Nagaoki Toyoda

Structure-activity relationships for thyroid hormone deiodination by mammalian type I iodothyronine deiodinases.

The bioactivity of thyroid hormone is determined to a large extent by the monodeiodination of the prohormone T4 by the hepatic selenoenzyme type I iodothyronine deiodinase (ID1), i.e. by outer ring deiodination (ORD) to the active hormone T3, or by inner ring deiodination (IRD) to the inactive metabolite rT3. ID1 also catalyzes the IRD of T3 and the ORD of rT3, both to T2, as well as the deiodination of different iodothyronine sulfates, e.g. IRD of T3S and ORD of T2S. Previous studies have indicated important differences in catalytic specificity between dog ID1 (dID1) and human ID1 (hID1), in particular with respect to the ORD of rT3. This study was done to investigate the relationship between structure and catalytic function of this enzyme by comparing the deiodination of T4, T3, rT3, T3S, and T2S by native dID1 and hID1 in liver microsomes as well as by recombinant wild-type, chimeric and mutated d/hID1 enzymes expressed in HEK293 cells. With both native and recombinant wild-type enzymes, the substrate ...

Type 2 Iodothyronine Deiodinase Is Expressed in Human Preadipocytes

BACKGROUND Type 2 iodothyronine deiodinase (D2) is an enzyme that catalyzes the production of triiodothyronine (T3) from thyroxine (T4) and plays a critical role in providing the local intracellular T3. Although D2 is highly expressed in brown adipose tissue, it was thought that D2 is hardly expressed in white adipose tissue. In the present study, we examined whether D2 is expressed in human preadipocytes, using human mesenteric and subcutaneous preadipocytes (HMPA and HSCPA, respectively). METHODS HMPA and HSCPA were purchased and cultured in the preadipocyte medium containing 10% fetal bovine serum. We measured D2 activity and mRNA level in HMPA and HSCPA incubated with or without dibutyryl cyclic adenosine monophosphate [(Bu)₂cAMP]. RESULTS D2 activity and mRNA were detectable in human HMPA and HSCPA. The apparent Michaelis-Menten constant (K(m)) value for T4 in HMPA was 2.1 ± 0.2 nM, and the maximum velocity (V(max)) value was 333.3 ± 28.0 femtomols of I⁻ released/mg protein/hour, respectively. On the other hand, the apparent K(m) value for T4 in HSCPA was 2.0 ± 0.2 nM and the V(max) value was 91.2 ± 8.7 femtomols of I⁻ released/mg protein/hour, respectively. D2 activities in HMPA and HSCPA incubated with 1 mM (Bu)₂cAMP for 24 hours were 7-fold (HMPA) and 3-fold (HSCPA) higher than those without (Bu)₂cAMP, respectively. D2 mRNA levels in HMPA and HSCPA incubated with 1 mM (Bu)₂cAMP for 3 hours were 10-fold (HMPA) and 5-fold (HSCPA) higher than those without (Bu)₂cAMP, respectively. CONCLUSIONS In the present study, we have clearly demonstrated that D2 activity and mRNA are present in the human preadipocytes from both mesenteric and subcutaneous adipose tissue. Our experiments are the first ones that identify human preadipocytes as one of the sources of T3 production.

Thyroid Hormone Activation in Vascular Smooth Muscle Cells Is Negatively Regulated by Glucocorticoid

BACKGROUND Type 2 iodothyronine deiodinase (D2) catalyzes the production of triiodothyronine from thyroxine. D2 is present in rat aorta media, and there is a circadian variation in the D2 expression. In rat aorta media, the D2 activity exhibited the maximal value at 1200 hour and low value between 1800 and 2400 hour. To understand the mechanisms that induce the circadian variation in the D2 expression, we examined the effects of glucocorticoid on the D2 activity and mRNA in rat aorta media and cultured vascular smooth muscle cells (VSMCs). METHODS The effects of intrinsic and extrinsic glucocorticoid on the D2 activity and mRNA in rat aorta media were studied using metyrapone, a corticosterone synthesis inhibitor, and dexamethasone (DEX). Further, the effects of DEX on D2 expression were studied using the cultured rat VSMCs. RESULTS The trough values of D2 activity and mRNA at 2100 hour were increased by the treatment with metyrapone. On the other hand, the peak values of D2 activity and mRNA were decreased by the treatment with DEX. D2 activity and mRNA in cultured rat VSMCs were increased by the addition of 10(-3) M dibutyryl cyclic adenosine monophosphate [(Bu)(2)cAMP]. The increments were reduced by coincubation with 10(-6) M DEX. CONCLUSIONS These results suggest that glucocorticoids might directly suppress the D2 expression in rat VSMCs induced by a cAMP-dependent mechanism.

Efficacy of clonidine in patients with essential hypertension with neurovascular contact of the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is an important center for regulation of sympathetic nerve activity. Several clinical studies have suggested an association between neurovascular contact (NVC) of RVLM and essential hypertension. Microvascular decompression (MVD) of RVLM decreases blood pressure (BP) in hypertensive patients with NVC of this region. Therefore, MVD could be a useful therapeutic strategy to reduce BP in these patients. However, as MVD is an invasive procedure, it is worthy to seek useful antihypertensive agents for hypertensive patients with NVC. It is reported that sympathetic nerve activity is elevated in patients with hypertension accompanied by NVC of RVLM. It is anticipated that sympatholytic agents could be effective in lowering BP in these patients. In this study, we investigated the efficacy of clonidine, an α2 adrenergic agonist, in essential hypertensives with NVC of RVLM. Thirty consecutive essential hypertensive patients with NVC and 30 consecutive essential hypertensive patients without contact were treated with clonidine for 4 weeks, and decreases in BP and plasma norepinephrine levels were compared between the two groups. Decreases in BP and plasma norepinephrine levels were significantly greater in patients with NVC than in those without contact. These results suggest that clonidine exhibits significantly greater reductions of BP and sympathetic nerve activity in essential hypertensive patients with NVC compared with those without contact of the rostral ventrolateral medulla.

Critical appraisal and pooled analysis of telmisartan alone or in combination with hydrochlorothiazide for achieving blood pressure goals

Rigid control of blood pressure (BP) is essential to prevent cardiovascular disease. However, only about 40% of hypertensive patients undergoing pharmacological intervention with a single agent achieve their BP goals in contemporary clinical practice. Combined therapy using currently available agents is effective in maximizing treatment outcome, although it raises medical costs and decreases the drug compliance rate. To overcome such negative consequences, a combination tablet containing an angiotensin II receptor blocker (ARB) with a small dose of hydrochlorothiazide (HCTZ) is now available on the international market, including Japan. This article briefly describes the unique properties of telmisartan, a highly selective ARB for the angiotensin II type 1 receptor, including its long-acting characteristics and recent prospective multicenter randomized clinical trials, followed by a description of a newly-introduced combination tablet in Japan, which contains telmisartan and HCTZ. This article also reviews its safety and efficacy based on currently available evidence. Finally, evidence comparing telmisartan/HCTZ with other combination therapies is presented.