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 E2 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 strain-specific 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.

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, sigmaIRI (the sum of the insulin levels 0, 30, 60 and 120 min after the OGTT), insulinogenic index and Homa's 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 sigmaIRI values, but they also had higher Homa's 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 > or = 15, sigmaIRI > or = 150 or Homa's index > or = 4 was between 5 and 9 times higher than that in the group with fasting IRI < 10, sigmaIRI < 100 or Homa's 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. Homa's index, fasting and sigmaIRI may be useful predictors of the subsequent development of hypertension.

Glucose intolerance in spontaneously hypertensive and Wistar-Kyoto rats: enhanced gene expression and synthesis of skeletal muscle glucose transporter 4.

To clarify the relationship between blood pressure and insulin resistance, we studied the role of glucose transporter 4 (GLUT4) in skeletal muscle and the effect of angiotensin-converting enzyme inhibitor on insulin resistance. Blood pressure and plasma glucose and plasma insulin responses to glucose loading (2 g/kg, i.p.) were measured in spontaneously hypertensive rats (SHRs), Wistar-Kyoto rats (WKYs), and Wistar rats at 8, 12, and 20 wk of age. GLUT4 gene expression and plasma membrane protein content were also determined in the gastrocnemius muscle. SHRs and WKYs at the age of 8 wk had significantly higher plasma glucose levels than did age-matched control Wistar rats. Insulin response also tended to be higher. Glucose intolerance was also present in 12-wk-old SHRs, but normalized at the age of 20 wk. In contrast, WKYs were glucose intolerant at 12 and 20 wk. Gene expression and plasma membrane content of GLUT4 were augmented in both 8-wk-old SHRs and WKYs, indicating a compensatory increase in these variables. Effects of captopril (20-30 mg/kg/d from 8 to 20 wk) on GLUT4 were also investigated in these three strains. Captopril improved steady state plasma glucose levels in association with 1.2- to 2.5-fold higher GLUT4 gene expression and a 1.4-fold increase in skeletal muscle GLUT4 protein in SHRs and WKYs. Our results suggest that (1) not only SHRs but also WKYs may have glucose intolerance and hence insulin resistance; (2) gene expression and protein synthesis of skeletal muscle GLUT4 are probably increased compensatorily, indicating that abnormalities in GLUT4 do not have a pivotal role in the development of insulin resistance in SHRs and WKYs; and (3) captopril stimulates skeletal muscle gene expression and synthesis of GLUT4, providing further evidence of its beneficial effect on glucose metabolism.

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 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.

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.

Effect of alpha 1-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.