive patients with impaired glucose metabolism and diabetes.

Objectives: We evaluated the predictive power of home blood pressure and clinic blood pressure based on the long-term cardiovascular outcome in hypertensive patients with and without impaired glucose metabolism (IGM). Method: The multicentre Hypertension Objective Treatment Based on Measurement by Electrical Devices Blood Pressure trial (HOMED-BP) involved 3080 patients (50.5% women; mean age 59.7 years) with a baseline, untreated home/clinic blood pressure as well as follow-up, on-treatment blood pressure. Of those, 979 had IGM and 475 of these patients had diabetes. We applied Cox regression pooling all participants in a cohort analysis in which IGM and normal glucose metabolism (NGM) were separated. Results: During median 5.45 years follow-up, cardiovascular events occurred in 48 patients with IGM and 53 patients with NGM. Baseline home SBP significantly predicted cardiovascular outcome among IGM group [hazard ratio 1.68, 95% CI 1.26–2.26, P = 0.0005]. On-treatment home blood pressure was a significant predictor for cardiovascular risk even after the further adjustment of baseline blood pressure level (P ⩽ 0.027), whereas on-treatment clinic blood pressure was not in NGM group (P ≥ 0.37). The event rate in IGM was approximately two times higher than that in NGM (9.95 vs. 4.88 per 1000 patient-years), resulted to the low 5-year number needed to treat in IGM patients [83 vs. 121 for 1–SD (13.1 mmHg) home SBP reduction, and 62 vs. 104 for 1–SD (9.5 mmHg) home DBP reduction). Conclusion: The present findings suggest that long-term cardiovascular risk in IGM patients should be assessed based on home blood pressure, not on clinic blood pressure.

A Case of Renin-producing Juxtaglomerular Tumor: Effect of ACE Inhibitor or Angiotensin II Receptor Antagonist

We report a case of a renin-producing juxtaglomerular cell tumor and the effects of angiotensin-converting enzyme (ACE) inhibitor captopril or angiotensin II receptor antagonist TCV-116. A 19-year-old female visited our clinic because of hypertension (162/122 mmHg). Plasma renin activity (PRA) was 25 ng/ml/h and plasma aldosterone concentration (PAC) was 880 pg/ml. Abdominal sonography revealed a low echoic tumor in the center of the right kidney. The mass was shown to have isodensity on a computed tomography scan, iso- or slightly lower intensity on T1-weighted magnetic resonance imaging (MRI), and low intensity on T2-weighted MRI. Renal angiography disclosed a hypovascular tumor. Plasma renin activity was not decreased in response to oral administration of captopril (50 mg) or TCV-116 (4 mg), which is associated with a marked decrease in PAC and blood pressure. The average of the mean blood pressure determined by an ambulatory monitoring system every hour for 24 h was lowered from 118 +/- 10.6 (SD) to 85 +/- 11.4 mmHg by TCV-116. Plasma renin activity did not show any difference between the right and left renal vein. Removal of the tumor successfully decreased PRA to 0.3 ng/ml/h and PAC to 33 pg/ml, resulting in a decrease in 24-h average of the mean blood pressure to 78 +/- 16.9 mmHg. The tumor was well capsulated and stained with an antibody against mouse renin. In the tumor, but not normal tissues, renin mRNA was detected at 1.6 kb using rat renin cDNA. The content of active renin in the tumor amounted to 182 micrograms/g tissue, which is 109 times higher than that in normal tissue. The plasma- or tumor-inactive renin concentration was 3.6- or 1.8-fold the active renin concentration, respectively. These results suggest that the juxtaglomerular tumor had an MRI image of iso- to low intensity on T1 and low intensity on T2, and that renin secretion from the tumor may be due mainly to the constitutive pathway and angiotensin II receptor antagonist, as well as to ACE inhibitors, and may be very effective for lowering the blood pressure.

Effect of the vasodilatory β-blocker, nipradilol, and Ca-antagonist, barnidipine, on insulin sensitivity in patients with essential hypertension

Objectives To assess the effects of a vasodilatory β -adrenoceptor blocker, nipradilol, and a long-acting Ca channel blocker, barnidipine, on insulin sensitivity.Design Insulin sensitivity was determined using a euglycemic hyperinsulinemic clamp technique before and after a 12-week treatment period in eighteen patients with essential hypertension.Results Both drugs decreased blood pressure without affecting any serum parameters of glucose and lipid metabolism. Nipradilol significantly augmented glucose infusion rate (GIR) from 3.11 ± 0.28 to 4.69 ± 0.57 mg/kg/min (p=0.027). Barnidipine also increased GIR from 3.91 ± 0.43 to 5.29 ± 0.43 mg/kg/min (p=0.028). Plasma norepinephrine concentrations significantly increased with barnidipine treatment, while nipradilol had no effect on plasma norepinephrine levels. No adverse events were reported during the study.Conclusions These results suggest that vasodilatory /3 -blockers such as nipradilol and long-acting Ca channel blockers such as barnidipine may be usefui...

Increased renal TXA2 synthesis in diabetes mellitus: Simultaneous determination of urinary TXB2 and 2,3-dinor-TXB2

The present study was designed to determine urinary excretion of kallikrein(KAL)-kinin as well as prostaglandin (PG) E2, TXB2 and 2,3-dinor-TXB2, a major urinary metabolite of TXA2 synthesized in platelets, by specific RIAs in patients with diabetes mellitus (DM). KAL or kinin excretion in 26 type II DM did not differ from control values obtained in 18 age-matched healthy subjects (C), although DM with HbA1 greater than 11% excreted less KAL. Urinary PGE2 excretion (7.6 +/- 2.8 ng/mg creatinine, mean +/- SE) was significantly lower in DM compared to C (17.5 +/- 3.9, p less than 0.05), while DM excreted more TXB2 (0.57 +/- 0.09, p less than 0.01) and 2,3-dinor-TXB2 (0.56 +/- 0.12, N.S.) than C (0.19 +/- 0.02 or 0.33 +/- 0.01). DM with or without mild proteinuria demonstrated lower PGE2, but higher TXB2 and 2,3-dinor-TXB2 excretion. A positive correlation of TXB2/2,3-dinor-TXB2 with proteinuria was observed in this group. However, in DM with massive proteinuria over 500 micrograms/mg creatinine, TXB2 and 2,3-dinor-TXB2 excretion decreased to levels almost identical to C. As a whole, a ratio of TXB2 to PGE2 or 2,3-dinor-TXB2 in DM was significantly higher than in C. The results suggest that a relative preponderance of TXB2 to 2,3-dinor-TXB2 may indicate an augmented renal, in addition to platelet, TXA2 synthesis. An excessive vasoconstrictive and proaggregatory TXA2 renal synthesis, concomitant with a decrease in vasodilatory and antiaggregatory PGE2, may have profound effects on renal functions such as protein excretion in DM.

Is Renoprotection by Angiotensin Receptor Blocker Dependent on Blood Pressure?: The Saitama Medical School, Albuminuria Reduction in Diabetics with Valsartan (STAR) Study

To explore the effects of various antihypertensive regimes on microalbuminuria, an angiotensin II receptor blocker (ARB), valsartan, was substituted for or added to treatment with a calcium channel blocker (CCB). After a 6-month CCB baseline period, 28 Japanese hypertensive patients with incipient diabetic nephropathy (defined as a urinary albumin excretion [UAE] of 30–300 mg/g creatinine), were assigned to two groups according to their blood pressure (BP) levels: in patients with a BP of more than 130/85 mmHg (n=17), valsartan was added to the CCB (Group A), while in patients with a BP <130/85 mmHg, valsartan alone was given (Group B: n=11) for 12 months. UAE was determined before and at 3, 6 and 12 months after the initiation of ARB. Although the initial BP was significantly higher in Group A (150/83 mmHg) than Group B (127/77 mmHg), BP was decreased to 141/78 mmHg in Group A and slightly, but not significantly, increased to 130/82 mmHg in Group B. In both groups, UAE was significantly decreased after ARB treatment (to 89% of the basal value in Group A and to 40.5% of the basal value in Group B) and did not differ each other and the amount of decrease did not differ significantly between the two groups. These results suggest that combination therapy with an ARB and CCB is very effective in lowering BP and UAE in cases in which BP is not well controlled, while, even in patients with a sufficient BP control of <130/85 mmHg, the use of ARB singly resulted in a significant decrease in UAE without a further decrease in BP, implying that the ARB had a renoprotective action independent of changes in BP.

Effect of captopril or enalapril on renal prostaglandin E2

Since one of the hypotensive mechanisms of angiotensin-converting enzyme inhibitor (ACEI) has been suggested to be mediated through the renal kinin-prostaglandin (PG) axis, the present study was designed to investigate the effect of captopril (C) or enalapril (E) on renal PGE2 excretion or synthesis. Wistar male rats (BW 200-250 g) were given orally captopril at 30 mg/kg/day or enalapril at 10 or 30 mg/kg for one week. Before and after ACEI, blood pressure (tail cuff method) as well as PRA and urinary PGE2 excretion was determined. Renopapillary slices were obtained from some of the rats including controls and incubated to determine PGE2 synthesis. C or E administration resulted in a blood pressure decrease of 21 to 36 mm Hg with an increase in PRA. Urine volume and sodium excretion increased after daily treatment with C or E at 30 mg/kg. Urinary PGE2 excretion increased 1.4-fold in response to C, but not to E. Papillary PGE2 synthesis demonstrated a marked decrease 2 h after in vivo administration of either ACEI compared to controls. However, when C or enalaprilat was added in vitro to renal slices obtained from controls, only C at 10(-5) M showed a significant 2-fold increase in renal PGE2 synthesis. These results suggest that (1) renal PGE2 synthesis may be dependent on circulating angiotensin II. (2) C, but not enalaprilat, has a direct stimulatory effect on renal PGE2 synthesis and (3) renal PGE2 may not be involved very much in the hypotensive effect of ACEI.

Increased night:day blood pressure ratio in microalbuminuric normotensive NIDDM subjects

OBJECTIVE To determine the relationship of day- and night-time blood pressure (BP) with the degree of albuminuria in subjects with non-insulin-dependent diabetes (NIDDM). RESEARCH DESIGN AND METHODS BP was determined hourly for 24 h in 27 NIDDM normotensive patients, and 10 age- and BMI-matched controls. Diabetic subjects were separated into normo- and microalbuminuric groups according to the urinary albumin excretion rate (AER < 15 and > or = 15 micrograms/min), respectively. RESULTS Non-dippers defined by a nocturnal fall in BP of less then 10/5 mmHg represented 68.8% of the normo- and 81.8% of the microalbuminuric patients. Microalbuminuric diabetics demonstrated a significantly higher ratio of night:day BP in comparison to controls, but not to normoalbuminuric diabetics. AER was significantly correlated with BP ratio in the normoalbuminuric, but not in microalbuminuric group. CONCLUSIONS Ambulatory 24-h BP monitoring is useful to find blunted nocturnal fall in BP even in normotensive NIDDM subjects with or without microalbuminuria. However, whether or not an increase in the night-time BP and/or the night:day ratio in NIDDM patients plays a pathogenetic role in the progression of diabetic nephropathy remains to be clarified.

Hyperreninemia due to increased renal renin synthesis in BioBreeding Worcester rats.

It is well known that diabetes mellitus is often associated with hypertension. We previously reported the unresponsiveness of renin release to volume depletion with impaired renal prostaglandin E⁁ synthesis in rats with streptozotocin-induced diabetes. However, we have found that BioBreeding Worcester rats, spontaneously susceptible to diabetes mellitus either before or after the onset of diabetes, showed a pronounced fourfold to ninefold increase in plasma renin activity in comparison with control Wistar rats. Furthermore, these rats developed mild hypertension as high as 134 mm Hg after the age of 90 days. The hyperreninemia responded to 1-week sodium loading or restriction; the blood pressure increased during sodium loading. Oral administration of captopril (30 mg/kg) for 1 week resulted in a large blood pressure decrease (−47.1±5.9 mm Hg, n=10) in comparison with controls (−17.0±4.7 mm Hg, n=12). Vascular response to angiotensin II was also attenuated. Plasma angiotensin II levels were 5.7-fold higher and associated with a 1.5-fold increase of plasma aldosterone concentration compared with control rats, whereas angiotensinogen-plasma concentrations were lower than in control rats. The renal renin content determined enzymatically or histochemically was more enhanced in BioBreeding Worcester rats than in control rats, but the renal renin messenger RNA levels did not differ. These results suggest that the strainspecific hyperreninemia in BioBreeding Worcester rats might be due to posttranscriptional abnormalities of renal renin synthesis. Further work is needed to elucidate the specific mechanism or mechanisms responsible.

Effects of nipradilol, a new nitroester-containing beta-blocker, on forearm blood flow

Abstract Beta-blockers without intrinsic sympathomimetic action have been reported to produce an increase in peripheral vascular resistance. The present study was designed to determine the effects of a new beta-blocker, nipradilol (3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1-benzopyran), on forearm blood flow (FBF) in seven patients (mean age, 51.6 ± 6.7 years) with essential hypertension. After overnight fasting, FBF was determined using venous occlusion strain-gauge plethysmography before and two hours after oral administration of 6 mg nipradilol or 20 mg propranolol. Both beta-blokers produced a significant decrease in blood pressure, and heart rate also tended to decrease. As a result, the product obtained by multiplying systolic blood pressure by heart rate was reduced after both nipradilol and propranolol. Nipradilol increased FBF from 0.78 ± 0.10 ml/100 ml/min to 1.72 ± 0.28 ml/100 ml/min ( P P 1 -blocking activity.