Background:The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 NOS genes. Methods and Results:Morphological, echocardiographic, and hemodynamic analyses were performed in wildtype (WT), singly nNOS -/-, iNOS -/-, eNOS -/-, and triply n/i/eNOS -/-mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS -/-mice and to a lesser extent in eNOS -/-mice, but not in nNOS -/-or iNOS -/-mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic -dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS -/-mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT1) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS -/-mice. Conclusions:These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT1 receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis. (Circ J 2010; 74: 2681 - 2692
These results provide the first direct evidence that complete disruption of all NOS genes causes severe dyslipidaemia, atherosclerosis, and sudden cardiac death in response to a high-fat diet in mice in vivo through the down-regulation of the hepatic LDL receptor, demonstrating the critical role of the whole endogenous NOS system in maintaining lipid homeostasis.
Nicotine acts on nicotinic acetylcholine receptors in the adrenal medulla and brain, thereby stimulating the release of monoamines such as norepinephrine (NE). In the present study, we examined the effects of prolonged exposure to nicotine on NE transporter (NET) activity in cultured bovine adrenal medullary cells. Treatment of adrenal medullary cells with nicotine increased [(3)H]NE uptake in both a time- (1-5 days) and concentration-dependent (0.1-10 muM) manner. Kinetic analysis showed that nicotine induced an increase in the V (max) of [(3)H]NE uptake with little change in K (m). This increase in NET activity was blocked by cycloheximide, an inhibitor of ribosomal protein synthesis, but not by actinomycin D, a DNA-dependent RNA polymerase inhibitor. [(3)H]NE uptake induced by nicotine was strongly inhibited by hexamethonium and mecamylamine but not by alpha-bungarotoxin, and was abolished by elimination of Ca(2+) from the culture medium. KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II, attenuated not only nicotine-induced [(3)H]NE uptake but also (45)Ca(2+) influx in the cells. The present findings suggest that long-term exposure to nicotine increases NET activity through a Ca(2+)-dependent post-transcriptional process in the adrenal medulla.
Abstract. The role of nitric oxide (NO) derived from all three NO synthases (NOSs) in renal lesion formation remains to be fully elucidated. We addressed this point in mice lacking all NOSs. Renal injury was induced by unilateral ureteral obstruction (UUO). UUO caused significant renal lesion formation (tubular apoptosis, interstitial fibrosis, and glomerulosclerosis) in wild-type, singly, and triply NOS −/− mice. However, the extents of renal lesion formation were markedly and most accelerated in the triply NOS −/− genotype. UUO also elicited the infiltration of inflammatory macrophages, up-regulation of transforming growth factor (TGF)-β1, and induction of epithelial mesenchymal transition (EMT) in all of the genotypes; however, the extents were again largest by far in the triply NOS −/− genotype. Importantly, long-term treatment with the angiotensin II type 1 (AT 1 )-receptor blocker olmesartan significantly prevented the exacerbation of those renal structural changes after UUO in the triply NOS −/− genotype, along with amelioration of the macrophage infiltration, TGF-β1 levels, and EMT. These results provide the first evidence that the complete disruption of all NOS genes results in markedly accelerated renal lesion formation in response to UUO in mice in vivo through the AT 1 -receptor pathway, demonstrating the critical renoprotective role of all NOSs-derived NO against pathological renal remodeling.
Strongyloidiasis, a chronic infection caused by the intestinal parasite Strongyloides stercoralis, is prevalent in the Nansei Islands of Japan. Here, we report our findings on a case of strongyloidiasis complicated with steroid-resistant minimal change nephrotic syndrome in a 69-year-old male resident of Fukuoka Prefecture who had lived in Yakushima, one of the Nansei Islands, until age 15. In October 2006, he developed proteinuria and edema, and was diagnosed with minimal change nephrotic syndrome on the basis of the renal biopsy findings. Following treatment with prednisolone, the level of proteinuria decreased to 0.29 g/day by day 35. However, 5 days later (day 40), the patient developed persistent watery diarrhea and vomiting, leading to dehydration and malnutrition. Pneumonia and bacterial meningitis subsequently developed (day 146); filarial (infectious-type) and rhabditiform (noninfectious-type) S. stercoralis larvae were detected for the first time in the patient's sputum, gastric juice, feces, and urine. Although treatment with ivermectin was started immediately and the parasitosis responded to the treatment, the patient died of sepsis. Consequently, although strongyloidiasis is a rare infection except in endemic regions, it is essential to consider the possibility of this disease and begin treatment early for patients who have lived in endemic areas and who complain of unexplained diarrhea during steroid-induced or other immunosuppression.
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