© 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
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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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
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|
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|
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|
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|
|
|
|
|
|
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|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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