Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats
Dysfunction of vascular endothelium has been associated with several cardiovascular risk factors including hypertension, hypercholesterolemia, and congestive heart failure. We tested the hypothesis whether or not endothelial dysfunction also participates in the pathogenesis of spontaneously diabetic Goto-Kakizaki (GK) rats, an animal model for type 2 diabetes. Furthermore we evaluated the influence of high sodium diet (6 % NaCl w/w) and chronic AT1 receptor blockade (valsartan 10 mg/kg p.o. for 8 weeks starting at age 8 weeks). Compared to age-matched non-diabetic Wistar controls, GK rats had higher b-glucose levels (9.3±0.5 vs 6.9±0.2 mmol/l), 2.7-fold higher s-insulin levels, impaired glucose tolerance in oral glucose tolerance test, and moderately increased s-cholesterol and s-triglyserides levels (all variables p<0.05). Mean arterial blood pressure, measured by radiotelemetry, was 15 mm Hg higher in GK rats (p<0.01), whereas no difference in heart rate was observed. Heart weight- and kidney weight -to-body weight ratios were higher in GK rats (p<0.05), and 24-hour albuminuria was 1.5-fold. Endothelium-mediated vascular relaxation of noradrenaline-precontracted mesenteric arterial rings to acetylcholine was markedly impaired in GK rats compared to Wistar rats (p<0.05), whereas the endothelium-independent relaxations to sodium nitroprusside were similar in both strains. Semiquantitative scoring of ED-1 positive cells showed perivascular monocyte/macrophage infiltration in kidneys of GK rats. High sodium diet increased blood pressure in GK rats by 24 mm Hg, 24-hour albuminuria by 350 %, induced cardiac hypertrophy, and further impaired endothelium-dependent vascular relaxation (all variables p<0.05). Inflammatory cell response was also aggravated by high sodium diet. Chronic AT1 receptor blockade did not decrease blood pressure, but partially protected against albuminuria, inflammatory cell response, and endothelial dysfunction in salt-loaded GK rats. Our findings indicate that hypertension in diabetic GK rats is salt-sensitive and associated with endothelial dysfunction and perivascular inflammation.