Inhibition of nitric oxide synthesis accentuates blood pressure elevation in hyperinsulinemic rats

Objectives To examine the role of endogenous nitric oxide (NO) in the patho genesis of hypertension and insulin resistance in chronic hyperinsulinemic rats. Methods Sustained hyperinsulinemia was achieved by insulin infusion (21.5 p mol/kg per min) via subcutaneous osmotic minipump for 6 weeks, NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg per day) was given orally after 4 weeks of vehicle or insulin infusion. The systolic blood pressure (SBP) was measured under conscious state by an electrosphyg momanometer before and after drug treatments. Results Insulin infusion alone significantly increased SEP from 134 +/- 3 t o 156 +/- 2 mmHg by week 4 and further to 158 +/- 3 mmHg by week 6 of insul in infusion. The insulin-infused rats had markedly decreased insulin sensit ivity, as reflected by an elevated steady-state plasma glucose level estima ted by the insulin suppression test. There were no significant differences in plasma glucose and triglyceride levels between rats with and without ins ulin infusion. When hypertension had been established in rats receiving ins ulin infusion for 4 weeks, superimposed L-NAME on insulin infusion for addi tional 2 weeks further increased SEP by 18 +/- 2 mmHg (from 157 +/- 2 to 17 5 +/- 2 mmHg), Plasma levels of NO metabolites (NOx) significantly decrease d from 13.7 +/- 1.1 mu mol/l during the control period to 6.1 +/- 0.6 mu mo l/l after 4 weeks of insulin infusion and further reduced to 4.1 +/- 0.5 mu mol/l after combined infusion of L-NAME and insulin. L-NAME treatment alon e for 2 weeks in control rats significantly increased SEP by 33 +/- 2 mmHg (from 133 +/- 2 to 166 +/- 2 mmHg) and plasma insulin levels, as a conseque nce of insulin resistance. Despite marked increases in blood pressure due t o infusion of insulin alone or in combination with L-NAME, the sodium balan ce, urinary sodium and water excretions, water intake and body weight gain of insulin/L-NAME-treated rats were not significantly different from rats w ithout insulin infusion. Conclusions Sustained hyperinsulinemia causes partial impairment of NO prod uction that may contribute to the development of insulin resistance and hyp ertension. Additional inhibition of NO synthesis by L-NAME accentuates the blood pressure elevation and insulin resistance in hyperinsulinemic rats. F urthermore, a rightward shift of the renal arterial pressure-natriuretic fu nction relationship occurred in this hypertensive model. (C) 2001 Lippincot t Williams & Wilkins.