title: Inhibition of nitric oxide synthesis accentuates blood pressure elevation in hyperinsulinemic rats.
abstract: OBJECTIVE
  To examine the role of endogenous nitric oxide (NO) in the pathogenesis of hypertension and insulin resistance in chronic hyperinsulinemic rats.
  
  
  METHODS
  Sustained hyperinsulinemia was achieved by insulin infusion (21.5 pmol/kg per min) via subcutaneous osmotic minipump for 6 weeks. NO synthase inhibitor, Nomega-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 electrosphygmomanometer before and after drug treatments.
  
  
  RESULTS
  Insulin infusion alone significantly increased SBP from 134 +/- 3 to 156 +/- 2 mmHg by week 4 and further to 158 +/- 3 mmHg by week 6 of insulin infusion. The insulin-infused rats had markedly decreased insulin sensitivity, as reflected by an elevated steady-state plasma glucose level estimated by the insulin suppression test. There were no significant differences in plasma glucose and triglyceride levels between rats with and without insulin infusion. When hypertension had been established in rats receiving insulin infusion for 4 weeks, superimposed L-NAME on insulin infusion for additional 2 weeks further increased SBP by 18 +/- 2 mmHg (from 157 +/- 2 to 175 +/- 2 mmHg). Plasma levels of NO metabolites (NOx) significantly decreased from 13.7 +/- 1.1 micromol/l during the control period to 6.1 +/- 0.6 micromol/l after 4 weeks of insulin infusion and further reduced to 4.1 +/- 0.5 micromol/l after combined infusion of L-NAME and insulin. L-NAME treatment alone for 2 weeks in control rats significantly increased SBP by 33 +/- 2 mmHg (from 133 +/- 2 to 166 +/- 2 mmHg) and plasma insulin levels, as a consequence of insulin resistance. Despite marked increases in blood pressure due to infusion of insulin alone or in combination with L-NAME, the sodium balance, urinary sodium and water excretions, water intake and body weight gain of insulin/L-NAME-treated rats were not significantly different from rats without insulin infusion.
  
  
  CONCLUSIONS
  Sustained hyperinsulinemia causes partial impairment of NO production that may contribute to the development of insulin resistance and hypertension. Additional inhibition of NO synthesis by L-NAME accentuates the blood pressure elevation and insulin resistance in hyperinsulinemic rats. Furthermore, a rightward shift of the renal arterial pressure-natriuretic function relationship occurred in this hypertensive model.
authors.affiliation: Department of Internal Medicine, Tzu Chi General Hospital, Hualien, Taiwan, Republic of China.
authors.forename: T C
authors.initials: TC
authors.lastname: Fang
authors.forename: C C
authors.initials: CC
authors.lastname: Wu
authors.forename: W C
authors.initials: WC
authors.lastname: Huang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006946:Hyperinsulinism / Q000150:complications / Q000503:physiopathology*; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009318:Natriuresis; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester