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Johannes-Müller Institut für Physiologie, 10117 Berlin, Germany
BASTRON AND KALOYANIDES
(2) had already investigated the effects of sodium
nitroprusside in the isolated kidney 8 years before the postulate of an
endothelium-derived relaxing factor was made by Furchgott and Zawadzki
(14). More recent studies aim at the importance of nitric
oxide (NO) for kidney development (36, 37) and kidney
function during pregnancy, efferent and afferent renal nerve activity
(21), renal hemodynamics (17) and excretion
(26, 39), as well as renal injury and pathophysiology (6, 25).
Renal vascular resistance is low in pregnancy, possibly relying on NO
(7, 20, 33), which could be released by relaxin (9). Hefler et al. (16) found that mice
either deficient for endothelial NO synthase (eNOS) or overexpressing
angiotensinogen and mice with mutations in both genes showed higher
blood pressures throughout pregnancy compared with common laboratory
strains (16). This increased blood pressure was not of
renal origin; at least the measured renal functional parameters did not
significantly change. At first sight, this might seem surprising: a
reduced renal arterial smooth muscle cell contractility has been
observed in pregnant rats. In these pregnant rats, unspecific
inhibition of NO synthesis enhances renal vascular cell contraction
contractility, presumably by increases of intracellular
Ca2+ concentration (30). NOS inhibition
increases vascular resistance in many beds in the pregnant rabbit
(3). It also abrogates the reduced myogenic reactivity of
small renal vessels from gravid rats (15). The latter
occurs without affecting myogenic reactivity in arteries from virgin
animals (15). However, it seems that neuronal NOS (nNOS),
and not eNOS, is the NOS isoform that helps maintain renal perfusion
and filtration during pregnancy (1). Although nNOS
inhibition does not alter basal renal blood flow in normal rats
(19), this may be different in pregnancy, which would
explain the insignificant changes of creatinine clearance in pregnant
eNOS-deficient mice (16).
There can be little doubt that renal sympathetic efferent nerves are
important for renal function (10, 11, 24, 27, 29).
Conversely, many features of the kidney's afferent innervation are
still being unraveled (21, 22). nNOS in the kidney is not
only localized in the macula densa cells; the renal pelvis also seems
to contain nNOS. It is colocalized with substance P and CGRP in
renal pelvic sensory nerves (21). Release of substance P
produced by increased renal pelvic pressure appears to enhance NO
production, which, in turn, results in desensitization of substance P
receptors via increased cGMP production. Activation of NO may function
as an inhibitory neurotransmitter, regulating the activation of renal
mechanosensory nerve fibers by mechanisms related to activation of
substance P receptors (21). In theory, this mechanism is a
second potential link between nNOS and renal functional changes that
can be important during pregnancy or pathophysiological states.
The renal medullary circulation is important for blood pressure
(12, 13) and fluid and electrolyte homeostasis
(8). Reduction of medullary blood flow, e.g., by local
infusion of nNOS antisense, can lead to salt-induced
hypertension (28). However, salt-dependent
hypertension is also found during inducible NOS (iNOS) inhibition.
Moreover, the effect of blocking nNOS on blood pressure without any
further challenge has been a matter of dispute (19, 31).
Changes in local renal blood flow do not seem to occur when nNOS is
blocked (19). An important role of medullary NO production
might be associated with the activation of As of yet, the relevance of NO for many kidney functions is not clear.
For instance, NO has been reported to stimulate, inhibit, and to not
change renin levels (23, 32). This might rely on the
potential of NO to inhibit phosphodiesterase 3 (5, 35), which, in turn, degrades cAMP. Moreover, NO blockade increases blood
pressure (4, 18, 41), which reduces renin release (34, 38) by a different mode of action than does NO.
NO is also essential in regulating proximal tubular reabsorption of
fluid, sodium, bicarbonate, and phosphate. NO controls most renal
transporters and the permeability of the proximal tubule. Whether the
renal tubules, particularly the proximal tubule, produce NO under basal
conditions is still unclear. However, it seems that the proximal tubule
is exposed to NO and that great amounts of NO are released by a variety
of stimuli (25). This may also be of pathophysiological
importance: enhanced production of NO, perhaps iNOS from macrophages,
may participate in hypoxic/ischemic proximal tubular injury
(25). Glomerular NO production is also increased by
ischemia (40). In this context, NO seems to stem from the eNOS isoform and has a protective influence. Unspecific blockade of the NOS isoforms enhance the severity of renal
ischemia. A protective effect of NO in certain forms of renal
failure is supported by experiments using vena cava occlusion
(6). This procedure leads to acute renal failure by
impairing renal venous draining. The renal outer medulla is pivotal in
the pathophysiology of ischemic renal failure. The long-term
outcome relies more on this region of circulation than on glomerular
filtration. Remarkably, renal failure by vena cava occlusion is
aggravated by NO depletion (6).
N-acetyl-L-cysteine, a free radical scavenger,
enhanced outer medullary blood flow in this model of renal failure and ameliorated the renal failure. The effect of the free radical scavenger, however, relied on an intact NO production (6).
Taken together, NO plays an important role for maintaining volume,
electrolyte, and blood pressure homeostasis. This is brought about by
controlling the local renal circulation, modulating renal efferent and
afferent nerve activity, and by directly affecting the reabsorption of
fluids and electrolytes. Changes occurring during pregnancy and in
various pathophysiological states, such as acute renal failure or
salt-sensitive hypertension, critically depend on the renal NO systems.
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2-adrenergic
receptors: this NO release counteracts the vasoconstrictor effects of
norepinephrine in the renal medulla, which is essential for the
maintenance of renal medullary blood flow (42).
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. B. Persson, Johannes-Müller Institut für Physiologie, Tucholskystr. 2, 10117 Berlin (E-mail: pontus.persson{at}charite.de).
10.1152/ajpregu.00445.2002
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