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Abstract-The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O 2 Ϫ ) was examined. O 2 Ϫ generation, measured by lucigenin chemiluminescence, was studied in 12-to 16-week male and female Wistar-Kyoto rats (WKY) Key Words: superoxide Ⅲ endothelium Ⅲ nitric oxide Ⅲ rats, inbred SHR Ⅲ nitric oxide synthase E ndothelial dysfunction and a relative deficiency in nitric oxide (NO) may be associated with hypertension in humans 1,2 and in some models of experimental hypertension. 3,4 In the spontaneously hypertensive stroke-prone rat (SHRSP), a model of genetic hypertension, we have shown an attenuation of functional basal NO despite increased eNOS enzymatic activity. 5 Although endothelial NO synthase (eNOS) enzymatic activity was greater in SHRSP than in Wistar-Kyoto rats (WKY) when examined in vitro the possibility that the actual amount of eNOS was reduced in SHRSP in vivo could not be excluded from these results. Alternatively, eNOS levels could be similar or elevated but NO availability decreased because of more rapid removal after synthesis. Superoxide anion (O 2 Ϫ ) is produced in the vasculature and can scavenge NO forming peroxynitrite. Increased scavenging of NO by O 2 Ϫ could lead to a decrease in NO availability despite increased synthesis. Raised O 2 Ϫ levels have been reported recently in a number of models of endothelial dysfunction including hypertension, induced by either angiotensin infusion 6 or aortic banding. 7 In the majority of cases the source of excess O 2 Ϫ is uncertain, although involvement of NADH/NADPH oxidases 8 and xanthine oxidase 9 have been suggested.The aim of this study was to examine the hypothesis that the decreased NO availability observed in SHRSP is due to excess O 2 Ϫ , to identify the source of this O 2 Ϫ , and to examine other molecular mechanisms involved such as the expression of the gene-encoding enzyme involved in NO generation in the endothelium (eNOS). Methods AnimalsThree-to 4-month-old male and female WKY and SHRSP were obtained from the colonies established in Glasgow by brother and sister mating as previously described. 9 Blood pressure was measured 1 week before study by tail plethysmography according to our published protocol. 10

Studies performed in the past two decades have unequivocally shown that several of the components of the metabolic syndrome are associated with indirect and direct markers of adrenergic overdrive. This is the case for hypertension and obesity, in which resting tachycardia, elevated plasma norepinephrine values, increased sympathetic nerve traffic, as well as augmented levels of total and regional norepinephrine spillover have been reported. This is also the case for insulin resistance, i.e. a metabolic condition frequently complicating the various components of the pathological condition identified as the 'metabolic syndrome'. After briefly describing the epidemiological and the cardiovascular risk profile of the disease, this paper will examine the behaviour of the sympathetic nervous system in the metabolic syndrome as well as the mechanisms potentially responsible for this neurogenic abnormality. This will be followed by an analysis of the role played by neuroadrenergic factors in disease progression as well as in the pathogenesis of its complications. Finally, the therapeutic implications of these findings will be highlighted.