Recordings of multiunit sympathetic activity were made in muscle branches of the peroneal nerve in 22 healthy subjects at rest in recumbent position. Nerve activity was quantitated in terms of burst incidence (number of pulse synchronous sympathetic bursts per 100 heart beats or per min). In a separate session, 4-45 months later, blood was drawn from an antecubital vein for noradrenaline analysis. Both sympathetic activity and plasma concentrations of noradrenaline varied widely between subjects and both parameters increased with age. There was a significant positive correlation between a subject's level of sympathetic activity and his plasma concentration of noradrenaline. It is suggested that overflow of transmitter from sympathetic terminals in muscles contributes significantly to plasma levels of noradrenaline at rest.

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SUMMARY Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and dopamine-/3-hydroxylase (DBH) activities were decreased in specific nuclei of the hypothalamus and in the nucleus interstitialis striae terminalis ventralis, in both young and adult rats. The decrease in the formation of norepinephrine can result in a reduced activation of central a-adrenergic receptors which may be related causally to the onset of hypertension. The activity of the epinephrine-forming enzyme, phenylethanolamine-A'-methyltransferase (PNMT), was increased in the A, and A 2 areas of the brainstem in young SH rats, but it was normal in adult hypertensive animals. These results implicate adrenergic neurons in the brainstem and noradrenergic neurons in the hypothalamus in the development of spontaneous (genetic) hypertension in rats.CATECHOLAMINES have been implicated in the pathophysiology of hypertension. "4 The most compelling evidence of the involvement of catecholamines in hypertension is the demonstration that many drugs therapeutically useful in the treatment of hypertension also affect the adrenergic nervous system at a variety of sites, modifying the uptake, release, and storage of the neurotransmitter or acting directly on the adrenergic receptors. 5It now is recognized that not only peripheral catecholaminergic nerves and the adrenal medulla play roles in the physiological regulation of blood pressure and in the expression of at least some forms of hypertension, but that central catecholaminergic neurons also are implicated.1 ' 4 ' 6 Some of the catecholamine-rich areas in the brain that have been proposed to be involved in cardiovascular regulation are localized in the anterior hypothalamus and in the brainstem (areas A, and A 2 ). These areas are densely supplied with noradrenergic nerves. Area A, of the rat brain contains the cell bodies of the catecholaminergic neurons that send axons to the spinal cord, 7 " and area A 2 corresponds in part to the nucleus of the tractus solitarii in which the majority of the fibers of the carotid sinus nerve terminate. 4 ' 7 In addition to norepinephrine, the A, and A 2 areas of the brainstem have the highest levels of the epinephrineforming enzyme, phenylethanolamine jV-methyltransferase (PNMT) found in the brain.9 ' 10 Epinephrine also has been detected in the A, region" and in the A 2 area as well (Saavedra et al., unpublished results).By the use of sensitive isotopic-enzymatic micromethods Received April 15, 1977; accepted for publication, November 17, 1977. volved in their formation in discrete brain areas associated with central autonomic control and blood pressure regulation is now possible.An examination of norepinephrine content and the norepinephrine-forming enzyme in specific brain areas during the development o...

1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but signi®cant eects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the eect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible in¯uence of salt intake on the eects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F 1a in WKY rats fed a normal salt diet (0.6% NaCl, wt wt 71 ), without aecting serum thromboxane (TX)B 2 levels. 3 Rofecoxib signi®cantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt 71), but not in rats on low salt intake (0.02% NaCl, wt wt 71). 4 Rofecoxib signi®cantly decreased plasma levels of 6-keto PGF 1a in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no in¯uence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was signi®cantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib,¯uid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.

Kurtz. Role of prostanoids in regulation of the renin-angiotensin-aldosterone system by salt intake. Am J Physiol Renal Physiol 283: F294-F301, 2002. First published February 26, 2002 10.1152/ajprenal.00347.2001.-We investigated the effect of cyclooxygenase (COX) activity on the regulation of the renin-angiotensin-aldosterone system by salt intake. Therefore, Sprague-Dawley rats were subjected to different salt diets [0.02, 0.6, and 8% NaCl (wt/wt)] and treated with the selective COX-2 inhibitor rofecoxib (10 mg ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 ) or with ketorolac at a dose selective for COX-1 inhibition (2 mg ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 ) for 3, 7, 14, and 21 days. Rofecoxib and ketorolac caused a similar reduction of renocortical PGE 2 formation with a low-salt diet. Rofecoxib did not change plasma renin activity or renocortical renin mRNA abundance with any of the diets but clearly lowered plasma aldosterone concentration. In contrast, ketorolac delayed the increase in plasma renin activity and of renin mRNA in response to low salt intake but did not change plasma aldosterone concentration. Prolonged treatment with rofecoxib but not with ketorolac caused an upregulation of COX-2 expression while COX-1 mRNA abundance remained unchanged. These findings suggest that COX-1-derived, but not COX-2-derived, prostanoids are of relevance for the regulation of the renin system by salt intake. cyclooxygenase; kidney THE ACTIVITY OF THE RENIN-angiotensin-aldosterone system (RAAS) is determined by several factors, including the rate of salt intake (12). It is activated in states of low salt intake and suppressed by high salt intake (1, 32). The regulation of the RAAS by salt intake depends on the regulation of renin synthesis and renin secretion, because the protease renin is regarded as the rate-limiting enzyme of the RAAS. However, the mechanisms linking renin with salt intake have long remained obscure (12). Several studies have shown that the stimulation of the renin system by low salt intake is attenuated by COX inhibitors, suggesting a possible mediator role for prostanoids in the stimulation of the renin system by low salt intake (6, 10). However, COX inhibitors also cause volume retention, particularly in states of sodium depletion (2, 27, 35), and the effect of COX inhibitors on the renin system could therefore be related to volume changes rather than to interference with a direct action of prostanoids in the juxtaglomerular apparatus (29, 31). The demonstration that a low-salt diet enhances the expression of COX-2 in the macula densa cells (15) has reinforced the concept that COX-2-derived prostanoids in the macula densa may directly mediate the effect of salt intake on renin secretion and of renin gene expression in neighboring juxtaglomerular epithelioid cells (7,24).Such a concept is in good agreement with the idea of a direct stimulatory effect of PGE 2 and PGI 2 on juxtaglomerular epithelioid cells (22). It is further supported by reports that selective COX-2 inhibitors attenuate the stimulation of the renin system b...

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NAGATSU REPLIEs-The findings of Grobecker et aU agree with previous results 2 on increased serum DBH of SHRs at 3 weeks of age, and are consistent with the view that sympathetic neuronal activity in young SHRs is increased. As additional evidence, I have found that DBH activity in the mesenteric vessels of SHR at 3 weeks of age is

We investigated a possible involvement of the sympathetic nervous system in the parallel increase of renin, cyclooxygenase-2 (COX-2), and neuronal nitric oxide synthase (nNOS) gene expression in the juxtaglomerular apparatus of rat kidneys induced by salt deficiency. Therefore, we determined the effects of renal denervation and the beta-adrenoreceptor antagonist metoprolol (50 mg/kg body wt po, twice a day) on renocortical expression of renin, COX-2, and nNOS in rats fed a low-salt (0.02% wt/wt) diet or treated for 1 wk with ramipril (10 mg/kg body wt) in combination with a low-salt diet. We found that a low-salt diet in combination with ramipril strongly increased renocortical mRNA levels of renin, COX-2, and nNOS 9-, 7-, and 2.5-fold, respectively. Treatment with metoprolol did not change basal expression of the three genes or induction of renin and COX-2 gene expression, while induction of nNOS expression was clearly attenuated. Similarly, unilateral renal denervation attenuated induction of nNOS expression but had no effect on all other parameters. These findings suggest that beta-adrenergic stimulation is not required for stimulation of renin and COX-2 gene expression in the juxtaglomerular apparatus during salt deficiency. However, beta-adrenoreceptor activity or renal nerve activity appears to be required for the full stimulation of nNOS expression by low salt intake or combined with angiotensin-converting enzyme inhibition.