L-Arginine Prevents and Reverses the Hypertension Produced by Combining Chronic Hyperinsulinemia and Subpressor Inhibition of Nitric Oxide Synthase.
Previously we found that chronic hyperinsulinemia does not cause hypertension without sugar supplementation. An explanation may be insulin’s nitric oxide (NO) mediated vasodilation. To test this hypothesis we studied 4 groups of rats: INS (n=9) treated by a gradual increase of a subcutaneous insulin pellet; LNM (n=9) treated by L-NAME, 50mg/l in drinking water; INM (n=19) treated by the combination of insulin+L-NAME; and controls(CON)(n=9). Systolic blood pressure (SBP), was (mean±SD) by week 3, 122±17, 118±17, 118±24 mmHg in the CON, LNM, INS and 136±14 mmHg in the INM p≤0.03. By week 6, SBP was 128±14, 127±15, 118±13 mmHg in CON, LNM, INS and, 150±14 mmHg in the INM respectively p≤0.0005. Body weight was not affected. Excretion of urinary NO metabolites (NOx) (μmol/24h) was 21.6±2.5, and 24.3±2.9, in CON and INS, ,and 13.9±1.2, and 16.6±1.7 p≤0.05, in INS, and LNM respectively. Insulin levels were doubled 534±66, and 654±60pmol/l in INS and INM, vs 270±18, and 264±50 pmol/l in CON, and LNM by week 6. There was no hypoglycemia and fructosamine levels were comparable. Urinary norepinephrine (nmol/24h) was lower in LNM 5.8±1.8 vs CON 8.8±1.3, p≤0.05. In a subsequent experiment rats treated by both insulin+L-NAME as above received L-arginine 2g/l in drinking water, either from day 1 INMARG (n=12), or from day 30 INMAR30 (n=9), INM (n=4) and L-arginine ARG(n=4) served as controls. By week 4, SBP was 156±12, and 160±10 mmHg in INM and INMARG30 vs 126±26, and 132±18mmHg in ARG and INMARG p≤0.03. By week 8 SBP was 165±15 in INM, and 141±10, 116±24, 132±13 mmHg in INMARG, ARG, and INMARG30 respectively,p≤0.005. Urinary NOx(μmol/24h) were higher in ARG, and INMARG 23.7±3.7, and 19.2±3.8, p≤0.005 vs 14.5±6.5, and 13.2±5.2 in INM and INMARG30 respectively. Urinary norepinephrine was not affected. In both experiments food and water intake, urine volume, creatinine clearance and urinary Na+ excretion were also not affected.In conclusion whereas hyperinsulinemia does not cause hypertension it does so when endothelial function is compromised. This effect reflects action of NOS as it is reversible and preventable with L-arginine.