(Hypertension. 2001;37:433.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats
From the Institute of Biomedicine (Z.J.C., T.V., K.N., H.V., E.M.A.M.), Department of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland; the Department of Medicine (I.T.), Helsinki University Central Hospital and Minerva Institute for Medical Research, Helsinki, Finland; the Department of Pharmacology and Toxicology (H.R., D.M., J.-K.P., F.C.L.), University of Oulu, Oulu, Finland; and the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.
Correspondence to Eero Mervaala, MD, PhD, Assistant Professor, Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, PO Box 8, FIN-00014 Helsinki, Finland. E-mail eero.mervaala{at}helsinki.fi
Endothelial
dysfunction is associated with hypertension,
hypercholesterolemia, and heart failure. We
tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK)
rats, a model for type 2 diabetes, exhibit endothelial
dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt])
and chronic angiotensin type 1 (AT1)
receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with
age-matched nondiabetic Wistar control rats, GK rats had higher blood
glucose levels (9.3±0.5 versus 6.9±0.2 mmol/L for control rats),
2.7-fold higher serum insulin levels, and impaired glucose tolerance
(all P<0.05).
Telemetry-measured mean blood pressure was 15 mm Hg higher in GK
rats (P<0.01) compared with
control rats, whereas heart rates were not different. Heart weight–
and kidney weight–to–body weight ratios were higher in GK rats
(P<0.05), and 24-hour
albuminuria was increased 50%.
Endothelium-mediated relaxation of
noradrenaline-precontracted mesenteric arterial
rings by acetylcholine was impaired compared with the control condition
(P<0.05), whereas the sodium
nitroprusside–induced relaxation was similar. Preincubation of the
arterial rings with the NO synthase inhibitor
NG-nitro-L-arginine
methyl ester and the cyclooxygenase
inhibitor diclofenac inhibited relaxations to acetylcholine
almost completely in GK rats but not in Wistar rats, suggesting that
endothelial dysfunction can be in part attributed to
reduced relaxation via arterial
K+ channels. Perivascular
monocyte/macrophage infiltration and intercellular adhesion
molecule-1 overexpression were observed in GK rat kidneys. A
high-sodium diet increased blood pressure by 24 mm Hg and 24-hour
albuminuria by 350%, induced cardiac
hypertrophy, impaired endothelium-dependent
relaxation further, and aggravated inflammation (all
P<0.05). The serum level of
8-isoprostaglandin F2
, a
vasoconstrictor and antinatriuretic
arachidonic acid metabolite produced by oxidative
stress, was increased 400% in GK rats on a high-sodium diet. Valsartan
decreased blood pressure in rats fed a low-sodium diet and prevented
the inflammatory response. In rats fed a high-sodium diet, valsartan
did not decrease blood pressure or improve endothelial
dysfunction but protected against albuminuria,
inflammation, and oxidative stress. As measured by quantitative
autoradiography, AT1 receptor
expression in the medulla was decreased in GK compared with Wistar
rats, whereas cortical AT1 receptor expression,
medullary and cortical angiotensin type 2
(AT2) receptor expressions, and adrenal ACE and
neutral endopeptidase expressions were unchanged. A
high-sodium diet did not influence renal AT1,
AT2, ACE, or neutral
endopeptidase expressions. In valsartan-treated GK
rats, the cortical and medullary AT1 receptor
expressions were decreased in the presence and absence of a high-sodium
diet. A high-sodium diet increased plasma brain natriuretic
peptide concentrations in presence and absence of valsartan treatment.
We conclude that hypertension in GK rats is salt sensitive and
associated with endothelial dysfunction and
perivascular inflammation. AT1 receptor blockade
ameliorates inflammation during a low-sodium diet and partially
protects against salt-induced vascular damage by blood
pressure–independent
mechanisms.
Key Words: acetylcholine • nitroprusside • receptors, angiotensin • angiotensin-converting enzyme • peptides
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