Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginlne orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angjotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164±6 mm Hg at 4-6 weeks, compared with 108±3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125±6 mm Hg, still elevated compared with rats receiving losartan alone (98±3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfuslon, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomerull. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension. Activation of the renin-angiotensin system may account, at least in part, for the vasoconstrictor activity after such inhibition. (Hypertension 1992^0:298-303) KEY WORDS • endothelium-derived relaxing factor • kidney • hypertension, malignant • blood pressure • nitric oxide • rat studies T he endothelium releases a labile, diffusable vasorelaxing substance that has been termed endothelium-derived relaxing factor (EDRF). 1Recent observations have suggested that a major portion of the vascular effects of EDRF can be attributed to nitric oxide (NO). inhibition of NO biosynthesis. 4-67 These observations indicate that local release of NO in the microcirculation may occur on a continuous basis, thus modulating the effects of local and circulating vasoconstrictors and helping to finely regulate blood pressure and organ blood flow. In addition, micropuncture studies have suggested that angiotensin II (Ang II) may account for some of the renal microcirculatory alterations associated with acute NO inhibition. 6If NO exerts a tonic vasorelaxing effect on the microcirculation, its persistent inhibition might lead to the predominance of vasoconstrictor agents, resulting in arterial hypertension similar to that observed after chronic infusion of Ang II, 8 norepinephrine, 9 or thromboxane. 10 Recently, Gardiner and coworkers" demonstrated a marked blood pressure elevation in Brattleboro rats receiving ...

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The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3,5-triiodothyronine (T3), the disruption of which (Dio2 ؊/؊ ) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2 ؊/؊ BAT sympathetic stimulation ϳ10-fold (normal ϳ4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor ␥ coactivator 1, increased well above the levels detected in the coldexposed wild-type animals. The sustained Dio2 ؊/؊ BAT adrenergic hyperresponse suppressed the three-to fourfold stimulation of BAT lipogenesis normally seen after 24 -48 h in the cold. Pharmacological suppression of lipogenesis with ␤␤-methyl-substituted ␣--dicarboxylic acids of C14 -C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2 ؊/؊ mice. A dequate quantities of thyroid hormone are required for the maintenance of basal energy expenditure (1,2) and are also critical for adjustments in energy homeostasis during acute exposure to cold, without which survival is not possible (3). These adjustments in nonshivering adaptive thermogenesis are initiated by an increase in the activity of the sympathetic nervous system (SNS). In human newborns and other small mammals, brown adipose tissue (BAT) is the main site of the sympathetic-mediated adaptive thermogenesis. During cold exposure, there is an acute ϳ50-fold increase in type 2 iodothyronine deiodinase (D2) activity in BAT that accelerates thyroxine (T4) to 3,3Ј,5-triiodothyronine (T3) conversion (4). This increases thyroid hormone receptor (TR) saturation and leads to intracellular thyrotoxicosis specifically in this tissue (5), which in turn increases adrenergic responsiveness (6 -8) in a feed-forward mechanism that allows BAT to produce heat in a sustainable manner.The current paradigm of thyroid-adrenergic synergism is based on the principle that hypothyroidism causes a generalized decrease in adrenergic responsiveness and, therefore, frustrates the homeostatic role of the SNS, including the stimulation of BAT (9,10). However, these studies are largely based on the hypothyroid animal as a model, which has serious limitations for this purpose. The reduced obligatory energy expenditure caused by systemic hypothyroidism leads to a generalized and gradual increase in sympathetic activity that, in the BAT, activates adaptive energy expenditure to sustain normal core temperature, even at room temperature (11). However, chronic norepi...

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