Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice.

Aims/hypothesis: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice.

Effect of caffeine contained in a cup of coffee on microvascular function in healthy subjects.

Recent epidemiological studies have demonstrated that coffee drinking is associated with reduced mortality of cardiovascular disease. However, its precise mechanisms remain to be clarified. In this study, we examined whether single ingestion of caffeine contained in a cup of coffee improves microvascular function in healthy subjects.

Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse.

We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4months after the surgery.

Long-term treatment with san'o-shashin-to, a kampo medicine, markedly ameliorates cardiac ischemia-reperfusion injury in ovariectomized rats via the redox-dependent mechanism.

Background: Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san'o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model.

Methods And Results: Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes.

Na(+)/H(+) exchanger inhibitor induces vasorelaxation through nitric oxide production in endothelial cells via intracellular acidification-associated Ca2(+) mobilization.

The objective of this study was to determine the mechanism by which Na(+)/H(+) exchanger (NHE) inhibitors induce vasodilatation. The NHE inhibitors, 5-(N,N-dimethyl)-amiloride (DMA), cariporide, and amiloride, evoked endothelium-dependent relaxation in rat aortas with ED50 values of 16, 89, and 148μM, respectively, and these effects were abolished by treatment with N(G)-nitro-l-arginine methyl ester (L-NAME). The relaxation effects induced by DMA and cariporide were strongly attenuated in aortas of the endothelial NO synthase (eNOS)-deficient mice, as compared to the effects in wild-type mice.

Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo.

An elevation of oxidized forms of tetrahydrobiopterin (BH(4)), especially dihydrobiopterin (BH(2)), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH(2) in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH(2) concentration causes endothelial dysfunction in rats. To increase vascular BH(2) levels, the BH(2) precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH(2) to BH(4).

Improvement of impaired endothelial function by tetrahydrobiopterin in stroke-prone spontaneously hypertensive rats.

To investigate the role of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase, in endothelial function in a model of genetic hypertension, acetylcholine- and sodium nitroprusside (SNP)-induced vasodilator responses were examined in the absence and presence of BH4 in age-matched adult stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. Acetylcholine-induced depressor responses attenuated significantly in SHRSP compared with those in WKY rats. Acetylcholine-induced relaxations in phenylephrine-precontracted aortic rings of SHRSP were also significantly impaired as compared to those of WKY rats, while SNP-induced relaxations were similar between both strains.

Effect of decreased levels of intrinsic tetrahydrobiopterin on endothelial function in anesthetized rats.

Tetrahydrobiopterin (BH4) deficiency has been suggested to be an important factor in vascular endothelial dysfunction. In this study, we investigated the influence of decreased BH4 level produced by administration of 2,4-diamino-6-hydroxypyrimidine (DAHP), a specific inhibitor of the rate-limiting enzyme of BH4 synthesis, on vascular endothelial function in anesthetized rats. Wistar rats were given DAHP (0.

Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats.

Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED(50) value was higher in ZDF (-6.

Prostacyclin causes splenic dilation and haematological change in dogs.

1. The effect of vasodilators on spleen volume and the blood storage function is not yet well elucidated. To this end, in the present study the effects of prostacyclin, a potent vasodilator, on splenic diameter and blood cell concentrations in arterial and splenic venous blood were evaluated in anaesthetized dogs.

Cardiovascular effects and lethality of venom from nematocysts of the box-jellyfish Chiropsalmus quadrigatus (Habu-kurage) in anaesthetized rats.

Haemodynamic effects of saline-extracted venom from nematocysts isolated from Chiropsalmus quadrigatus (Habu-kurage) were studied in anaesthetized rats. Intravenous administration of venom (0.2-5 microg protein/kg) produced immediately dose-dependent hypertension and bradycardia.

Haemodynamic effects of the crude venom from nematocysts of the box-jellyfish Chiropsalmus quadrigatus (Habu-kurage) in anaesthetized rabbits.

Haemodynamic effects of saline-extracted venom from nematocysts isolated from tentacles of the box-jellyfish Chiropsalmus quadrigatus (Habu-kurage) were investigated. In anaesthetized rabbits, i.v.

Cardioprotective effects of extracts from Psidium guajava L and Limonium wrightii, Okinawan medicinal plants, against ischemia-reperfusion injury in perfused rat hearts.

The aim of this study was to determine whether the medicinal herbs growing in Okinawa and possessing a radical-scavenging activity would exert cardioprotective effects against ischemia-reperfusion injury using isolated perfused rat hearts. Effects of the aqueous extracts from Psidium guajava L. and Limonium wrightii at concentrations having an equipotent radical-scavenging activity on myocardial injury produced by global ischemia followed by reperfusion were tested and were further compared with those of quercetin and gallic acid, major antioxidative components of P.

Effects of glutathione S-transferase inhibitors on nitroglycerin action in pig isolated coronary arteries.

1. The present study was designed to clarify the role of glutathione S-transferase (GST) in the vasorelaxation response and development of tolerance to nitroglycerin (GTN) using GST inhibitors. 2.

Beneficial effect of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts.

Objective: It has recently been proposed that nitric oxide synthase, in the presence of suboptimal levels of tetrahydrobiopterin, an essential cofactor of this enzyme, might favor increased production of oxygen radicals. The aim of this study was to clarify whether supplement with tetrahydrobiopterin would exert a cardioprotective effect against ischemia-reperfusion injury.

Methods: Isolated perfused rat hearts were subjected to 30 minutes of global ischemia and 30 minutes of reperfusion at 37 degrees C.

Uneven changes in circulating blood cell counts with adrenergic stimulation to the canine spleen.

1. Responses of splenic diameter measured by sonomicrometry to alpha- and beta-adrenoceptor stimulants were estimated together with simultaneously measured systemic arterial and splenic venous concentrations of red blood cells (RBC), white blood cells (WBC) and platelets (PLT) in anaesthetized dogs. 2.