(Hypertension. 1995;25:1090-1095.)
© 1995 American Heart Association, Inc.
Articles |
Nitroxidergic Innervation in Dog and Monkey Renal Arteries
From the Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu, Japan.
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Abstract |
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Abstract We analyzed mechanisms underlying neurogenic vasodilatation in dog and Japanese monkey renal arteries. Isometric mechanical responses of the arterial strip to nerve stimulation by nicotine were recorded. Nicotine-induced contractions were abolished by hexamethonium and potentiated by NG-nitro-L-arginine, a nitric oxide synthase inhibitor. The potentiating effect was reversed by L-arginine. NG-Nitro-L-arginine did not potentiate the contraction caused by norepinephrine. The nicotine-induced contraction was reversed to a relaxation by prazosin. The relaxation was not influenced by indomethacin, timolol, or atropine but was abolished by NG-nitro-L-arginine, methylene blue (a guanylate cyclase inhibitor), oxyhemoglobin (a nitric oxide scavenger), and hexamethonium. In the strips treated with NG-nitro-L-arginine, the nicotine-induced relaxation was restored by L-arginine. Histochemical study demonstrated perivascular nerves containing NADPH diaphorase and nitric oxide synthase immunoreactivity in dog and monkey arteries. We conclude that renal arteries are innervated by nitric oxide–mediated vasodilator and adrenergic vasoconstrictor nerves, and depression of the vasodilator nerve function by nitric oxide synthase inhibition potentiates the contraction caused by adrenergic nerve excitation.
Key Words: nitric oxide • vasodilation • nervous system • immunohistochemistry • primates • renal artery
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Introduction |
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The physiological role of the kidney is to maintain the volume and composition of electrolytes in body fluids by changing the urinary excretion of NaCl and water. Retention of Na+ and water by an impairment of kidney function is one of the important factors responsible for the genesis of hypertension, and diuretics have long been evaluated clinically as useful therapeutics in hypertensive patients. Inhibition of nitric oxide (NO) production by arginine analogues decreases the urinary excretion of Na+ and water, possibly by preferential actions on tubuli and also by reduced glomerular blood flow.1 2 Therefore, NO derived from the vascular endothelium or elsewhere is speculated to be an important endogenous diuretic substance.
It is recognized that endothelium-derived relaxing factor (EDRF)3 is identical to NO or an NO analogue produced in the endothelium.4 5 NO is reportedly liberated by chemical stimuli from renal arterial endothelium.6 7 8 Our recent studies have indicated that NO is derived also from perivascular nerves.9 10 11 12 However, no information is available concerning NO-mediated vasodilator innervation in the renal artery.
The present study aimed to determine the nature of the vasodilator nerves innervating the renal arterial wall in dogs and monkeys and to clarify mechanisms underlying neurogenic vasodilatation by the use of pharmacological and histochemical methods, with special reference to NO. We used nicotine to stimulate perivascular nerves because this agent produces consistent responses and shares pharmacological actions with electrical nerve stimulation, except for the fact that the response to electrical stimulation is abolished by tetrodotoxin but not by hexamethonium, and the opposite is the case in the response to nicotine.13 14
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Methods |
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The studies review board at our university approved the use of animal blood vessels in this study.
Tension Recording
Ten mongrel dogs of either sex weighing 7 to 13 kg were
anesthetized with sodium thiopental (30 mg/kg IV) and killed by
bleeding from the common carotid arteries. Eleven Japanese monkeys
(Macaca fuscata) of either sex (6 to 11 kg) were also killed
by bleeding under anesthesia with ketamine (40 mg/kg IM) and sodium
thiopental (20 mg/kg IM). Interlobar branches of the renal artery (0.5
to 0.8 mm outside diameter) were isolated and cut into helical strips
approximately 20 mm long. The endothelium was removed from some strips
by gently rubbing the intimal surface with a cotton ball. The specimens
were vertically fixed between hooks in a muscle bath containing a
modified Ringer-Locke solution that was maintained at 37±0.3°C and
aerated with a mixture of 95% O2 and 5% CO2.
The hook anchoring the upper end of the strips was connected to the
lever of a force-displacement transducer (Nihonkohden Kogyo). The
resting tension was adjusted to 1.5 g for dog artery and 1.0 g for
monkey artery, which were optimal tensions for inducing maximal
contraction. The composition of the solution was (mmol/L) NaCl 120,
CaCl2 2.2, MgCl2 1.0, NaHCO3 25.0,
and dextrose 5.6 (pH 7.38 to 7.46). Before the start of experiments,
all strips were allowed to equilibrate for 60 to 90 minutes in the
bathing medium, during which time the fluid was replaced every 10 to 15
minutes.
Isometric mechanical responses were displayed on an ink-writing
oscillograph (Nihonkohden Kogyo). The contractile response to 30 mmol/L
K+ was first obtained, and the arterial strips were
repeatedly washed with fresh medium and equilibrated. The
K+-induced contraction was taken as a standard for the
contraction caused by agonists. The strips were partially contracted
with prostaglandin (PG) F2
(4 to 15x10-7
mol/L), the contraction being in a range between 28% and 41% of the
contraction induced by 30 mmol/L K+. Endothelium denudation
of the strips was determined by the abolishment of relaxations caused
by 10-6 mol/L acetylcholine. Nicotine and NO (acidified
NaNO2 solution) in single concentrations were successively
applied to the bathing medium, unless otherwise mentioned. At the end
of each series of experiments, 10-4 mol/L papaverine was
added to attain maximal relaxation, which was taken as 100% for
relaxation induced by agonists. NaNO2 solution was
acidified just before the application, and the vehicle of the solution
was without effect. Arterial strips had been treated for 15 to 20
minutes with blocking agents before the effect of agonists was
obtained.
Histochemical Study
The renal artery was fixed in ice-cold 0.1 mol/L
phosphate-buffered saline (PBS, pH 7.4) containing 0.3% glutaraldehyde
and 4% paraformaldehyde and then postfixed overnight in 0.1 mol/L PBS
with 4% paraformaldehyde, followed by cryoprotection in 15% sucrose.
The fixed blocks were cut into sections (20 µm thick) in a
cryostat (Cryotom, Nakagawa Seisakusho Co).
For NADPH diaphorase staining,15 the tissue sections were mounted onto gelatin/chrome-alum–coated glass slides and incubated with 0.1 mol/L PBS at pH 8.0 containing 1 mmol/L NADPH (Kohjin Co), 2 mmol/L nitro blue tetrazolium (Sigma Chemical Co), and 0.3% Triton X-100 at 37°C. The incubation period (30 to 60 minutes) was determined by staining intensity. The reaction was terminated by washing the sections in 0.1 mol/L PBS. Counterstain with eosin followed. The sections were air-dried and cover-slipped with xylene plus alkylacrylate (Entellan, Merck). A histochemical control experiment, in which NADPH was excluded from the reaction mixture, gave no positive staining.
For immunohistochemical staining of NO synthase,16 tissue sections were kept in 0.1 mol/L PBS containing 0.3% Triton X-100 at 4°C for 4 days. The specimens were exposed to affinity-purified rabbit antiserum against rat cerebellum NO synthase (1:300) in PBS with 0.3% Triton X-100 for 4 days at 4°C. Subsequently, biotinylated goat anti-rabbit IgG antibody and avidin-biotinylated peroxidase complex (Vector Laboratories Inc) were conjugated to the primary antibody at room temperature for 1 hour each. Immunolabeled peroxidase was visualized by incubation at room temperature for 3 to 5 minutes with 0.56 mmol/L 3,3'-diaminobenzidine tetrahydrochloride (Dojindo Laboratories), 1.3 µmol/L hydrogen peroxide, and 10 mmol/L nickel ammonium sulfate. The specimens were mounted onto gelatin/chrome-alum–coated glass slides. After several washes with distilled water, the sections were air-dried and cover-slipped with Entellan. An immunohistochemical control experiment, in which the antiserum against NO synthase was excluded from the reaction mixture, gave no positive staining.
Statistics and Drugs
The results shown in the text and figures are mean±SEM.
Statistical analyses were made using Student's paired and unpaired
t tests and Tukey's method after one-way ANOVA. Drugs used
were NG-nitro-L-arginine
(L-NA), NG-nitro-D-arginine
(D-NA) (Peptide Institute Inc), L- and
D-arginine, nicotine (base), methylene blue trihydrate,
hexamethonium bromide (Nacalai Tesque), acetylcholine chloride (Daiichi
Co), dl-norepinephrine hydrochloride (Sankyo Co), atropine
sulfate (Tanabe Co), indomethacin (Sigma), timolol hydrochloride (Banyu
Co), PGF2 (Upjohn Co), prazosin hydrochloride
(Pfizer-Taito), and papaverine hydrochloride (Dainippon Co). Responses
to NO were obtained by addition of NaNO2 solution adjusted
at pH 2.17
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Results |
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Dog Renal Artery
The addition of nicotine (10-5 to 10-3 mol/L) produced a concentration-related contraction of dog renal arterial strips that was abolished by treatment with 10-5 mol/L hexamethonium. To avoid tachyphylaxis, we applied a single concentration of the drug in each series. The response to 10-4 mol/L nicotine was consistent and reproducible; thus, we used this concentration for the remainder of the study. The mean contraction induced by 10-4 mol/L nicotine (459±63.1 mg, n=13) was 22.7±4.5% of the contraction caused by 30 mmol/L K+.
Treatment with L-NA (10-6 and 10-5 mol/L) potentiated the response to nicotine (10-4 mol/L) in a dose-dependent manner, and the potentiation was reversed by L- but not D-arginine (Fig 1). D-NA was without effect. The potentiating effect of L-NA was also obtained in four strips denuded of endothelium. The contractile response to exogenously applied norepinephrine was not altered by L-NA; mean values of the response at 10-7 mol/L norepinephrine in control media and those containing 10-6 and 10-5 mol/L L-NA were 7.2±3.0%, 8.4±3.5%, and 5.4±2.2% (n=5) of the contraction caused by 30 mmol/L K+, respectively, and those at 5x10-7 mol/L norepinephrine were 64.6±6.7%, 69.2±8.4%, and 58.6±8.7% (n=5), respectively.
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The contraction induced by nicotine was abolished by treatment with
10-5 mol/L prazosin in the strips under resting conditions
and was reversed to a relaxation when the strips were contracted
partially with PGF2. The relaxation was not
influenced by 10-6 mol/L indomethacin (n=3) and
10-7 mol/L timolol (n=5) but was abolished by
10-5 mol/L hexamethonium (n=5), 10-5 mol/L
oxyhemoglobin (n=3), or 10-5 mol/L methylene blue (n=3)
(data not shown). The nicotine-induced relaxation was also abolished by
L-NA (10-6 mol/L) and reversed by L-arginine
(3x10-4 mol/L) (Fig 2) but not by
D-arginine (3x10-4 mol/L). Relaxations
elicited by 10-7 mol/L NO were not influenced by L-NA (Fig 2) but were abolished by 10-5 mol/L oxyhemoglobin and
methylene blue.
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Monkey Renal Artery
Nicotine (10-4 mol/L) elicited a contraction in
monkey renal arterial strips under resting conditions that averaged
78.5±7.2 mg (n=10) and was 8.3±1.6% of the contraction caused by 30
mmol/L K+. The nicotine-induced contraction was potentiated
by L-NA (10-6 mol/L) but not by D-NA (10-6
mol/L) (Fig 3). The potentiation was reversed by
L-arginine (3x10-4 mol/L). Hexamethonium
(10-5 mol/L) abolished the nicotine-induced contraction
(n=4) (data not shown).
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The contraction caused by nicotine was reversed to a relaxation by
treatment with 10-5 mol/L prazosin in the strips
contracted with PGF2, which was not altered by
timolol (10-7 mol/L), indomethacin (10-6
mol/L), or atropine (10-7 mol/L) but was abolished by
methylene blue (10-5 mol/L) (Fig 4).
Similar results were also obtained in additional three strips from
different monkeys. The relaxant response was not affected by D-NA
(10-6 mol/L, n=3) but was almost abolished by L-NA
(10-6 mol/L); L-arginine (3x10-4
mol/L) restored the response (Fig 5). Typical recordings
are illustrated in Fig 6. D-Arginine did not
restore the response abolished by L-NA. NO (10-7
mol/L)–induced relaxations were not influenced by L-NA but were
abolished by oxyhemoglobin (10-5 mol/L, n=3) or methylene
blue (10-5 mol/L, n=3) (data not shown).
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Histological Study
In dog and monkey renal arteries, perivascular nerve fibers
containing NADPH diaphorase were histochemically determined. Fig 7 shows positively stained fibers in the adventitia and
some fine fibers also in the media in a dog renal arterial section. In
the monkey renal artery (Fig 8A and 8B), which is
surrounded by renal tubules containing NADPH diaphorase, positive
staining of perivascular nerves is also observed in the adventitia. The
presence of nerves containing NO synthase immunoreactivity was also
determined by the use of NO synthase antiserum. Fig 8C shows NO
synthase immunoreactive nerve fibers and a big bundle in the adventitia
of a monkey renal artery. Some tubular cells in the outer medulla are
also positively stained by anti–NO synthase antiserum (Fig 8D). The
type of the stained cells was not determined in the section for light
microscopy.
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Discussion |
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Contractions induced by nicotine of dog and monkey renal arterial strips were abolished by treatment with hexamethonium (present study and Reference 18), and in addition, those of dog mesenteric and renal arteries were suppressed or abolished by cocaine, phentolamine, and bretylium,18 suggesting that the response is mediated via norepinephrine released by activation of nicotinic receptors from adrenergic nerves. Abolishment by prazosin of the response suggests the involvement of the
1-adrenoceptor subtype. Treatment
with L-NA significantly potentiated the contractile response to
nicotine but not the norepinephrine-induced contraction.
The potentiating effect was reversed by L- but not
D-arginine. The similar effect of L-NA was also seen
in endothelium-denuded strips. The 3H
overflow by transmural electrical stimulation from superfused dog
mesenteric and temporal arterial strips that had been exposed for
60 minutes to [3H]norepinephrine was not altered by
treatment with NO synthase inhibitors19 20 or
EDRF/NO,21 indicating that locally produced NO does not
interfere with the release of the transmitter amine from adrenergic
nerves. These findings may indicate that depression of NO synthesized
from L-arginine in extraendothelial tissues results in a
potentiated contraction in response to adrenergic nerves.
In the dog and monkey renal arteries treated with prazosin and
contracted partially with PGF2, nicotine produced
a relaxation that was abolished by hexamethonium, oxyhemoglobin (an NO
scavenger22 ), and methylene blue (an inhibitor of soluble
guanylate cyclase23 ). Inhibitions by indomethacin of
cyclooxygenase and by timolol of ß-adrenoceptors were without effect.
The nicotine-induced relaxation was also abolished by treatment with
L-NA but not D-NA and was restored by L-arginine. The
relaxation caused by NO was not influenced by L-NA but was abolished by
oxyhemoglobin and methylene blue. Similar results with NO synthase
inhibitors and arginine were also observed in dog and monkey cerebral,
temporal, and mesenteric arteries.10 11 12 From
endothelium-denuded dog cerebral and temporal arterial
strips, nitroxy compounds are liberated in response to transmural
electrical stimulation and nicotine,10 20 which also
increases the content of cGMP in the tissue.11 19
Therefore, it is hypothesized that NO liberated as a neurotransmitter
from vasodilator nerve (called nitroxidergic nerve by Toda and
Okamura12 ) activates soluble guanylate cyclase in smooth
muscle cells and increases the production of cGMP, resulting in the
vasodilatation of dog and monkey renal arteries. This hypothesis is
supported by a histological demonstration of perivascular nerves
containing NADPH diaphorase in those arteries that is suggested to be
identical to NO synthase in the nervous system.24 In fact,
NO synthase immunoreactive nerve fibers are also observed in the monkey
renal artery.
Intra-arterial injections of L-NA in a dose sufficient to exert antidiuretic and antinatriuretic actions do not significantly alter renal blood flow and glomerular filtration rate, suggesting a role of NO in promoting water and Na+ excretion by a mechanism independent of blood flow and the glomerular capillary filtration coefficient.25 Our histochemical findings suggest the presence of NO synthase in the tubular wall. In addition, mRNAs coding for NO synthase have been detected in the nephron segments26 ; therefore, NO locally synthesized may regulate tubular functions. This possibility remains to be clarified.
NO is regarded as a diuretic that acts directly on renal tubules and also increases renal blood flow by dilating arteries and arterioles.1 Although many investigators suggest a role for NO derived from the arterial endothelium,27 the present study provided evidence suggesting the importance of NO derived from vasodilator nerves in regulating kidney function. The presence of NO synthase–containing perivascular nerve in renal arterioles (unpublished data, 1994) suggests the neural control of renal vascular resistance. Dog and monkey renal arteries, as well as superficial temporal and mesenteric arteries,11 12 appear to be innervated reciprocally by nitroxidergic vasodilator and adrenergic vasoconstrictor nerves, and ablation of the vasodilator nerve function by NO synthase inhibitors is expected to exaggerate neurogenic vasoconstriction and diminish blood flow.
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Acknowledgments |
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The authors would like to thank Drs D.S. Bredt and S.H. Snyder for providing the NO synthase antiserum.
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Footnotes |
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Reprint requests to Dr Noboru Toda, Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu 520-21, Japan.
Received October 21, 1994; first decision December 1, 1994; accepted January 11, 1995.
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