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 (AT(1)) 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
N(G)-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 F(2alpha), 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, AT(1) receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT(1) receptor expression, medullary and cortical
angiotensin type 2 (AT(2)) receptor expressions, and adrenal ACE and
neutral endopeptidase expressions were unchanged. A high-
sodium diet did not influence renal AT(1), AT(2), ACE, or
neutral endopeptidase expressions. In
valsartan-treated GK rats, the cortical and medullary AT(1) 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. AT(1) receptor blockade ameliorates
inflammation during a
low-sodium diet and partially protects against
salt-induced vascular damage by blood pressure-independent mechanisms.