Nitric oxide, the kidney, and hypertension.

The acute administration of nitric oxide (NO) synthesis inhibitors reduces the renal capacity to excrete sodium under normal or volume expanded conditions and increases renovascular resistances in the absence of changes in systemic blood pressure (BP). This indicates a sensitivity of renal vasculature higher than that of systemic vessels to NO synthesis inhibition. Medullary circulation is the renovascular territory most dependent on NO availability. Thus, alterations in medullary blood flow seems to account for the blunted pressure-natriuresis and sodium retention during acute NO synthesis inhibition. By contrast, during chronic administration of L-arginine analogs, systemic BP rises and overrides initial sodium retention by a resetting of the pressure-natriuresis relationship. This BP increase appears to be dependent on an overexpression of the actions of vasoconstrictor systems due to an imbalance created by the diminished NO production. Prolonged NO synthesis inhibition not only elevates BP, but also produces renal vascular and parenchymal damage. Antihypertensive therapy impedes BP elevation and ameliorates kidney deterioration. Finally, there is evidence of the possibility that a certain alteration in the L-arginine-NO pathway exists in genetic models and in human essential hypertension. In conclusion, according to the data contained in the literature, NO plays a significant role in the regulation of systemic and renal hemodynamics and excretory function, and could participate in the development of hypertension.

renal capacity to excrete sodium. Furthermore, the ex-portant in maintaining renal function and the renal capacity to excrete sodium. 17,18 The mechanism by istence of an impairment of renal function, with a decrease in renal blood flow and glomerular filtration which elevations in preglomerular vascular resistance induce hypertension remains undefined. Hall 19 has rate, has recently been shown to precede the establishment of sustained hypertension in spontaneously hy-suggested that the systemic alterations are comparable to those produced experimentally by the constric-pertensive rats. 6 These results are consistent with the hypothesis that BP increases to compensate for im-tion of the renal artery. In the one-kidney, one-clip model of hypertension developed by Goldblatt et al, 20 paired renal function in genetic hypertension.
Evidence also exists relating the kidney and the de-a decrease in renal perfusion pressure, which increases renin release and produces sodium retention, velopment of arterial hypertension in humans. Such a relationship is certainly the case for the hypertension is responsible for the elevation in systemic BP. This hypertension restores renal perfusion distal to the that accompanies renal failure. The elevated BP in this situation is consequence of the renal incapacity to clamp and normalizes renin release and sodium excretion. The mechanism( s ) underlying the appearance of fully excrete the sodium of the diet. 7 In primary hypertension, Curtis et al 8 showed, in a manner similar renal vasoconstriction remain to be clarified. Nevertheless, we might point to a lack of modulation of to that previously done in animals, that cross-transplantation with a renal graft from a normotensive do-renal vasculature to angiotensin II, an increased sympathetic activity, or a suppresed renal dopaminergic nor decreases BP in the absence of any therapy in patients with terminal renal failure resulting from activity as being among the possibilities. 16 Thus, renal vasoconstriction can constitute not an isolated phe-nephrosclerosis. Indirect arguments favoring the hypothesis that the kidney participates in the origin of nomenon, but the consequence of cardiovascular adaptation in primary hypertension. 21,22 In this sense it arterial hypertension involve the correlation between daily sodium excretion in urine and both systolic and has been shown that, in parallel with the gradual pressure rise in SHR, preglomerular resistance becomes diastolic BP 9,10 and the BP lowering effect of dietary salt restriction. 11 structurally elevated, while glomerular filtration capacity remains unaltered. 23 This possibility does not Different theories have tried to explain the renal defect ( s ) accounting for the initiation of arterial hy-exclude the pivotal role played by the kidney in the development of hypertension and does not exclude pertension. Hereditary hypertension is characterized, both in animals and humans, by the presence of gener-the hypothesis that the increase in BP is needed to maintain glomerular filtration rate and sodium excre-alized membrane abnormalities, 12 thereby suggesting that membrane transport functions could be markers tion within normal limits.
The pioneering reports of Furchgott and co-of individual susceptibility to the pressor effects of dietary salt. 13 Brenner et al 14 proposed that hyperten-workers 24,25 showed that the responses of vascular preparations to acetylcholine and other agents were sion may be the consequence of a congenital reduction in the number of nephrons or in the filtration area per dependent on the integrity of endothelial function.
Subsequent investigations, initially in animals 26 -28 glomerulus. A congenital reduction in the filtration surface area would contribute not only to a limited and then in humans, 29 -31 have demonstrated that the endothelium significantly modulates vascular tone by ability to excrete sodium, but also to an increased susceptibility to renal failure. Sealey et al 15 reported a regulating the contractile activity of the underlying smooth muscle. Moreover, this regulatory function of theory based on the existence of nephron population heterogeneity, with a subpopulation of ischemic the endothelium has been shown to be abnormal in some cardiovascular conditions, 32 -35 suggesting the nephrons with reduced capacity for sodium excretion and with chronic hypersecretion of renin. Elevated possibility that such endothelial dysfunction could play a pathophysiological role in those disease states. renin secretion, by increasing tubular sodium reabsorption and enhancing tubuloglomerular feedback-Essential hypertension is one of the conditions in which endothelium-dependent vascular relaxation mediated afferent vasoconstriction, would interfere with the capacity of remaining nephrons to excrete has been shown to be abnormal. Previous studies have demonstrated that hypertensive patients have a re-sodium.
In addition, we have recently published 16 that, ac-duced vasodilator response to the endothelium-dependent agent acetylcholine, in spite of the fact that cording to the literature, the most common renal manifestation of arterial hypertension in humans is an in-response to sodium nitroprusside ( a direct smooth muscle dilator ) was similar to normal controls. 34,35 crease of intrarenal vascular resistance that is present since the very early stages of the disease. Further-These findings are compatible with either of two pathophysiologic mechanisms: an endothelial dys-more, this renal vasoconstriction is functional in nature until renal vascular damage secondary to hyper-function of patients with essential hypertension as a primary phenomenon that plays a causal role in the tension appears. Renal hemodynamics are very im-hypertensive process, or a hypertension that injures cretion back to normal. The effects of L-NAME on renal function appear to be dependent on a decreased the endothelium and thereby causes endothelial dysfunction as a secondary process. Considerable interest availability of cGMP to the kidney. This was demonstrated by the ability of exogenous 8-Br-cGMP, but was raised by these two posibilities and an experimental model with chronic deficiency of nitric oxide ( NO ) not by dibutyril-cAMP, to prevent hemodynamic and excretory actions of L-NAME. 47 These results support production was created through the administration of L-arginine analogs that have the capacity to inhibit the concept of an NO-dependent continuous formation of cGMP responsible for maintaining the vascular NO formation. 36 -39 Acute and chronic deficiency of NO production can be induced in animals by the ad-tone and renal function. ministration of L-arginine analogs that inhibit NO The primary force determining glomerular filtrasynthesis in a competitive manner. 36 -39 It was initially tion, as well as the amount of sodium to be excreted shown that the administration of such compounds in the urine, is the renal perfussion pressure. Elevaleads, in a dose dependent manner, to a rise in both tion of renal perfusion pressure evokes an efficient BP and peripheral resistances. 40,41 This allowed for inautorregulatory response which maintains constant troducing a new model in which arterial hypertension renal blood flow and glomerular filtration in spite of is obtained through the chronic inhibition of NO syna markedly increased urinary sodium excretion. This thesis. 36,37 Furthermore, the participation of a depressure-induced natriuresis is a complex phenomecreased NO production in the genesis of arterial hynon in which changes in medullary circulation, interpertension in some animal models, such as the Dahl stitial pressure and intrarenal concentration of angiosalt sensitive rat, has also been shown. 42,43 All this tensin II are mainly involved. The participation of NO generated a huge amount of interest in understanding in the natriuresis induced by acute increases of perfuthe relationship between the kidney and NO in the sion pressure was demonstrated by Salom et al, 48 who development and maintenance of arterial hypertenshowed that the intrarenal infusion of L-NAME in sion. 16,44,45 The aim of this paper is to review the evidogs abolished the increase in urinary sodium excredences in favor of or against a direct participation tion produced by an elevation of the renal perfusion of the kidney in arterial hypertension occurring as a pressure. Since L-NAME was given at a dose that does consequence of a deficiency in NO production. not disturb either BP or autoregulation, it is proposed that NO is essential in coupling renal perfusion pres-

EFFECTS OF NO SYNTHESIS INHIBITION ON sure with a decrease in tubular sodium reabsorption THE REGULATION OF SODIUM EXCRETION
by mechanisms that are independent of vascular and AND ITS RELEVANCE FOR HYPERTENSION glomerular events. The significance of NO as a mediator of renal function Effects on Medullary Blood Flow The consequences in the absence of changes in BP was explored in a of NO inhibition on excretory function could also be a previous study 46 by giving intravenous infusions of consequence of changes in renal medullary blood flow, progressively increasing doses of the NO synthesis which are associated with parallel changes in sodium inhibitor N G -nitro-L-arginine methyl ester ( L-NAME ) and water excretion. This is consistent with biochemical to normal rats. The earliest and most sensitive alterreports that indicate that the renal medulla has a greater ations produced by small doses of L-NAME ( 0.1 to capacity than the cortex to synthesize NO. 49 Mattson et 1.0 mg / kg /min ) consisted in decreases in urine volal 50,51 showed that the acute infusion of L-NAME into ume and sodium excretion, which occurred 60 min the medullary interstitium of anesthetized rats selecafter starting the infusion. By 120 min after beginning tively decreased renal inner medullary blood flow and the infusion, intrarenal vascular resistance was found sodium and water excretion without changing glomerto be increased as suggested by a decrease of renal ular filtration rate, BP, or contralateral kidney function. plasma flow. Glomerular filtration rate was also in-In subsequent studies using uninephrectomized rats, creased ( Figure 1 ) . All these changes occurred withthese investigators demonstrated that administration of out any alteration in systemic BP, suggesting that kid-L-NAME for 5 days into the renal medullary interstitial ney functions are more sensitive to NO synthesis inspace selectively and reversibly decreased renal medulhibition than are peripheral resistances and BP. lary blood flow without altering cortical blood flow. 51 Administration of higher doses of L-NAME  During these maneuvers, the animals achieved a posimg / kg /min ) reduced renal plasma flow and glomertive sodium balance, and their BP was increased. The ular filtration rate and increased systemic BP. After onset of hypertension paralleled the observed reduction an initial reduction, urinary volume and sodium exin medullary blood flow and the retention of sodium cretion were normalized ( Figure 2 ) . Thus, this BP eleand water. However, it is unclear why the rats continvation can be regarded as an important compensatory ued to retain sodium even on the fifth day of L-NAME mechanism that overcomes the initial antinatriuretic effect of NO synthesis inhibition, bringing sodium ex-infusion at a time when a state of electrolyte balance / 2e11$$2140 12-08-96 19:29:54 eajha EL: AJH would have been expected. It is likely that more than control of medullary hemodynamics and associated excretory changes. one mechanism participates in the development of this type of experimental hypertension, as will be discussed Consequences of Sodium Load and Volume Expanlater. Although interstitial L-NAME infusion signifision The results mentioned above initially suggest the cantly decreased medullary blood flow, the site of NO possibility that a deficient renal synthesis of NO might production in the renal medulla and the mechanism of contribute to the development of systemic hypertensodium retention are not clear, because both vascular sion, because it interferes with the ability of the kidney and tubular alterations could be involved in the develto excrete sodium and it also increases systemic and opment of hypertension during interstitial L-NAME inrenal vascular resistances. However, it is unlikely that fusion. Decreased renal medullary blood flow in the the increases in BP induced by acute L-NAME adminisvasa recta could indirectly alter tubular sodium and tration could be related to the modest sodium retention water reabsorption by altering renal interstitial hydrothat occurs in such a short period of time, except that static pressure or by changing the renal medullary conthe kidney would be challenged by maneuvers such as centration gradient. The physiological importance of sodium load or volume expansion. This concept was this renal medullary NO has been clearly shown in used by Salazar 56 in a subsequent study in dogs submitother situations. The renal excretory response to an isoted to an intravenous infusion of isotonic saline load tonic saline load is blunted in the presence of a dose of the NO inhibitor that reduces papillary blood flow and for 4 consecutive days in the absence and presence of a nonhypertensinogenic dose of L-NAME. The concur-renal interstitial hydrostatic pressure. 52 The reduced sensitivity of the pressure diuresis and natriuresis rent administration of L-NAME and the sodium overload induced a significant increase in arterial pressure mechanism found after blockade of NO can be related to specific decreases in papillary blood flow. 53,54 The that seemed to be secondary to a significant sodium retention, because the increment of cumulative sodium pressure dependency or lack of autoregulation of the renal papillary circulation plays a pivotal role in the balance was larger than that observed in the control groups. Under these circumstances, the resultant pressure-natriuresis phenomenon and is reduced after NO inhibition at all levels of arterial pressure. 55 There-expansion of extracellular fluid volume elevates arterial pressure in order to overcome this excretory deficit and fore, renal NO, most specially NO produced within the renal medulla or papilla, plays a prominent role in the thereby to return body fluid volume to a normal state.  Other investileft kidney was perfused with L-NAME, and the right gators 36,37 also reported sustained hypertension durkidney was used as a control. It was found that the ing long-term oral administration of NO synthesis insodium excretion rate by the kidney infused with Lhibitors. As a consequence of the studies described NAME was 15% to 20% below the excretion rate of above, many investigators have tried to evaluate the the control kidney. All these changes occurred in the renal mechanisms involved in the hypertensive effect absence of significant modifications in baseline renal produced by chronic inhibition of NO. Although an hemodynamics and excretory function. These findings altered renal sodium handling could participate in the further support the importance of NO in the regulation origin of the hypertension induced by acute adminisof renal handling of sodium and extracellular fluid voltration of NO synthesis inhibitors, it appears not to ume even in the absence of changes in systemic BP. The be the case under chronic circumstances. In a previous relationship between NO production and renal sodium study, 39 we evaluated the evolution of renal excretory handling was further demonstrated by Schultz and Tolfunction and circulating vasoactive systems during ins, 58 who showed that an enhanced NO production is progressive increases in BP induced in rats by oral needed for the renal adaptation to a high salt intake.
administration of L-NAME ( 5 to 30 mg / 100 mL ) for Moreover, these investigators also showed that chroni-5 weeks. L-NAME induced a stepped elevation ( P õ cally salt loaded rats presented elevated renal hemody-.05 ) in BP levels without changing creatinine clearnamic responses to NO synthesis inhibition as compared with control rats.
ance, urine flow, or sodium excretion rate throughout the study. Similarly, the groups of Manning 60 and Mim-gesting that NO may contribute to the stimulation of renin secretion, with diminished renal perfusion. Circuran 38 observed sustained hypertension during longlating catecholamine levels have been reported to be term intravenous infusion of L-NAME in both rats and enhanced during chronic NO synthesis inhibition. 68 dogs without altering sodium or volume balance. These This activation of the sympathoadrenal system might results indicate that the increase in BP induced by be dependent on the degree of inhibition of NO synchronic NO synthesis inhibition could be able to counthase because, during moderate inhibition of NO synteract any retention of sodium at the renal level, thus thase, plasma concentrations of norepinephrine and resetting the pressure-natriuresis relationship. Howepinephrine were elevated only during the administraever, the existence of a certain sodium retention during tion of high doses of L-NAME. 39 Previous studies althe first hours of L-NAME administration, as did occur ready pointed out a central action of NO synthesis inin the above mentioned acute experiments, could not hibitors. 69 There is evidence that L-NAME crosses the be ruled out. Illustrating this concept, we have recently blood-brain barrier when administered orally, and shown a blunted natriuretic response to increases in sympathetic activation might have consequently been perfusion pressure below the levels ( 100 to 150 mm Hg ) triggered by the inhibition of NO synthase in the observed in L-NAME hypertensive rats. 61 Conversely, brain. 68 Therefore, it is proposed that the effects prosystemic administration of L-NAME to uninephrectomduced by NO synthesis inhibitors on renal function and ized rats produced hypertension accompanied by retensystemic circulation are produced by a decreased availtion of sodium and water, as would be predicted from ability of NO, which leaves unbalanced the activity of the analysis of the pressure-diuresis and -natriuresis pressor systems such as the renin-angiotensin or symrelationships. 62 These investigators demonstrated that pathetic nervous systems. Thus, an elevation of the cirthese effects seem to be related to a selective reduction culating levels of these systems would not be necessary in medullary blood flow. 63 An explanation for this apto observe the manifestation of their actions. Regarding parent contradiction is that the presence of one or two the renin-angiotensin system, Ito et al 70 and DeNicola kidneys might be a key factor for the differences found et al 71 have suggested that at least part of the systemic in renal sodium handling in this particular model of and renal effects produced by the inhibition of NO synhypertension. In favor of this concept is the need of thesis are the result of the biological activity of angiouninephrectomy for the development of hypertension tensin II that becomes manifest after NO tissue availin the DOCA-salt model. 64 Thus, it is conceivable that ability is lowered. In fact, Sigmon et al 72 showed that a diminution of the total number of nephrons, as occurs the retention of sodium seen during NO synthesis inhiwith uninephrectomy, could render the medullary cirbition with L-NAME was significantly decreased by the culation particularly sensitive to NO synthesis inhibiprior administration of an angiotensin II receptor antagtion in the remaining kidney. The absence of sodium onist, whereas the increase in systemic BP remained retention in chronic NO-deficient animals with two kidunaltered. This issue has been further investigated by neys could, therefore, be attributed to the changes in the Oliveira et al and Pollock et al, 73 who have shown that systemic BP that overrides the renal defect impeding a the administration of either an angiotensin II type 1 normal sodium excretion.
receptor antagonist or an angiotensin converting enzyme ( ACE ) inhibitor minimizes the hypertension that Vasoactive Systems During Chronic NO Inhibition develops after the inhibition of NO. Moreover, the re-The consequences of the hypertension induced by duction in BP induced by an angiotensin II type 1 recepchronic NO synthesis inhibitors on circulating vasotor antagonist is further enhanced by the administration active neurohumoral systems have yielded controverof an a 1 -receptor antagonist. 74 These results suggest a sial results. In vitro, NO directly inhibits renin release contribution of the renin-angiotensin and sympathetic through the increase of cGMP hemodynamic and excrenervous systems to the L-NAME induced hypertension. tory alteration, such as structural damage in the juxta-In addition, it has been observed that plasma concenglomerular cells. 65 By contrast, during the stepped eletrations of endothelin-1, and urinary excretion of prosvation in BP levels induced by oral administration of Ltaglandin ( PG ) E 2 , 6-keto-PGF 1a and thromboxane B 2 NAME ( 5 to 30 mg / 100 mL ) for 5 weeks, we observed were not significantly affected by L-NAME treatment. 39 reductions in either plasma renin activity or plasma Thus, it seems that L-NAME administration affects neialdosterone during treatment with 30 mg / 100 mL of Lther the production nor the release of endothelium de-NAME, when the maximal BP increases were found. 39 rived constrictors nor that of vasodilatory prostanoids. However, it has been reported 66 that when the renal However, administration of either an antagonist of ennerves and renal baroreceptor are controlled, endothedothelin receptors or endothelin converting enzyme inlial NO appears to inhibit renin release. In addition, hibitors reduced BP and renovascular resistances dur-Persson et al 67 reported that renin stimulation by reing L-NAME administration in rats. 75 This suggests the duced renal perfusion pressure below the range of autoparticipation of endothelin in the vascular alterations induced by L-NAME administration. regulation is blunted by NO synthesis inhibition, sug-/ 2e11$$2140 12-08-96 19:29:54 eajha EL: AJH The imbalance between NO and vasoconstrictor sys-of L-NAME on urine protein excretion ( Figure 3 ) . The antiproteinuric effect of indomethacin has been attrib-tems is further supported by the demonstration of altered vascular reactivity in the L-NAME-induced hy-uted to a fall in glomerular filtration rate. 80,81 In addition, the participation of thromboxane ( TX ) A 2 in the pertension. Enhanced sensitivity of vascular smooth muscle to vasoconstrictors or decreased sensitivity to renal damage induced by chronic NO inhibition is provasodilators might also account for BP elevation during posed. In fact, many reports have emphasized the parchronic L-NAME administration. In fact, we observed ticipation of TXA 2 in glomerular injury, since treatincreased constriction to angiotensin II and phenylephments with TXA 2 / PGH 2 receptor antagonists have rine in isolated mesenteric vascular beds from rats been shown to ameliorate renal damage in diabetic rats treated for 8 weeks with L-NAME. 76 However, sensitivand in rats with subtotal renal ablation. 82 Therefore, the ity to sodium nitroprusside, bradykinin, or acetylchopreventive effect of indomethacin on the proteinuria line seemed to be unchanged. 76 The elevated response induced by chronic L-NAME administration might also was prevented by the treatment with either an ACE be attributed to inhibition of TXA 2 synthesis, whose inhibitor or a calcium channel blocker. 76 actions would be overexpressed in the absence of NO in the kidney. Finally, L-NAME hypertension in rats Renal Damage Induced by Chronic NO Inhibition has also been associated with rapid, local, and revers-Several investigators 36,37 have reported that daily oral ible development of sudanophilic lesions along renal administration of L-NAME for 2 months was associated preglomerular vessels. 83 These lesions are characterized with arterial hypertension and diminished single nephby medial cell proliferation, macrophage invasion, and ron glomerular filtration rate. Elevation in glomerular infiltration of LDL, thus providing the hallmark of an hydraulic pressure as well as a decrease in glomerular early atherosclerotic process. Furthermore, sudanophiultrafiltration coefficient has also been observed. This lic lesions most likely develop from local pressure-inlong-term inhibition of NO synthase was associated duced aneurysms. The same investigators reported that with a mild degree of renal failure, as evidenced by proteinuria and glomerular sclerotic injury. Similarly, Fujihara et al 77 reported that daily oral administration of an elevated dose of L-NAME for 30 days resulted in marked hypertension, interstitial expansion, and glomerular ischemia. These alterations were exacerbated by the concomitant sodium load, suggesting that additional glomerular stress impairs the damage induced by NO synthesis inhibition. In rats treated with L-NAME for 8 weeks, we have shown that the administration of the ACE inhibitor quinapril or the calcium channel blocker diltiazem reduced elevated BP and proteinuria. 76 Since quinapril and diltiazem were not equally effective in preventing the increase in BP induced by L-NAME, their abilities to reduce proteinuria seems to be, at least partially, independent of their actions on BP. Similar results have been obtained with the administration of AT 1 receptor antagonists 36,77,78 suggesting that the renin-angiotensin system plays a prominent role in the development of renal damage in this model. Although in these experiments the glomerular filtration rate was normalized, the filtration fraction was not reduced by angiotensin II inhibition, suggesting that other vasoconstrictor agents might also have contributed to raise BP and to promote renal circulatory abnormalities in the setting of persistent NO inhibition. The participation of the renin-angiotensin system in the nephrosclerosis associated with chronic NO blockade has also been described in spontaneously hypertensive FIGURE 3. Systolic blood pressure ( SBP ) and 24 h urine prorats, 79 where ACE inhibition prevents and reverses Ltein excretion ( U protein ) in control rats and in rats treated for NAME -exacerbated severe nephrosclerosis. angiotensin II contributes to raising BP during the early phase of hypertension, whereas endogenous endothelin contributes little to raising BP, but endothelin selectively mediates the formation of sudanophilic lesions. 83 The mentioned functional and structural changes induced by the chronic administration of NO inhibitors may be the expression, at the renal level, of a more general process ocurring in the systemic vasculature.
In fact, several studies have shown [84][85][86] that chronic L-NAME treatment in the rat produces medial thickening and increased wall-to-lumen ratios. It should be mentioned that vascular hypertrophy also occurs during prolonged administration of L-NAME without produc- These vascular changes also have relevance for the kidney, since renal arteriolar and glomerular damage are present during long term L-NAME administration and that may at least partly account for both the increased contribute to the worsening of hypertension.
vascular resistance under basal conditions and the im-

MODELS AND ESSENTIAL HYPERTENSION
tors. This defect appears not to be related to a decreased availability of substrate for NO production 92,93 nor to Several groups of investigators have demonstrated an alteration at the muscarinic receptor level. 94 It could the existence of an altered renal NO regulation in difbe due to the presence of constrictor prostanoids, acferent models of arterial hypertension. 42,43,87 -90 Evicording to Taddei et al, 95 who showed that in essential dences for the existence of an abnormal renal NO synhypertension patients the intrabrachial infusion of inthase function in hypertension came from studies in domethacin increases forearm vasodialtion in response a model of salt-sensitive hypertension, the Dahl rat.
to acetylcholine, indicating that the production of a Studies from Chen and Sanders showed that the adcyclooxygenase-dependent endothelium-derived conministration of the precursor of NO, L-arginine, abolstricting factor could participate in the endothelial dysished salt-induced hypertension in this strain of function. In addition, controversial results regarding rats. 42,43 In these animals, administration of L-arginine the effects of antihypertensive therapy on impaired reincreased the elimination of NO-derived products and sponse to endothelium-dependent vasodilators have prevented the development of hypertension and assobeen published. 96,97 While Panza et al 96 reported no efciated renal lesions when salt intake was infect of antihypertensive drugs on forearm endothelial creased. 42,43,89,90 Moreover, it has also been shown that dysfunction, Schiffrin showed that ACE inhibitors, but long-term L-arginine administration normalized the not b-blockers, ameliorate acetylcholine-dependent reright-shifted pressure-natriuresis relationship in this laxation in resistance arteries from essential hypertentype of hypertension. 89 Again, the improvement of sive patients. 97 The apparent contradiction between pressure natriuresis seems essential to the beneficial both studies could reside in the different vascular terrieffect of L-arginine in this salt-sensitive model. 89,90 In tories used. spontaneously hypertensive rats, administration of The role of NO on kidney functions in humans has the NO precursor, L-arginine, improves pressure nabeen investigated by the evaluation of the renal retriuresis, and this is accompanied by an increased prosponses to systemic infusions of L-arginine. Initial reduction of NO-derived metabolic products. 87 Other sults 98 showed the existence of a blunted renal vasodilaauthors have demonstrated that this beneficial effect tion in response to L-arginine in essential hypertensive of L-arginine on the spontaneously hypertensive rat patients as compared to normotensives. Moreover, an is related to the restoration of the pressure depenimprovement of this blunted renal vasodilation was obdency of the renal medullary circulation. 88 Conseserved after prolonged treatment with ACE inhibitors. 99 quently, it could be proposed that NO production is In a recent study, we tested the hypothesis that aging needed in the kidney for a normal sodium excretion, impairs kidney function in essential hypertension and that a derangement of this function could lead to through a derangement of NO-dependent renal mecha-BP elevation.
nisms. 100 We observed that young essential hyperten-Studies in essential hypertensive patients 34,35,91 using sives exhibited elevations in renal plasma flow, glomerforearm plethysmography suggested the existence of an alteration in the endothelium-derived NO system ular filtration rate and renal excretory function in re- In summary, the acute administration of NO synthe- ( Figure 4 ) .