In spontaneously hypertensive rats (SHR), the renal expression of NOS and the urinary excretion of NO are increased at 9-12 weeks of age7). The hypertension could be exaggerated by NOS inhibition. An enhanced O₂^- production and its interaction with NO play an important role in the pathogenesis of salt sensitivity in SHR. A two-fold increase of renal cortical nitrotyrosine deposition suggests an enhanced interaction of NO with ROS in SHR8), in which AII is implicated in increases of ROS and decreases of SOD. In SHR, the activity of antioxidant enzymes is diminished, and anti-oxidant treatment increases NO bioavailability to reduce the arterial pressure.

Nevertheless, the regulation of NO differs according to the age of the animal. With advanced age, SHR show reduced urinary NO excretion and depressed expression of NOS proteins in the kidney9). The decreased expression of NOS underscores the importance of these enzymes in the pathophysiology and maintenance of hypertension.

A reduced synthesis of NO in the renal medulla has been implicated in the pathogenesis of Dahl salt-sensitive (DS) hypertension. In response to salt loading, DS rats cannot but Dahl salt-resistant (DR) rats may markedly increase renal NOS activity10). In the kidney of DS rats, the activity of nNOS is decreased with its mRNA expression reduced11).

L-Arginine prevented the development of hypertension and normalized the pressure-natriuresis relationship in DS rats12). A selective iNOS inhibition with aminoguanidine augmented the increase of arterial pressure in DS rats on high salt intake13). Conversely, compensatory upregulation of iNOS expression and NOS activity may represent a novel mechanism regulating the increased volume load and blood pressure in DR rats. However, the activity eNOS in the kidney of DS rats seems to be unaltered.

Furthermore, DS rats on high-salt diet showed a significant correlation between the urinary excretion of ADMA and the degree of hypertension, suggesting that ADMA play a role in the pathogenesis of hypertension14). The hypertension in DS rats is also associated with renal artery hypertrophy, increased vascular and renal ET-1 protein contents, and glomerulosclerosis10).

The administration of tempol attenuates DS hypertension, indicating that the hypertension is also in part related to an increase in oxidative stress and a decrease in anti-oxidant capacity. It is indeed associated with marked decreases in medullary SOD activity and increases in oxidative tissue damage15).

Deoxycorticosterone acetate (DOCA)-salt treatment increases the urinary excretion of nitrite and nitrate, along with the elevation of blood pressure16). NOS inhibition exaggerates the hypertensive response, whereas L-arginine markedly reduces the blood pressure and improves the cardiovascular dysfunction in DOCA-salt rats17). However, there may be uncoupling of NOS/NO and soluble guanylyl cyclase (sGC)/cGMP pathways in the inner medulla in this model of hypertension18). Although the urinary cGMP excretion increases after 1 week of DOCA-salt treatment, it gradually decreases to restore the normal values by the third week16). An attenuation of the hypertensive response by anti-oxidant treatment was also noted in DOCA-salt rats19).

An infusion of N^G-nitro-L-arginine methyl ester (L-NAME) into the renal medulla of rats causes sodium retention and arterial hypertension. A strong negative correlation exists between NOS activity and blood pressure in rats chronically treated with L-NAME. Its hemodynamic changes have been primarily attributed to an abrupt withdrawal of tonic vasodilator effect, leaving unopposed of an equally tonic action of endogenous vasoconstrictors. However, the development of hypertension represents a complex mechanism which may not simply be attributed to an inactivation of NO system. The hypertension could be partly reversed by inhibition of vasoconstrictors such as AII, vasopressin or ET20). The circulating plasma renin activity may bear no consistent relationship with the protective action of chronic AII blockade, because the plasma renin activity was increased, unchanged or decreased in this model of hypertension.

In addition, NOS inhibition increases O₂^- activity and increases the urinary excretion of 8-isoprostane (a marker of enhanced O₂^- activity)21). The exaggerated hypertensive response during high-salt intake is abolished by concomitant administration of tempol19). It is suggested that O₂^- contributes to the development of salt sensitivity in L-NAME hypertension.

Liu et al.22) observed no changes of plasma vasopressin levels in animals chronically treated with L-NAME. However, although administration of L-arginine and NO donors have variable effects on vasopressin secretion, the most common one is inhibition, and blockade of NO synthesis increases vasopressin secretion23). Furthermore, the hypertension is attenuated by inhibition of vasopressin20). In this context, it is worth to note an upregulation of aquaporin-2 (AQP2) in the kidney in L-NAME hypertension24), which may in fact be related with altered vasopressin levels. On the contrary, a more recent study demonstrated a downregulation of AQP2, which may represent compensatory effects increasing the urinary excretion25).

An increased sympathetic drive may also be involved in the development of L-NAME hypertension. Acute ganglionic blockade produced a large fall of blood pressure, and chronic sympathectomy by daily injections of ganglionic blockers attenuated the hypertension. Furthermore, chronic bilateral renal denervation delayed and attenuated the hypertension26). In this context, water channels may also be affected in L-NAME-treated rats, since some water channels are under tonic excitatory influence of the sympathetic nerves27). On the contrary, it has been found that the hemodynamic actions of acute NOS inhibition in the unstressed rat are independent of the sympathetic nervous system. A more recent study also failed to demonstrate changes in renal sympathetic nerve activity in L-NAME hypertension in conscious rabbits, indicating that the renal nerves do not mediate the increase of blood pressure28).

Prostacyclin (PGI₂) inhibits NO release from cultured endothelial cells29). In the dog kidney, the full renal vasodilator potential of NO (or PGI₂) is expressed only in the presence of prostaglandin (or NO) inhibition, suggesting that these autacoids are mutually antagonistic. It is thus likely that some of the constrictor responses seen with chronic NOS inhibition may result from enhancement of the actions of vasoconstrictor arachidonic acid products. Nevertheless, acute cyclooxygenase inhibition does not affect the hypertension in rats treated with L-NAME, although additional renal vasoconstriction does occur30).

Chronic two-kidney, one-clip (2K1C) hypertension has been associated with an impaired endothelium-dependent vasorelaxation31). Both early and chronic phases of 2K1C hypertension are augmented by NO synthesis inhibitors. Furthermore, 2K1C hypertension is associated with reduced levels of eNOS proteins in the medulla of both clipped and contralateral kidneys, being causally related with reduction of medullary blood flow32). In the early reversal of hypertension and changes of renal function following unclipping of the clipped artery, an upregulation of eNOS and enhanced release of NO is an important component33). It is likely that NO contributes a significant vasodilator tone to buffer the hypertension and maintains perfusion of kidneys in this model.

NO has been shown to provide renoprotection in AII-induced hypertension. Salt-sensitive hypertension develops after short-term exposure to AII, in association with a loss of intrarenal NO formation that could alter the ability of the kidney to excrete a salt load34). The sodium-retaining effect of AII in the absence of NO is mediated mainly by enhanced O₂^- activity35), suggesting that an interaction between NO and O₂^- in the kidney plays an important role in the development of salt sensitivity and hypertension. In fact, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase - one important source for free superoxide - was activated and the superoxide production was enhanced due to AII10). AII can also reduce ecSOD expression36).

In rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension, AII mediates renal production of bradykinin, which, in turn, releases NO and cGMP via stimulation of AT2R37). Aortic banding resulted in significant upregulation of eNOS, iNOS and nNOS in the renal cortex and medulla38). The aortic coarctation-induced hypertension is associated with increased nitrotyrosine abundance in all tissues exposed to high arterial pressure, denoting enhanced ROS-mediated inactivation and sequestration of NO39).

Table 1 summarizes the alterations of NO system in the kidney in various models of hypertension. A chronic consumption of a high salt diet results in moderate hypertension, which is accompanied by downregulation of various NOS isoforms that undoubtedly contributes to the development and maintenance of hypertension40). In fructose-fed rats, while the vascular expression of NOS proteins is not altered41), the medullary NO production is reduced during high sodium load, resulting in salt-sensitive hypertension42). The renal expression of iNOS and eNOS mRNA is reduced in hypertension induced by adrenocorticotropic hormone (ACTH) or corticosterone43). A chronic exposure to low levels of lead results in a marked elevation of blood pressure, in association with significant reduction in urinary NO excretion and upregulation of eNOS and iNOS abundance in the kidney44). Chronic elevation of plasma vasopressin levels enhances the medullary eNOS protein expression, which enables sustained elevations of NO concentrations to buffer the hypertensive effects of vasopressin45). It has been also found that the hypertensive effect of intravenous infusion of norepinephrine was chronically buffered by the α2 receptor-mediated increase of NOS activity within the renal medulla46). In hydronephrotic rats, a reduced NO availability through reduced expression of nNOS and eNOS proteins in the diseased kidney and subsequent resetting of TGF mechanism plays an important role in the development of hypertension47). Although eNOS protein and tissue nitrate contents are decreased along with enhanced ET-1 proteins in the aorta of type II 11β-hydroxysteroid dehydrogenase-deficient rats48), their changes in the kidney have not been documented. Oral contraceptive users exhibit elevated AII levels and AT1R expression, of which hemodynamic effects may be modulated by an increased activity of NO pathway49).