| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
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.
ARTICLE
TOP
ARTICLE
REFERENCES
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).
| |
FOOTNOTES |
|---|
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
| |
REFERENCES |
|---|
|
TOP
ARTICLE
REFERENCES
|
|---|
1.
Abram, SR,
Alexander BT,
Bennett WA,
and
Granger JP.
Role of neuronal nitric oxide synthase in mediating renal hemodynamic changes during pregnancy.
Am J Physiol Regul Integr Comp Physiol
281:
R1390-R1393,
2001
2.
Bastron, RD,
and
Kaloyanides GJ.
Effect of sodium nitroprusside on function in the isolated and intact dog kidney.
J Pharmacol Exp Ther
181:
244-249,
1972
3.
Brooks, VL,
Clow KA,
Welch LS,
and
Giraud GD.
Does nitric oxide contribute to the basal vasodilation of pregnancy in conscious rabbits?
Am J Physiol Regul Integr Comp Physiol
281:
R1624-R1632,
2001
4.
Cases, A,
Haas J,
Burnett JC,
and
Romero JC.
Hemodynamic and renal effects of acute and progressive nitric oxide synthesis inhibition in anesthetized dogs.
Am J Physiol Regul Integr Comp Physiol
280:
R143-R148,
2001
5.
Chiu, T,
and
Reid IA.
Role of cyclic GMP-inhibitable phosphodiesterase and nitric oxide in the beta adrenoceptor control of renin secretion.
J Pharmacol Exp Ther
278:
793-799,
1996
6.
Conesa, EL,
Valero F,
Nadal JC,
Fenoy FJ,
Lopez B,
Arregui B,
and
Salom MG.
N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure.
Am J Physiol Regul Integr Comp Physiol
281:
R730-R737,
2001
7.
Cook, JL,
Zhang Y,
and
Davidge ST.
Vascular function in alcohol-treated pregnant and nonpregnant mice.
Am J Physiol Regul Integr Comp Physiol
281:
R1449-R1455,
2001
8.
Cowley, AW, Jr.
Long-term control of arterial blood pressure.
Physiol Rev
72:
231-300,
1992
9.
Danielson, LA,
Kercher LJ,
and
Conrad KP.
Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats.
Am J Physiol Regul Integr Comp Physiol
279:
R1298-R1304,
2000
10.
DiBona, GF.
Neural control of the kidney: functionally specific renal sympathetic nerve fibers.
Am J Physiol Regul Integr Comp Physiol
279:
R1517-R1524,
2000
11.
DiBona, GF,
and
Kopp UC.
Neural control of renal function.
Physiol Rev
77:
75-197,
1997
12.
Dukacz, SA,
Feng MG,
Yang LF,
Lee RM,
and
Kline RL.
Abnormal renal medullary response to angiotensin II in SHR is corrected by long-term enalapril treatment.
Am J Physiol Regul Integr Comp Physiol
280:
R1076-R1084,
2001
13.
Feng, MG,
Dukacz SA,
and
Kline RL.
Selective effect of tempol on renal medullary hemodynamics in spontaneously hypertensive rats.
Am J Physiol Regul Integr Comp Physiol
281:
R1420-R1425,
2001
14.
Furchgott, RF,
and
Zawadzki V.
The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.
Nature
288:
373-376,
1980[Medline].
15.
Gandley, RE,
Conrad KP,
and
McLaughlin MK.
Endothelin and nitric oxide mediate reduced myogenic reactivity of small renal arteries from pregnant rats.
Am J Physiol Regul Integr Comp Physiol
280:
R1-R7,
2001
16.
Hefler, LA,
Tempfer CB,
Moreno RM,
O'Brien WE,
and
Gregg AR.
Endothelial-derived nitric oxide and angiotensinogen: blood pressure and metabolism during mouse pregnancy.
Am J Physiol Regul Integr Comp Physiol
280:
R174-R182,
2001
17.
Hercule, HC,
and
Oyekan AO.
Role of NO and cytochrome P-450-derived eicosanoids in ET-1-induced changes in intrarenal hemodynamics in rats.
Am J Physiol Regul Integr Comp Physiol
279:
R2132-R2141,
2000
18.
Janssen, BJ,
Leenders PJ,
and
Smits JF.
Short-term and long-term blood pressure and heart rate variability in the mouse.
Am J Physiol Regul Integr Comp Physiol
278:
R215-R225,
2000
19.
Kakoki, M,
Zou AP,
and
Mattson DL.
The influence of nitric oxide synthase 1 on blood flow and interstitial nitric oxide in the kidney.
Am J Physiol Regul Integr Comp Physiol
281:
R91-R97,
2001
20.
Kanashiro, CA,
Cockrell KL,
Alexander BT,
Granger JP,
and
Khalil RA.
Pregnancy-associated reduction in vascular protein kinase C activity rebounds during inhibition of NO synthesis.
Am J Physiol Regul Integr Comp Physiol
278:
R295-R303,
2000
21.
Kopp, UC,
Cicha MZ,
Smith LA,
and
Hokfelt T.
Nitric oxide modulates renal sensory nerve fibers by mechanisms related to substance P receptor activation.
Am J Physiol Regul Integr Comp Physiol
281:
R279-R290,
2001
22.
Kopp, UC,
Farley DM,
Cicha MZ,
and
Smith LA.
Activation of renal mechanosensitive neurons involves bradykinin, protein kinase C, PGE2, and substance P.
Am J Physiol Regul Integr Comp Physiol
278:
R937-R946,
2000
23.
Kurtz, A,
and
Wagner C.
Cellular control of renin secretion.
J Exp Biol
202:
219-225,
1999[Abstract].
24.
Leonard, BL,
Malpas SC,
Denton KM,
Madden AC,
and
Evans RG.
Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity.
Am J Physiol Regul Integr Comp Physiol
280:
R62-R68,
2001
25.
Liang, M,
and
Knox FG.
Production and functional roles of nitric oxide in the proximal tubule.
Am J Physiol Regul Integr Comp Physiol
278:
R1117-R1124,
2000
26.
Llinas, MT,
Rodriguez F,
Moreno C,
and
Salazar FJ.
Role of cyclooxygenase-2-derived metabolites and nitric oxide in regulating renal function.
Am J Physiol Regul Integr Comp Physiol
279:
R1641-R1646,
2000
27.
Lohmeier, TE,
Lohmeier JR,
Reckelhoff JF,
and
Hildebrandt DA.
Sustained influence of the renal nerves to attenuate sodium retention in angiotensin hypertension.
Am J Physiol Regul Integr Comp Physiol
281:
R434-R443,
2001
28.
Mattson, DL,
and
Higgins DJ.
Influence of dietary sodium intake on renal medullary nitric oxide synthase.
Hypertension
27:
688-692,
1996
29.
Menegaz, RG,
Kapusta DR,
Mauad H,
and
de Melo CA.
Activation of 2-receptors in the rostral ventrolateral medulla evokes natriuresis by a renal nerve mechanism.
Am J Physiol Regul Integr Comp Physiol
281:
R98-R107,
2001
30.
Murphy, JG,
Fleming JB,
Cockrell KL,
Granger JP,
and
Khalil RA.
[Ca2+]i signaling in renal arterial smooth muscle cells of pregnant rat is enhanced during inhibition of NOS.
Am J Physiol Regul Integr Comp Physiol
280:
R87-R99,
2001
31.
Ollerstam, A,
Pittner J,
Persson AE,
and
Thorup C.
Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase.
J Clin Invest
99:
2212-2218,
1997[Web of Science][Medline].
32.
Peterson, TV,
Emmeluth C,
and
Bie P.
Renal effects of nitric oxide synthase inhibition in conscious water-loaded dogs.
Am J Physiol Regul Integr Comp Physiol
281:
R584-R590,
2001
33.
Ramirez, RJ,
Novak J,
Johnston TP,
Gandley RE,
McLaughlin MK,
and
Hubel CA.
Endothelial function and myogenic reactivity in small mesenteric arteries of hyperlipidemic pregnant rats.
Am J Physiol Regul Integr Comp Physiol
281:
R1330-R1337,
2001
34.
Rosnes, JS,
Valego N,
Wang JJ,
Perez FM,
and
Rose JC.
Renin mRNA response to reduced perfusion pressure conserved despite denervation in mature ovine fetuses.
Am J Physiol Regul Integr Comp Physiol
280:
R1830-R1836,
2001
35.
Sayago, CM,
and
Beierwaltes WH.
Nitric oxide synthase and cGMP-mediated stimulation of renin secretion.
Am J Physiol Regul Integr Comp Physiol
281:
R1146-R1151,
2001
36.
Solhaug, MJ,
Dong XQ,
Adelman RD,
and
Dong KW.
Ontogeny of neuronal nitric oxide synthase, NOS I, in the developing porcine kidney.
Am J Physiol Regul Integr Comp Physiol
278:
R1453-R1459,
2000
37.
Solhaug, MJ,
Kullaprawithaya U,
Dong XQ,
and
Dong KW.
Expression of endothelial nitric oxide synthase in the postnatal developing porcine kidney.
Am J Physiol Regul Integr Comp Physiol
280:
R1269-R1275,
2001
38.
Stocker, SD,
Sved AF,
and
Stricker EM.
Role of renin-angiotensin system in hypotension-evoked thirst: studies with hydralazine.
Am J Physiol Regul Integr Comp Physiol
279:
R576-R585,
2000
39.
Stulak, JM,
Juncos LA,
Haas JA,
and
Romero JC.
Systemic hemodynamics and renal function in hemorrhaged dogs resuscitated with cross-linked hemoglobin.
Am J Physiol Regul Integr Comp Physiol
278:
R28-R33,
2000
40.
Valdivielso, JM,
Crespo C,
Alonso JR,
Martinez-Salgado C,
Eleno N,
Arevalo M,
Perez-Barriocanal F,
and
Lopez-Novoa JM.
Renal ischemia in the rat stimulates glomerular nitric oxide synthesis.
Am J Physiol Regul Integr Comp Physiol
280:
R771-R779,
2001
41.
Yang, ZW,
Gebrewold A,
Nowakowski M,
Altura BT,
and
Altura BM.
Mg2+-induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO.
Am J Physiol Regul Integr Comp Physiol
278:
R628-R639,
2000
42.
Zou, AP,
and
Cowley AW.
2-Adrenergic receptor-mediated increase in NO production buffers renal medullary vasoconstriction.
Am J Physiol Regul Integr Comp Physiol
279:
R769-R777,
2000
This article has been cited by other articles:
|
|
 |
|
  C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Herrera and J. L. Garvin Recent Advances in the Regulation of Nitric Oxide in the Kidney Hypertension, June 1, 2005; 45(6): 1062 - 1067. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
