Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats

Endothelial dysfunction is associated with hypertension, hypercholesterolem ia, 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 ch ronic angiotensin type 1 (AT(1)) receptor blockade (10 mg/kg PO valsartan f or 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 gluc ose tolerance tall P<0.05). Telemetry-measured mean blood pressure was 15 m m Hg higher in GK rats (P<0.01) compared with control rats, whereas heart r ates were not different. Heart weight- and kidney weight-to-body weight rat ios were higher in GK rats (P<0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesente ric 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 inhibito r NG-nitro-L-arginine methyl ester and the cyclooxygenase inhibitor diclofe nac 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 mo nocyte/macrophage infiltration and intercellular adhesion molecule-1 overex pression were observed in GK rat kidneys. A high-sodium diet increased bloo d pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hyp ertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation tall P<0.05), The serum level of 8-isoprostaglandin F-2<alpha >, a vasoconstrictor and antinatriuretic arachidonic acid metabolite produc ed 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 prev ented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but prot ected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT(1) receptor expression in the medulla w as decreased in GK compared with Wistar rats, whereas cortical AT(1) recept or expression, medullary and cortical angiotensin type 2 (AT(2)) receptor e xpressions, and adrenal ACE and neutral endopeptidase expressions were unch anged. A high-sodium diet did not influence renal AT(1), AT(2), ACE, or neu tral 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 n atriuretic peptide concentrations in presence and absence of valsartan trea tment. We conclude that hypertension in GK rats is salt sensitive and assoc iated with endothelial dysfunction and perivascular inflammation. AT(1) rec eptor blockade ameliorates inflammation during a low-sodium diet and partia lly protects against salt-induced vascular damage by blood pressure-indepen dent mechanisms.