© 1999 American Heart Association, Inc.
Cellular Biology |
Downregulation of Soluble Guanylyl Cyclase in Young and Aging Spontaneously Hypertensive Rats
From Hoechst Marion Roussel (H.R., W.L.), DG Cardiovascular, Frankfurt/Main, Germany; Department of Pharmacology and Toxicology (U.Z., H.H.H.W.S.), Julius-Maximilians-University, Wuerzburg, Germany.
Correspondence to Hartmut Ruetten, MD, Hoechst Marion Roussel, DG Cardiovascular, Bldg H821, D-65926 Frankfurt a.M. E-mail hartmut.ruetten{at}hmrag.com
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Abstract |
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Abstract—Endothelial dysfunction, as observed in hypertension and atherosclerosis, is associated with a reduction in the bioavailability of endothelium-derived nitric oxide (NO). We tested the hypothesis that alterations in the soluble guanylyl cyclase (sGC) pathway may also contribute to the pathogenesis of hypertension. Therefore, we investigated the expression and activity of sGC in young (6 weeks) and aging (17 months) spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY). Endothelium-independent relaxation of aortic rings in response to the sGC activator YC-1 was attenuated in SHR, and expression of both
1 and ß1 subunits
of heterodimeric sGC and the basal contents of cGMP were reduced
specifically in SHR aorta. Moreover, mRNA expression of the cGMP
receptor and effector protein cGMP-dependent protein kinase type I
(cGKI) was also reduced. Interestingly, downregulation of both sGC
and cGKI expression was observed in young, ie, normotensive SHR,
whereas impairment of the endothelium-independent
relaxation was found only in aging SHR. Accordingly, similar cGMP
levels were reached in response to YC-1 in young SHR and young WKY,
suggesting a compensatory increased sensitivity or effectiveness of the
sGC pathway in young SHR. In aging SHR, however, increased sensitivity
to YC-1 no longer compensated for the impairment of
endothelium-independent relaxation, suggesting that
other mechanisms were involved. In fact,
endothelium-independent relaxations were partially
restored by superoxide dismutase, suggesting a
pathophysiological role of superoxide
production, particularly at later disease stages. Thus,
tissue-specific downregulation of components of the sGC/cGMP pathway is
an early event in the pathogenesis of hypertension.
Key Words: hypertension • soluble guanylyl cyclase • aorta • heart • kidney
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nitric oxide (NO) has been implicated in a wide range of physiological functions including endothelium-dependent relaxation of blood vessels, inhibition of platelet aggregation, and vascular smooth muscle cell proliferation.1 In target cells such as vascular smooth muscle cells and platelets, NO activates the key enzyme that mediates vascular relaxation, the soluble guanylyl cyclase (sGC) to convert GTP to cGMP.2 The increase in cGMP content in vascular smooth muscle cells is associated with an activation of cGMP-dependent protein kinase type I
(cGKI) and
subsequent phosphorylation of numerous intracellular
proteins.3 The sGC was purified as a heterodimeric
heme-containing protein, consisting of a larger
1 (82 kDa) and a smaller
ß1 (
70 kDa) subunit.4 5 The
cDNA clones for both 1 and
ß1 subunits were isolated from different
species including rat.6 7 Moreover, sGC is the major
physiological target of NO-donor compounds such as
molsidomine.8 Recently, an NO-independent direct
activator of sGC has been introduced,
YC-1.9
Endothelial dysfunction, characterized by an impairment
of endothelium-dependent relaxation, is associated with
hypertension and
hypercholesterolemia10 11 and is
thought to be an early common mechanism in the development of
atherosclerosis. A decreased bioavailability of
endothelium-derived NO has been suggested to be
responsible for endothelial dysfunction and, hence,
hypertension.12 13 Furthermore, systemic administration of
NOS inhibitors markedly increases arterial
blood pressure,14 and knocking out the gene encoding
endothelial NO synthase (eNOS) in mice results in the
development of hypertension and abolishes the
endothelium-dependent relaxation elicited by
acetylcholine.15 However, an increase in the
endothelial superoxide anion
(O2-) production has
also been implicated in the development of endothelial
dysfunction in hypertension. Indeed, an enhanced formation of
O2- has been demonstrated in
vessels from spontaneously hypertensive rats (SHR).16 An
increase in the production of
O2- rapidly scavenges NO to
form the cytotoxic metabolite of NO and
O2-, peroxynitrite and hence
reduces the bioavailability of NO.17 This may explain the
findings that in SHR the effectiveness of NO is reduced, whereas
the NO release remains unaffected or even is
increased.18 19 20 It is unclear, however, whether
alterations in the sGC/cGMP/cGKI pathway are involved also in the
pathogenesis of hypertension.21 22 Therefore, we tested
the hypothesis that alterations in the sGC pathway may also contribute
to the development of hypertension.
In the present study, we investigated the
endothelium-independent relaxation of aortic rings
mediated by sGC as well as the expression (protein and mRNA) of the
1 and ß1 subunit of
sGC in aortic rings, hearts, kidneys, and brains from young (6 weeks
old) and aging (17 months old) SHR and normotensive Wistar-Kyoto rats
(WKY). In addition, we determined the mRNA expression of cGMP-dependent
protein kinase type I (cGKI) in aortic rings and hearts
from these animals.
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Materials and Methods |
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Animals
The studies were performed using aortas, hearts, brains, and kidneys from young (6 weeks old) and aging (17 months old) male SHR and WKY. Before the experiments, rats were housed under standardized conditions of temperature, humidity, and light. The animals had free access to standard diet (Altromin maintenance diet 1320; sodium content 0.2%) and drinking water ad libitum. All experiments were performed in accordance with the German animal protection law.
Vascular Reactivity Studies
SHR and WKY were decapitated, and the descending aorta was
removed, cleaned of connective tissue, and dissected into 3 sections.
The upper section (20 mm) was immediately frozen in liquid
nitrogen for reverse transcriptase–polymerase chain reaction (RT-PCR)
and Western blot analyses. The lower section (10 mm) was
used for the measurement of cGMP formation, whereas the remaining part
of the aorta was cut into 4 rings (3 mm in length) and the
endothelium was mechanically removed. The rings were
equilibrated in an organ bath (Schuler-Organbad; Hugo Sachs Elektronik)
for 30 minutes under a resting tension of 1 g in carbonated
(95% O2/5% CO2)
Krebs-Henseleit solution, pH 7.4 (composition in mmol/L:
Na+ 144.0, K+ 5.9,
Cl- 126.9, Ca2+ 1.6,
Mg2+ 1.2,
H2PO4-
1.2, SO42- 1.2,
HCO3- 25.0, and
D-glucose 11.1), in the presence of the
cyclooxygenase inhibitor
indomethacin (1 µmol/L). Subsequently, rings
were contracted with phenylephrine (PE, 1 µmol/L),
and the functional loss of the endothelium was tested
by recording the relaxation to acetylcholine (1 µmol/L).
After a 30-minute washout period, rings were contracted with 1
µmol/L PE, and the relaxant response to a cumulative dose of YC-1 or
sodium nitroprusside (SNP) was assessed in the presence or absence of
superoxide dismutase (SOD, 0.1 µmol/L) and/or the
phosphodiesterase (PDE) V inhibitor zaprinast (30
µmol/L). At the end of the experiments, the selective
inhibitor of sGC, ODQ,23 was added.
Determination of cGMP Content in Isolated Blood Vessels
After mechanical removal of the endothelium, the
lower part of the aorta was cut into 4 rings (3 mm in length) and
treated with the PDE inhibitor 3-isobutyl-1-methylxanthine
(IBMX; 100 µmol/L) for 15 minutes in microtubes. After this
period, aortic rings were incubated with vehicle (0.3% DMSO), YC-1
(30 µmol/L), ODQ (10 µmol/L), or the combination of YC-1
(30 µmol/L) and ODQ (10 µmol/L) for 15 minutes. At the
end of the incubation, aortic rings were immediately frozen in liquid
nitrogen and stored at -80°C. cGMP was extracted by the addition of
4 volumes of HClO4 (1 N) followed by sonification
for 15 seconds and centrifugation (15 minutes,
13 000g). The pellets were used for protein determination
according to the method of Bradford.24 The
supernatant (100 µL) was neutralized with 100 µL KOH (1 N),
sonicated, and centrifuged again (2 minutes, 3000g)
and then used for the determination of cGMP by EIA (Amersham Life
Science).
Determination of sGC Protein Expression
Frozen rat aorta, heart, kidney, and brain tissue powder were
homogenized in 200 µL sample buffer (Novex) supplemented
with PMSF (1 mmol/L), pepstatin A (1 µmol/L), leupeptin
(2 µmol/L), and MESNA (0.2 mol/L) and subsequently
centrifuged at 13 000g for 30 minutes at 4°C. The
supernatant was boiled for 10 minutes and then loaded (50 µg
protein/20 µL) onto 4% to 12% Bis-Tris polyacrylamide gels
(Novex). The gels were run at 200 V for 50 minutes in a MOPS-SDS
running buffer, and subsequently separated proteins were transferred to
nitrocellulose (Novex) by semidry Western blotting. Blots were blocked
overnight at 4°C in TBST (20 mmol/L Tris-HCl, 137 mmol/L
NaCl [pH 7.6], and 0.05% Tween-20) containing 5% nonfat dry milk
and washed 3 times in TBST, and the blots were incubated with
polyclonal peptide–specific antibodies to either the
1 or the ß1 subunit of
sGC as described.25 Subsequently, blots were
incubated with an HRP-conjugated secondary antibody (Dianova,
1:10 000) in TBST for 1 hour, developed by using an enhanced
HRP/luminol chemiluminescence reaction (ECL Western blotting detection
reagents, NEN Life Science Products), and exposed to X-ray film for
30 to 60 seconds. The autoradiographs were analyzed by scanning
densitometry.
Determination of RNA Expression by PCR Analysis
Total RNA was prepared from the indicated tissues according to
the manufacturer's protocol using TRIzol reagent (Gibco BRL Life
Technologies, Inc). RT-PCR was performed using the GeneAmp RNA PCR kit
(Perkin-Elmer). cDNA was generated by incubating 2 µg of the total
RNA in the presence of Oligo d(T)16 primer in a 20-µL reaction for 10
minutes at room temperature. Subsequently, the reaction mixture was
incubated at 42°C for 30 minutes and at 99°C for 5 minutes. The
reverse transcription was stopped by incubating at 0°C for 5 minutes.
After an initial denaturation step at 94°C, 20 to 35 PCR cycles were
performed as follows: 1 minute at 94°C, 3 minutes at 55°C, and 1
minute at 72°C. In each PCR, the cDNAs for the sGC subunits
ß1 (70 kDa) and 1 (82
kDa), cGMP-dependent protein kinase, and GAPDH were coamplified. The
optimal cycle number for each primer was determined by a PCR run for
cycle dependency under the described conditions. The primers used to
amplify sGC 1 and
ß1,26 cGKI,27 and
GAPDH are provided in Table 1
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The PCR amplifications were performed in a reaction mixture containing 2 mmol/L MgCl2 and 20% Q-solution (Quiagen GmbH). The amplified cDNAs were size-fractionated using a 6% Tris-boric acid-EDTA gel (Novex) and stained with ethidium bromide. The fluorescence was detected densitometrically using a FluorImager (Molecular Dynamics GmbH).
Statistical Analysis
Results are expressed as mean±SEM. Unless otherwise stated,
each of the studies was performed in a minimum of 5 rats. Comparisons
were performed by ANOVA or paired and unpaired Student's t
tests when appropriate. The Bonferroni correction for multiple
comparison was used to determine the levels of significance of the
P values.
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Results |
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General Data
Global parameters of young and aging WKY and SHR are shown in Table 2
. The systolic
blood pressure of aging SHR as measured by tail-cuff plethysmography
was significantly higher when compared with young and aging WKY as well
as to young SHR. In addition, body weight of aging WKY was
significantly higher when compared with age-matched SHR. However, the
basal heart rate was not significantly different between groups.
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Endothelium-Independent Vasodilator Responses in
Aortic Rings and cGMP Content
In aortic rings preconstricted with PE, the
endothelium-independent, direct activator
of sGC YC-1 induced a concentration-dependent relaxation in young and
aging WKY and SHR. The EC50 for YC-1 was not
significantly different between young WKY and SHR (WKY 3.5±1.7
µmol/L, SHR 2.9±1.5 µmol/L) (Figure 1A). In contrast, the
concentration-response curve to YC-1 in aortic rings from aging SHR was
significantly shifted to the right when compared with age-matched WKY
as well as to young WKY and SHR (EC50: aging SHR
12.1±4.3 µmol/L, aging WKY 4.4±3.1 µmol/L;
P<0.05) (Figure 1B).
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) at the age of 6 weeks (A and
C) and 17 months (B and D) in the absence (•, 
,
) of SOD (100 nmol/L). C and D, Effect of YC-1 on
PE-preconstricted aortic rings from WKY (•) and SHR (
) and SHR (
) at the age
of 6 weeks (C) and 17 months (D) is also shown. Results are expressed
as mean±SEM from 5 separate experiments. *P<0.05
compared with WKY.
The addition of SOD (0.1 µmol/L) to PE-constricted aortic rings
resulted in a small but stable relaxation that was comparable in aortic
rings from aging WKY (21±5%) and SHR (23±4%). Interestingly, the
addition of SOD shifted the concentration-response curve to YC-1 in
aortic rings from aging SHR significantly to the left and, hence,
partially (46±6%) restored the impaired relaxation to YC-1 when
compared with age-matched WKY (Figure 1B
). In contrast, SOD had
only a small but insignificant effect on the relaxant response to YC-1
in aortic rings from aging WKY (Figure 1B). In addition,
cumulative concentrations of the selective cGMP PDE V
inhibitor zaprinast caused only relatively small
relaxations of aortic rings from young and aging SHR and WKY, which
were not significantly different between both strains (Figure 1C and 1D). In PE-constricted aortic rings from young and aging WKY and
SHR, pretreatment of aortic rings with a single concentration of
zaprinast (30 µmol/L, which, unlike cumulative concentrations,
does not affect isometric force relative to vehicle) significantly
potentiated the vasorelaxant response to YC-1. The
EC50 for YC-1 in the presence of zaprinast was
not significantly different between young WKY and SHR (WKY
0.9±1.1 µmol/L, SHR 0.6±1.2 µmol/L) (Figure 1C).
In contrast, the concentration-response curve to YC-1 in the presence
of zaprinast (30 µmol/L) in aortic rings from aging SHR was
significantly shifted to the right when compared with age-matched WKY
as well as to young WKY and SHR (EC50:
aging SHR 7.1±1.3 µmol/L, aging WKY 1.4±1.7;
P<0.05) (Figure 1D).
Finally, the addition of SOD also shifted the concentration-response curves to YC-1 or SNP in the presence of zaprinast in aortic rings from aging SHR significantly to the left and, hence, partially (39±9%) restored the impaired relaxation to YC-1 when compared with age-matched WKY (data not shown). In all groups, the relaxant response of YC-1 in endothelium-denuded aortic rings was reversed by the sGC inhibitor ODQ (10 µmol/L), and similar results were obtained when the NO donor compound SNP was used instead of YC-1 (data not shown).
The basal content of cGMP in aortic rings from both young (y) and aging
(o) SHR was significantly lower when compared with WKY (yWKY 2.3±0.4
pmol/mg protein, oWKY 1.9±0.5 pmol/mg protein, ySHR 0.2±0.1 pmol/mg
protein, oSHR 0.2±0.1 pmol/mg protein; P<0.05) (Figure 2A). However, stimulation with YC-1
(30 µmol/L) resulted in similar cGMP levels in aortic rings from
young WKY (40±6 pmol/mg protein) and young SHR (37±10 pmol/mg
protein) (Figure 2B). In contrast, in aortic rings from aging
SHR, the increase in the levels of cGMP caused by YC-1 was
significantly reduced when compared with age-matched WKY (oSHR 60±19
pmol/mg protein, oWKY 125±22 pmol/mg protein; P<0.05) and
was not significantly different when compared with young WKY and young
SHR (Figure 2B). The increase in the formation of cGMP by YC-1
was abolished in all groups in the presence of ODQ (10 µmol/L)
(data not shown).
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1/ß1 Subunit Expression of sGC in
Thoracic Aorta, Heart, Kidney, and Brain
In aortic rings, protein expression of 1
and ß1 subunits of sGC was significantly
reduced in young and aging SHR when compared with age-matched WKY
(Figure 3A and 3B). In contrast,
expression of sGC protein (ß1 and
1 subunits) was not significantly different in
hearts and kidneys from young WKY versus young SHR. Instead, sGC
expression was found to be increased in aging WKY and SHR when compared
with young WKY and SHR. However, there was no difference in the
expression of sGC in hearts and kidneys from aging WKY and SHR (Figures 4A and 4B and
5A and 5B). These sGC protein expression
patterns were reflected in the steady-state levels of
1/ß1 sGC mRNA, as
revealed in RT-PCR experiments from the same organs (Figures 3C, 4C, and 5C). Interestingly, no difference in the
expression of sGC (1 and
ß1 subunits) protein was detected in brains
from young and aging WKY and SHR (data not shown).
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cGKI mRNA Expression in Thoracic Aortas and Hearts
In aortic rings, expression of cGKI mRNA was significantly
reduced in young and aging SHR when compared with age-matched WKY
(Figure 6). However, there was no
difference between the expression of cGKI mRNA in hearts of WKY and
SHR, but expression was found to be increased in hearts from aging WKY
and SHR when compared with young rats (Figure 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several cardiovascular disorders, such as atherosclerosis and hypertension, are associated with endothelial dysfunction, which is characterized by an impairment of vasodilator-mediated release of NO from the endothelium. In contrast, the endothelium-independent relaxant response of the vascular smooth muscle to NO donor compounds is thought not to be affected.18 In the present study, we investigated a potential pathophysiological alteration of the sGC/cGMP pathway downstream of NO synthesis in SHR, an animal model of genetic predisposition to develop arterial hypertension during aging.
In SHR, specifically in the aorta, we found a significant reduction in mRNA and protein expression of both sGC subunits when compared with control WKY, which correlated with decreased basal intracellular cGMP levels. Moreover, mRNA expression of the cGMP target protein GK-I, which is essential for cGMP-dependent vascular smooth muscle relaxation,28 was also decreased in SHR aorta. A similar reduction of sGCß1 expression has been recently reported for aging and, thus, hypertensive SHR.20 In the present study, we observed reduced sGC and GK-I expression levels in young, normotensive SHR (6 weeks). Importantly, expression did not decrease further with age-dependent onset of hypertension. These findings demonstrate that tissue-specific downregulation of cGMP pathway components is an early event in the pathogenesis of hypertension and thus may be of pathophysiological relevance.
Interestingly, we observed an impairment of the endothelium-independent relaxant response exclusively in aging SHR, as evidenced by a significant increase of the EC50 value for YC-1 to induce vasorelaxation. This finding was surprising, as endothelium-independent vasorelaxation is thought not to be affected in SHR and other model systems of hypertension.18 Moreover, it cannot be readily correlated with the observed reduction of sGC and GK-I expression, because the relaxation response was normal in young, normotensive SHR, despite low basal cGMP levels. This decreased basal content of cGMP in aortic segments from young SHR was however not due to an increase in cGMP breakdown, because the relaxant response to the selective PDE V inhibitor zaprinast was not significantly reduced in aortic rings from young SHR when compared with WKY. Importantly, impaired YC-1–induced relaxation in aging SHR was partially restored by SOD. This suggested that an increased O2- production was involved in the observed relaxation defect. In fact, excessive vascular O2- production is thought to be involved in the pathomechanism of hypertension,17 because normal endothelial function and blood pressure could be restored by SOD16 or by inhibitors of the xanthine oxidase system.16 29 It has been suggested that the rapid formation of the cytotoxic metabolite of NO and O2-, peroxynitrite, reduces the bioavailability of NO.17 Moreover, the fact that impaired YC-1–induced relaxation in aging SHR was partially restored by SOD may be explained also by a direct inhibition of stimulated sGC activity by vascular O2-.30 A similar impairment of endothelium-independent vasorelaxation, induced by SNP, has recently been described for 63-week-old SHR, which, however, was not reversed by SOD.20 Therefore, these data collectively suggest that the sGC/cGMP pathway downstream of NO is specifically affected in hypertensive SHR; the functional impairment, however, is rather a late event in pathogenesis and, hence, might have escaped previous studies.
Endothelium-independent relaxation was not impaired in young, normotensive SHR, although sGC expression and intracellular basal cGMP levels were reduced. Interestingly, upon stimulation with YC-1, similar intracellular cGMP levels were reached in both young SHR and age-matched control rats, implying an apparently 10-fold increased sensitivity of the cGMP response to YC-1 in the former animals. It must be elucidated whether this sensitization is either directly mediated by changes in the sensitivity of sGC or mediated by a decrease in cGMP breakdown. Interestingly, we observed sensitization toward YC-1 in old WKY versus young WKY, as has been reported for the nitrovasodilator drug SNP in aging normotensive rats.31 This suggests a developmental sensitization effect in healthy animals, which may, together with an age-dependent increase in vascular NOS expression,32 provide an important adaptation mechanism that at least transiently can compensate for a diminished endothelium-dependent response to endothelium-dependent vasodilator upon aging.31 32
Downregulation of sGC subunits has been observed in several cell types
and occurs in response to several physiological
signaling molecules such as nerve growth factor33 and
cAMP.26 In agreement with the present study,
downregulation of sGC protein frequently coincides with decreased sGC
mRNA levels26 34 and seems to involve sGC mRNA
destabilization.33 In vascular smooth muscle cells, sGC
expression was inhibited by NO in a cGMP-dependent manner, suggesting a
negative autoregulatory mechanism.34 Interestingly, cGK-I
expression was also found to be reduced in response to NO and cGMP in
vascular smooth muscle cells.35 Strikingly, expressional
regulation of sGC1,
sGCß1, and cGK-I in SHR aorta, as well as in
heart of aging rats was concertedly affected. This suggests the
intriguing possibility that all 3 components of the cGMP pathway may
underlie a common transcriptional control. It must be elucidated
whether elevated amounts of aortic NO, produced by vascular NOS II upon
inflammatory processes and endothelial damage in
SHR,36 affect sGC and GK-I expression. On the other hand,
a tissue-specific defect in transcriptional control may contribute to
the genetic predisposition of SHR for arterial
hypertension.
Developmental regulation of sGC expression was described for rat lung,
in which the sGC content decreased after lung maturation in the
newborn.37 In the present study, we show an
age-dependent increase in sGC and GK-I expression in rat heart, which
was independent of the hypertensive phenotype. The
physiological relevance of this phenomenon remains
to be clarified. The increased expression of sGC and cGK-I upon aging
in heart, but not in brain, suggests a prominent role in
cardiovascular control, possibly as part of the
adaptation mechanism discussed above. In contrast to SHR, reduced
expression of sGCß1 mRNA in the kidney has been
associated with elevated blood pressure in an animal model of
salt-sensitive hypertension.38 Instead, mRNA levels of
sGCß2, a kidney-specific sGC
subunit,39 were increased, presumably leading to the
formation of NO-insensitive
1/ß2
heterodimers.38 The pathophysiological
relevance of this observation remains to be elucidated.
Taken together, full development of hypertension in SHR is a multifactorial process. In the early phase, a reduction in sGC, cGMP, and the cGMP receptor, cGK-I, was observed, which, at this stage, can be functionally compensated to the effect that blood pressure stays normotensive. At later stages, increased O2- formation reduces the availability of NO and further affects the sGC pathway to a level that cannot be functionally compensated, leading to development of arterial hypertension. Whether early impairment of the sGC pathway triggers the onset of other factors relevant for pathogenesis, such as O2- formation, reduction of endothelial NO synthesis, or development of inflammatory processes, remains to be elucidated.
Received February 4, 1999; accepted July 20, 1999.
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