Shinpei Morimoto

Effect of 24 weeks of treatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus

The effects of treatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy were studied in 45 patients with non-insulin-dependent diabetes mellitus (NIDDM). Epalrestat 150 mg three times daily was given for 24 weeks. Subjective symptoms, such as spontaneous pain in the lower extremities and numbness and hypoesthesia of the extremities or trunk, were significantly (P < 0.001) relieved after 12 and 24 weeks of epalrestat treatment. Vibratory perception thresholds, as measured by using a tuning fork (C-128) and a vibrometer, were improved after 24 weeks of treatment. Furthermore, there were no adverse effects on glucose or lipid metabolism during treatment. These results suggest that long-term (24-week) epalrestat therapy can be used effectively to treat peripheral neuropathy in NIDDM patients without affecting glucose or lipid metabolism.

Increased urinary excretion of β-hydroxyisovaleric acid in ketotic and nonketotic type II diabetes mellitus

To evaluate the catabolism of leucine in diabetes mellitus, the urinary excretion of β-hydroxyisovaleric acid, a by-product of leucine catabolism, in 21 nonproteinuric type II diabetic patients with and without ketosis and 21 control subjects was measured using gas chromatography-mass spectrometry. Urinary β-hydroxyisovaleric acid and serum leucine concentrations were higher in the 9 ketotic diabetic patients than in the 12 nonketotic diabetic patients (p 0.05), but urinary β-hydroxyisovaleric acid concentrations were significantly greater in the former (p < 0.01). These data suggest that in type II diabetic patients the catabolism of leucine is accelerated even in the absence of ketosis and that the urinary β-hydroxyisovaleric acid concentration is a useful marker of short-term metabolic control in these patients.

High-performance liquid chromatographic separation of corticosteroids in plasma of rats. Its application to the determination of the circadian rhythm of 18-hydroxycorticosterone related to aldosterone and corticosterone.

An efficient separation of corticosteroids in plasma of rats was obtained by reversed-phase high-performance liquid chromatography (HPLC). Plasma corticosteroid assays with HPLC separation were used to determine the circadian rhythm of 18-hydroxycorticosterone (18-OHB) and its possible relationship to aldosterone or corticosterone in conscious rats under standard conditions (regular diet; 12-hour light and 12-hour dark cycle). Significant circadian rhythms of plasma corticosterone, 18-OHB and aldosterone were observed with peak values at 20.00 h and nadir values at 08.00 h. The mean ratio of plasma 18-OHB to aldosterone during 24 h was 2.4. The circadian rhythm of 18-OHB was also correlated with that of plasma aldosterone or corticosterone.

Effects of posture on the plasma hormonal and renal water-electrolyte excretory responses to acute water loading in diabetic subjects with hypoadrenergic orthostatic hypotension.

The effects of posture on the plasma hormonal and renal water-electrolyte excretory responses to acute water loading (20 mL/kg BW, orally) were studied in six non-insulin-dependent diabetes mellitus (NIDDM) subjects with hypoadrenergic orthostatic hypotension (HOH), eight NIDDM subjects without HOH, and seven nondiabetic subjects. The three groups were similar with respect to basal levels of mean blood pressure (MBP), serum sodium and osmolality, plasma renin activity (PRA), the plasma volume regulatory hormones alpha-atrial natriuretic peptide (ANP), arginine vasopressin (AVP) and aldosterone, and urinary water and sodium excretion. In the supine state, while allowing the subjects to stand only to void, water loading resulted in no changes in MBP and similar responses of these plasma and urinary parameters in the three groups. In the standing state, water loading produced responses of MBP, and plasma and urinary parameters comparable to those in the supine state in the diabetic group without HOH and the nondiabetic group. In the diabetic group with HOH, however, MBP and hourly urinary water and sodium excretion rates were low compared to those in the other two groups. During water loading, plasma ANP decreased, and, despite the fall of MBP, plasma AVP remained unchanged, and PRA and plasma aldosterone increased normally in the diabetic group with HOH. These results demonstrate that, in NIDDM subjects with HOH, changing from lying to standing induces deranged renal water and sodium handling after water loading, accompained by a decrease in plasma ANP, and inadequate responses of plasma AVP, PRA, and plasma aldosterone to hypotension.

Adrenal adenoma with 18-hydroxycorticosterone excess and hypertension: a variant of aldosteronomas

A 46-year-old woman with hypertension, normokalemia, suppressed renin, normal catecholamines, and a left adrenal mass on the CT scan was found to have excessive 18-hydroxycorticosterone (18-OHB) and normal aldosterone levels in plasma, both of which responded poorly to sodium restriction and angiotension II, and supranormally to ACTH. Plasma 18-hydroxydeoxycorticosterone (18-OHDOC) was normal. After adrenalectomy, amelioration from hypertension occurred with a reduction in plasma 18-OHB and aldosterone. The plasma 18-OHDOC remained normal. The adrenal tumor was histologically an adenoma, containing a large amount of 18-OHB and a small amount of aldosterone. Thus, the present adenoma seems to be a variant of aldosteronomas.

Direct inhibition of smooth muscle myosin light chain kinase by arachidonic acid in a purified system

The direct effect of arachidonic acid (AA) on the phosphorylation of smooth muscle myosin light chain (SMLC) by smooth muscle myosin light chain kinase (SMLCK) was assessed in a purified system. AA inhibited the phosphorylation of SMLC by SMLCK in a dose dependent manner. Increasing the amount of calmodulin (59 nM and 590 nM) did not reverse this inhibition. Linoleic acid and oleic acid also inhibited the phosphorylation. The inhibitory potency of these unsaturated fatty acids paralleled the number of cis double bonds. These results show that SMLCK is directly inhibited by unsaturated fatty acids including AA.

The Characteristics of Renal Mineralocorticoid Receptors in Glycyrrhizinic Acid or Deoxycorticosterone-Induced Hypertensive Rats

The relationship between blood pressure and the characteristics of renal mineralocorticoid receptors was studied in glycyrrhizinic acid (GR) or deoxycorticosterone (DOC) induced hypertensive rats. The apparent maximum binding (Bmax) of aldosterone to renal mineralocorticoid receptors was 3.1 +/- 0.2 X 10(-13) mol/mg cytosol protein and the dissociation constant (Kd) was 1.6 +/- 0.5 nM. GR treatment reduced the concentration of cytosol mineralocorticoid receptors (Bmax) but did not affect the Kd. In unilaterally adreno-nephrectomized rats, GR induced hypertension and hypokalemia as seen in DOC treated rats. After the discontinuation of GR, blood pressure was normalized with concomitant recovery of free cytosol mineralocorticoid receptors in 14 weeks. On the contrary, in DOC treated rats, the characteristics of mineralocorticoid receptors in kidney were already normal one week after the cessation of DOC treatment. However, blood pressure remained high up to 15 weeks. These findings suggest that the persistence of hypertension after GR discontinuation might be caused by a long-standing effect of GR on renal mineralocorticoid receptor mechanisms.

Effect of atrial natriuretic factor on aldosterone and its precursor steroid production in adrenal zona glomerulosa cells from spontaneously hypertensive rats.

The effect of alpha-human atrial natriuretic factor (alpha-hANP, 10(-6) M- 10(-8) M) on basal, and maximum angiotensin II (AII, 4.8 X 10(-8) M)-, ACTH (4.3 X 10(-9) M)-, and potassium (8mM)-stimulated levels of corticosterone, 18-hydroxycorticosterone (18-OHB) and aldosterone production were studied in adrenal glomerulosa cells from spontaneously hypertensive rats (SHR) at 14 weeks of age as compared to those in the age-matched Wistar-Kyoto rats (WKY) on a normal sodium diet. Plasma corticosterone, 18-OHB and aldosterone levels and the aldosterone response in vitro to the graded doses of AII were similar in SHR and WKY. Basal, and maximum AII-, ACTH-, and potassium-stimulated levels of corticosterone, 18-OHB and aldosterone also were similar in the cells from SHR and WKY. alpha-hANP similarly inhibited basal and stimulated levels of these corticosteroids in the cells from SHR and WKY. These results indicate that the inhibitory effect of alpha-hANP on aldosteronogenesis is unaltered in SHR at 14 weeks of age on a normal sodium diet.

Direct effects of heparin on basal and stimulated aldosterone production in rat adrenal glomerulosa cells

Direct effects of heparin (0.1-10 IU/ml) on basal and stimulated aldosterone production have been studied using intact rat adrenal glomerulosa cells. Heparin at any dose did not affect basal aldosterone production when added to the incubation medium. Heparin at a 0.01 IU/ml dose had no effect on aldosterone production maximally stimulated by angiotensin II (AII, 4.8 X 10(-8) M), ACTH (4.3 X 10(-9) M) or potassium (8.0 mM). However, heparin at 0.1 and 0.3 IU/ml doses selectively blocked aldosterone production maximally stimulated by AII but not by ACTH or potassium, while the compound at 1 and 10 IU/ml doses inhibited aldosterone production maximally stimulated by these three stimuli. In addition, the inhibitory effect of 0.3 IU/ml heparin occurred as early as 30 min after incubation with heparin. These data suggest that heparin at 0.1 and 0.3 IU/ml doses acts directly on adrenal zona glomerulosa to selectively block the stimulatory action of AII, while the compound at 1 and 10 IU/ml doses inhibits all the stimulatory actions of AII, ACTH and potassium.

Effects of long-term cilazapril treatment on glucose and lipid metabolism in hypertensive patients with non-insulin-dependent diabetes mellitus.

The effects of long-term cilazapril treatment on glucose and lipid metabolism were assessed in 25 hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were treated with 0.5 to 1 mg of cilazapril once daily or a combination of cilazapril and other antihypertensive drugs once daily for 48 weeks. Both systolic and diastolic blood pressures were significantly reduced (P < 0.001) throughout the study with no significant changes in heart rate and no adverse effects such as cough. There were no significant changes in body mass index or serum levels of glycated hemoglobin A1c, fructosamine, total cholesterol, triglycerides, lipoproteins (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol), or apolipoproteins (apo A-I, apo C-II, apo C-III, apo B, and apo E). Cilazapril caused a significant increase (P < 0.05) in levels of apo A-II and a significant decrease (P < 0.05) in the apo B:apo A-I ratio, an index of arteriosclerosis. These results suggest that cilazapril has favorable effects on glucose and lipid metabolism and that it may be useful as the first or second choice of antihypertensive drugs in hypertensive patients with NIDDM.