Different divergence processes of isoglosses of folk nomenclature between wild trees and rice landraces imply the need for different conservation planning based on the type of plant resources.

BACKGROUND: The intensification of production and socio-economic changes have accelerated the loss of local traditional knowledge and plant resources. Understanding the distribution and determinants of such biocultural diversity is essential in planning efficient surveys and conservation efforts. Because the concept of biocultural diversity in socio-ecological adaptive systems comprises biological, cultural, and linguistic diversity, linguistic information should serve as a surrogate for the distribution of local biological and cultural diversity. In this study, we spatio-linguistically evaluated the names of local trees and rice landraces recorded in Ehime Prefecture, southwestern Japan. METHODS: Hierarchical clustering was performed separately for the names of local trees and rice landraces. By considering innate flora differences and species having multiple local names, a novel distance index was adopted for local tree names. For the names of rice landraces, Jaccard distance was adopted. V-measure and factor detector analysis were used to evaluate the spatial association between the isogloss maps of the folk nomenclature derived from the clustering and multiple thematic maps. RESULTS: Local tree names showed stronger spatial association with geographical factors than rice landrace names. One folk nomenclature group of trees overlapped well with the slash-and-burn cultivation area, suggesting a link between the naming of trees and the traditional production system. In contrast, rice landraces exhibited stronger associations with folklore practices. Moreover, influences of road networks and pilgrimages on rice landraces indicated the importance of human mobility and traditional rituals on rice seed transfer. High homogeneity and low completeness in the V-measure analysis indicated that the names of local trees and rice landraces were mostly homogenous within current municipalities and were shared with a couple of adjacent municipalities. The isogloss maps help to illustrate how the biological and cultural diversity of wild trees and rice landraces are distributed. They also help to identify units for inter-municipal collaboration for effective conservation of traditional knowledge related to those plant resources and traditional rice varieties themselves. CONCLUSIONS: Our spatio-linguistic evaluation indicated that complex geographical and sociological processes influence the formation of plant folk nomenclature groups and implies a promising approach using quantitative lexico-statistical analysis to help to identify areas for biocultural diversity conservation.

High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice.

BACKGROUND: It is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome. METHODS: We examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice. RESULTS: High-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice. CONCLUSIONS: We demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.

Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats.

Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensin-aldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress.

Mineralocorticoid receptor activation contributes to salt-induced hypertension and renal injury in prepubertal Dahl salt-sensitive rats.

BACKGROUND: Excessive prepubertal salt intake permanently increases blood pressure (BP). We examined the role that the mineralocorticoid receptor (MR) plays in the salt-induced hypertension and renal damage of prepubertal Dahl salt-sensitive (SS) rats. METHODS: Prepubertal (6 weeks old) and adult (10 weeks old) Dahl SS rats fed a high (8.0%) salt (HS) diet for 10 weeks were compared in terms of BP and renal function. The effect of treatment between the ages of 4 and 10 weeks with the MR antagonist eplerenone (0.125% in chow), the vasodilator hydralazine (50 mg/kg/day in drinking water) or the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (tempol) (0.6 mmol/kg/day in drinking water) on the BP and renal function of prepubertal rats fed a HS diet for 10 weeks was also examined. RESULTS: Excessive salt intake starting in prepuberty was associated with a higher BP increase and greater proteinuria than if it started in adulthood. Eplerenone moderately reduced BP and markedly improved renal injury during its administration in prepubertal rats. These effects continued after drug discontinuation. Hydralazine greatly decreased BP and reduced proteinuria, but these effects were completely lost after drug discontinuation. Excessive salt increased urinary 8-hydroxy-2'-deoxyguanosine levels, intrarenal macrophage infiltration and renal plasminogen activator inhibitor-1 and transforming growth factor-beta mRNA expression. Eplerenone, but not hydralazine, attenuated these salt-induced inflammatory reactions. Tempol improved salt-induced hypertension and renal injury, even after its discontinuation. CONCLUSIONS: Dahl SS rats exposed to excessive salt in prepubescence show a permanent increase in susceptibility to salt-induced hypertension and proteinuria. MR activation may promote these effects at least in part by inducing oxidation and inflammation.

Protective effect of dietary potassium against cardiovascular damage in salt-sensitive hypertension: possible role of its antioxidant action.

It is well known that high salt intake induces hypertension and cardiovascular damage, while dietary potassium supplementation counteracts these harmful effects. Actually, the protective effect of potassium is strengthened with excess salt as compared with salt depletion. Although the precise mechanisms have not been fully elucidated, in our previous reports, the antihypertensive effect of dietary potassium was accompanied by sympathetic nerve inhibition in salt-sensitive hypertension. Also, potassium supplement suppressed salt-induced insulin resistance. These effects of dietary potassium can explain its cardio- and vasculo-protective action in addition to the potassium supplementation induced decreased salt-induced rise in blood pressure. On the other hand, salt-sensitive hypertension is associated with reactive oxygen species (ROS) overproduction. Moreover, sympathoexcitation can be induced by central ROS upregulation and insulin resistance can be caused by ROS excess in the target organs of insulin, such as skeletal muscle. Conversely, the seemingly different actions of potassium can be explained by the antioxidant effect of dietary potassium; in our recent studies, potassium supplementation inhibits salt-induced progress of cardiac diastolic dysfunction and vascular neointima formation by cuff placement around arteries, associated with the inhibition of regional ROS overproduction, in salt-sensitive hypertension. Thus, it is possible that dietary potassium protects against salt-induced cardiovascular damage by the reduction of ROS generation and by central sympatholytic action and amelioration of insulin resistance induced through its antioxidant effect.

Antioxidant, EUK-8, prevents murine dilated cardiomyopathy.

BACKGROUND: Mice lacking manganese-superoxide dismutase (Mn-SOD) activity exhibit the typical pathology of dilated cardiomyopathy (DCM). In the present study, presymptomatic and symptomatic mutant mice were treated with the SOD/catalase mimetic, EUK-8. METHODS AND RESULTS: Presymptomatic heart/muscle-specific Mn-SOD-deficient mice (H/M-Sod2(-/-)) were treated with EUK-8 (30 mg x kg(-1) . day(-1)) for 4 weeks, and then cardiac function and the reactive oxygen species (ROS) production in their heart mitochondria were assessed. EUK-8 treatment suppressed the progression of cardiac dysfunction and diminished ROS production and oxidative damage. Furthermore, EUK-8 treatment effectively reversed the cardiac dilatation and dysfunction observed in symptomatic H/M-Sod2(-/-) mice. Interestingly, EUK-8 treatment repaired a molecular defect in connexin43. CONCLUSIONS: EUK-8 treatment can prevent and cure murine DCM, so SOD/catalase mimetic treatment is proposed as a potential therapy for DCM.

Additive Pummerer reaction of 3,5-O-(di-tert-butyl)silylene-4-thiofuranoid glycal: a high-yield and beta-selective entry to 4'-thioribonucleosides.

Upon reacting 3,5-O-(di-tert-butyl)silylene-4-thiofuranoid glycal S-oxide (6) with Ac(2)O/TMSOAc/BF(3) x OEt(2) in CH(2)Cl(2), the additive Pummerer reaction proceeded to furnish the corresponding 1,2-di-O-acetyl-4-thioribofuranose 7. Compound 7 serves as a highly beta-selective glycosyl donor in the Vorbruggen condensation carried out in the presence of TMSOTf. Thus, the 4-thio-beta-D-ribofuranosyl derivatives of uracil, thymine, N (4) -acetylcytosine, 6-chloropurine, and 2-amino-6-chloropurine were synthesized. The use of 7 can be extended to the beta-selective synthesis of 4'-thio-C-ribonucleosides.

Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension.

BACKGROUND: Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension. METHODS AND RESULTS: Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 mumol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. Central tempol reduced arterial pressure and renal sympathetic nerve activity to a significantly greater extent in high-fat diet-fed hypertensive rats than in low-fat diet-fed normotensive rats. Intracerebroventricular apocynin or diphenyleneiodonium, a reduced NADPH oxidase inhibitor, also elicited markedly greater reductions in arterial pressure and renal sympathetic nerve activity in the high-fat diet-fed rats. In addition, fat loading increased NADPH oxidase activity and NADPH oxidase subunit p22(phox), p47(phox), and gp91(phox) mRNA expression in the hypothalamus. CONCLUSIONS: In obesity-induced hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, may contribute to the progression of hypertension through central sympathoexcitation.

Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder.

Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt-induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor-dependent gene expression, such as Na(+)/H(+) exchanger-1 and serum- and glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals.

Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions.

BACKGROUND: Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors. METHOD: To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague-Dawley rats. RESULTS: Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and -dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na(+) -H(+) exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na(+) -H(+) exchanger isoform 1. CONCLUSION: These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.

Additive Pummerer reaction of 3,5-O-(di-t-butylsilylene)-4-thiofuranoid glycal and stereoselective synthesis of beta-anomer of 4'-thioribonucleosides.

Upon reacting 3,5-O-(di-t-butylsilylene) (DTBS)-4-thiofuranoid glycal S-oxide (7) with Ac2O in the presence of TMSOAc and BF3.OEt2, additive Pummerer reaction proceeded to furnish 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose (8) in 61% yield. When 8 was reacted with bis-O-TMS-uracil and TMSOTf, 2'-O-acetyl-3',5'-O-DTBS-4'-thiouridine (13a) was obtained along with it's beta-anomer (13b) in 93% yield (13a/13b = 22/1). This highly stereoselective glycosidation reaction was applicable to the synthesis of 14-17. The glycosyl donor 8 was also useful for the synthesis of 4'-thio-C-nucleoside 18 and 19. In contrast to the above results, treatment of 8 with TMSCN gave rise to the formation of the spiro derivative 20. To avoid this intramolecular cyclization, 2-O-TBDMS-protected 21 was prepared from 8. Bromination of 21 with TMSBr and substitution reaction of the resulting bromide 22 with Hg(CN)2 gave 1'-C-cyanide 23.

Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress.

Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-beta1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11beta-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.

Suppression of catechol-O-methyltransferase activity through blunting of alpha2-adrenoceptor can explain hypertension in Dahl salt-sensitive rats.

Catecholamines have been reported to be involved in the development of salt-sensitive hypertension. We investigated the relation between catechol-O-methyltransferase (COMT) and salt-sensitivity. In the first experiment, Dahl salt-sensitive (DS) rats were given a normal-salt (NS), high-salt (HS), or HS+hydralazine (80 mg/l water) diet for 4 or 13 weeks, and Dahl salt-resistant (DR) rats were given a NS or HS diet. COMT activities in both the kidneys and liver and urinary norepinephrine (NE) and dopamine (DA) excretion were measured. In the second experiment, HepG2 cells were used to investigate the role of NE in regulating COMT activity. In the third experiment, we investigated the reactivity of pre- and postsynaptic alpha(2)-adrenoceptor (AR) in DS rats. HS loading significantly suppressed the activities of membrane-bound COMT (MB-COMT) and, consistent with this finding, increased the urinary NE level in DS rats, but not in DR rats. Hydralazine did not restore the MB-COMT activities, which suggested that HS loading rather than elevated blood pressure suppressed the MB-COMT activities. The in vitro experiment using HepG2 cells revealed that NE increased the MB-COMT activity via the alpha(2)-AR. However, both the pre- and postsynaptic alpha(2)-AR reactivity was decreased by HS loading in DS rats. In conclusion, HS intake suppresses the MB-COMT activities in DS rats, presumably by blunting alpha(2)-AR signaling. The suppression of MB-COMT activities, consequent decrease in degradation of NE, and increase in NE release by blunting of alpha(2)-AR function may be involved in the development of salt-sensitive hypertension in DS rats, in whom DA-dependent natriuresis may be suppressed.

Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity.

We have demonstrated that adrenomedullin (AM) protects against angiotensin II (ANG II)-induced cardiovascular damage through the attenuation of increased oxidative stress observed in AM-deficient mice. However, the mechanism(s) that underlie this activity remain unclear. To address this question, we investigated the effect of AM on ANG II-stimulated reactive oxygen species (ROS) production in cultured rat aortic vascular smooth muscle cells (VSMCs). ANG II markedly increased ROS production through activation of NADPH oxidase. This effect was significantly attenuated by AM in a concentration-dependent manner. This effect was mimicked by dibutyl-cAMP and blocked by pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89), a protein kinase A inhibitor, and CGRP(8-37), an AM/CGRP receptor antagonist. This inhibitory effect of AM was also lost following the expression of a constitutively active Src. Moreover, AM intersected ANG II signaling by inducing COOH-terminal Src kinase (Csk) activation that, in turn, inhibits Src activation. These data, for the first time, demonstrate that AM attenuates the ANG II-induced increase in ROS in VSMCs via activation of Csk, thereby inhibiting Src activity.

New synthesis of (+/-)-isonucleosides.

[Structure: see text] A novel method for synthesizing isonucleosides, a new class of anti-HIV nucleosides, is described. 2,2-Dimethyl-1,3-dioxan-5-one was converted into a dioxabicyclohexane derivative in six steps. After cleaving the epoxide group with thiophenol, the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase to give the desired isonucleoside derivative via migration of the thiophenyl group. Removal of the thiophenyl group under radical conditions followed by deprotection led to the 4'-substituted 2',3'-dideoxyisonucleosides as a racemic mixture.

Protective effect of potassium against the hypertensive cardiac dysfunction: association with reactive oxygen species reduction.

Potassium supplementation has a potent protective effect against cardiovascular disease, but the precise mechanism of it against left ventricular abnormal relaxation, relatively early functional cardiac alteration in hypertensive subjects, has not been fully elucidated. In the present study, we investigated the effect of potassium against salt-induced cardiac dysfunction and the involved mechanism. Seven- to 8-week-old Dahl salt sensitive rats were fed normal diet (0.3% NaCl) or high-salt diet (8% NaCl) with or without high potassium (8% KCl) for 8 weeks. Left ventricular relaxation was evaluated by the deceleration time of early diastolic filling obtained from Doppler transmitral inflow, the slope of the pressure curve, and the time constant at the isovolumic relaxation phase. High-salt loading induced a significant elevation of blood pressure and impaired left ventricular relaxation, accompanied by augmentation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in the cardiac tissue, measured by the lucigenin chemiluminescence method. Blood pressure lowering by hydralazine could not ameliorate NADPH oxidase activity and resulted in no improvement of left ventricular relaxation. Interestingly, although the blood pressure remained high, potassium supplementation as well as treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide dismutase mimetic, not only reduced the elevated NADPH oxidase activity but also improved the left ventricular relaxation. In conclusion, a high-potassium diet has a potent protective effect on left ventricular active relaxation independent of blood pressure, partly through the inhibition of cardiac NADPH oxidase activity. Sufficient potassium supplementation might be an attractive strategy for cardiac protection, especially in the salt-sensitive hypertensive subjects.

Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia.

BACKGROUND: Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM+/-) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia. METHODS AND RESULTS: Ten-week-old male wild-type (AM+/+) or AM+/- mice were housed under 10% oxygen conditions for 3 to 21 days. In AM+/+ mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM+/- mice housed under hypoxia than in AM+/+ mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM+/- mice than in AM+/+ mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM+/+ but also AM+/- mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung. CONCLUSIONS: The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.

Angiotensin II-induced insulin resistance is enhanced in adrenomedullin-deficient mice.

Insulin resistance and hypertension are common disorders that are closely related. Among several factors, oxidative stress has been reported to be intimately related to these diseases. To elucidate the involvement of oxidative stress in the development of insulin resistance in a hypertensive model, we administered angiotensin II (Ang II), which raises blood pressure and induces reactive oxygen radicals, to adrenomedullin (AM)-knockout heterozygous mice and examined the resulting changes in blood pressure and insulin resistance. Ang II was administered ip at a dosage of 640 ng/kg.min for 4 wk. The systolic blood pressure was significantly elevated in both AM-knockout heterozygous and wild-type mice to the same extent. On the other hand, Ang II attenuated insulin sensitivity more strongly in AM-knockout heterozygous mice than in wild-type mice, when measured using 2- deoxyglucose uptakes in the soleus muscle. Ang II also induced a higher urinary excretion of isoprostane, a marker of oxidative stress. Furthermore, the production of oxidative stress in the soleus muscles of angiotensin-treated mice, measured using electronic spin resonance, was significantly higher than that in AM-knockout heterozygous mice. Moreover, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide scavenger mimetic, normalized the insulin resistance induced by Ang II without affecting the blood pressure in both groups. The present results suggest that, in an Ang II-treated mouse model, insulin resistance is induced by oxidative stress through a mechanism that is independent of blood pressure, and that AM can act as a protective peptide against insulin resistance via its intrinsic antioxidant effect.

Two cases of renovascular hypertension and ischemic renal dysfunction: reliable choice of examinations and treatments.

We experienced two aged patients with atherosclerotic renovascular stenosis associated with hypertension and ischemic nephropathy. Both patients exhibited sudden rise in blood pressure (BP) and progressive aggravation of renal dysfunction. In these patients, the use of contrast medium to screen for renal artery stenosis (RAS) ran the risk of further deterioration of renal function. We therefore used magnetic resonance angiography (MRA), which is less conducive to renal damage, to screen for RAS. One-sided RAS was treated by percutaneous transluminal angioplasty of the renal artery (PTRA) and stenting. As a result, BP decreased in both patients. Serum creatinine (Cr) decreased slightly in one patient, whereas, in the other, serum Cr increased transiently and then decreased and stabilized to pre-treatment levels. Thus, although it is unclear whether the combination of PTRA and stenting is among the best treatments for patients with RAS and moderate-to-severe renal dysfunction, PTRA and stenting are clearly of benefit in selected patients. In addition, recent progress in characterizing the pathophysiology of ischemic nephropathy associated with renovascular hypertension has created interest in the therapeutic potential of angiotensin II receptor antagonists, sympatholytic agents, and antioxidants. Therefore, we discuss the therapeutic utility of PTRA and stenting and the above-mentioned medications in patients with RAS and renal dysfunction.