Yoshiko Maruno

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.

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.

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.

Effect of dietary calcium on renal prostaglandins

The present study was designed to clarify the possible role of renal prostaglandins (PGs) on blood pressure (BP) regulation during calcium (Ca) restriction or supplementation. Twelve normotensive women with a mean age of 21.2 years participated in the study. After 1 week of normal Ca intake (mean +/- SE, 536 +/- 2 mg/day), a low-Ca diet (163 +/- 1 mg/day) was given for a further 1 week. Additional asparagine Ca (3 g as Ca/day) was also given to half of the subjects. BP, heart rate, and serum total and ionized Ca concentrations were measured at the end of each period. Levels of Ca, sodium, PGE2, 6-keto-PGF1 alpha and thromboxane (TX) B2 excreted into urine were also determined. The plasma level of ionized Ca was significantly increased without any change in total Ca in both groups. Low and high Ca intake decreased and increased urinary Ca excretion by 28% and 56%, respectively. BP was not altered after Ca deprivation or loading. However, urinary PGE2 excretion was significantly augmented from 668.9 +/- 68.1 to 959.7 +/- 183.1 ng/day by Ca loading, whereas Ca deprivation decreased PGE2 excretion (695.4 +/- 108.1 to 513.2 +/- 55.2 ng/day). No changes were observed in 6-keto-PGF1 alpha or TXB2 urinary excretion. These results suggest that renal PGE2 synthesis is stimulated or decreased by 1-week Ca loading or deprivation, indicating a possible antihypertensive role of renal PGE2 during high-Ca intake in hypertensives.

Effect of alpha1-blockade on diminished forearm blood flow in diabetics

An increased risk of atherosclerotic disease has been reported in patients with diabetes mellitus. The present study was therefore designed to determine forearm blood flow (FBF) in patients with essential hypertension or those with diabetes mellitus with or without hypertension. FBF determined by venous occlusion plethysmography decreased with age in controls as well as in patients with essential hypertension, whereas FBF in diabetics was significantly lower irrespective of age or blood pressure. As a result, vascular resistance was significantly higher in diabetics than in controls or patients with essential hypertension. Glycemic control in normotensive diabetics during 3 weeks significantly augmented a diminished FBF. alpha 1-Blockade by oral administration of 1 mg of prazosin also augmented the diminished FBF in diabetics, in association with a significant decrease in mean blood pressure and vascular resistance. These results suggest that FBF may be a simple and useful index for determining arterial and/or venous distensibility, and that alpha 1-blocker therapy, in addition to glycemic control, may be a first-line antihypertensive treatment for diabetics with associated hypertension.

Captopril-induced creatine kinase elevations: a possible role of the sulfhydryl group.

Since captopril, the first orally active angiotensin converting enzyme inhibitor, was introduced into clinical medicine, this new approach to blocking the formation of angiotensin II and lowering the blood pressure, appears to be tolerated well in most hyperten-sive patients. 1 However, during a randomized trial comparing the antihypertensive efficacy of captopril, 25 mg b.i.d., with captopril, 25 mg t.i.d., we found elevated creatine kinase (CK; EC 2.7.3.2) levels in several patients. In the present study, therefore, CK levels in 44 patients with mild to moderate hyperten-sion (24 men and 20 women; average age, 53.5 ± 2.0 [S.E.] years) treated with captopril were reviewed retrospectively. Thirty of these patients were treated with captopril alone, while 14 were treated with captopril in addition to other hypotensive agents: diuretics in eight, /3-blockers (atenolol) in two, diuretics with /3-blockade in three (atenolol in one, propranolol in two) and nifedipine in one. The duration of treatment ranged from 1 to 26 months. The average captopril dosage was 60.7 mg/day and ranged from 25 to 75 mg/day. (Unless otherwise specified, all data are expressed as means ± SE.) Blood pressure declined significantly from 167 ± respectively, of captopril administration. Before treatment with captopril, three of the 44 patients had a CK value that exceeded our hospitals normal range (11-136 IU/L). In the remaining 41 patients , CK activities were determined 47 times before and 161 times after treatment. Captopril administration significantly elevated CK activities from 71.9 ± 4.3 to 84.7 ± 3.3 IU/L (/><0.05). When reanalyzed according to the dosage of captopril, the average CK levels were 82.2 ± 3.7 (w = 56 determinations, NS) at 25 to 37.5 mg/day and 86.0 ± 4.6 IU/L (n = 105 deter-minations, p<0.05) at 50 to 75 mg/day. As a result, 20 CK determinations in six patients exceeded their pretreatment mean + 2 SD of 131.5 IU/L. The time course of CK values in five of these six hypertensive patients is illustrated in Figure 1. On the other hand, in one (Patient 7 in Figure 1) of three patients with a high initial CK level, combined treatment with captopril, 75 mg/day, and indapamide, 1 mg/day, resulted in a further , progressive, 3-month rise in CK (from 143 to 179 to 300 to 334 IU/L) followed by normalization of CK activity 1 month after drug administration was stopped. One month later, captopril challenge at 50 mg/day again increased CK activity …