Nitric Oxide Synthase Inhibition in a Spontaneously Hypertensive Rat Model of Diabetic Nephropathy

Abstract

1. To investigate the role of nitric oxide (NO) in diabetic nephropathy the effect of nitric oxide synthase (NOS) inhibition by NG-nitro-L-arginine methyl ester (L-NAME) was observed in a streptozotocin diabetic spontaneously hypertensive rat (SHR) model. 2. Two groups of SHR (n = 8) with streptozotocin-induced diabetes were studied. One group was given L-NAME 5 mg/kg bodyweight per day in the drinking water for 8 weeks while both groups received daily subcutaneous injections of Ultratard insulin. Creatinine clearance, urinary protein excretion, urinary nitrate concentration and systolic blood pressure were measured at fortnightly intervals. Rats were killed at 8 weeks and plasma angiotensin II (AngII) was measured by radioimmunoassay. 3. Renal function (endogenous creatinine clearance) remained stable in both groups. In the L-NAME group, however, there was a progressive increase in proteinuria that was highly significant at 6 weeks (22.1 +/- 2.9 compared with 6.5 +/- 0.7 mg/ 24 h per 100 g in control SHR diabetic rats P < 0.001). 4. Systolic blood pressure was significantly elevated in the L-NAME group throughout the study compared with the control group. 5. Plasma AngII was significantly elevated in the L-NAME group compared with controls (42.8 +/- 10.3 vs 15.1 +/- 1.9 pmol/L, respectively; P < 0.05). 6. Activation of the renin-angiotensin system may account, at least in part, for the resulting vasoconstrictor activity with chronic nitric oxide depletion.

Risk factors for renal failure: The WHO multinational study of vascular disease in diabetes

“…Alternatively it is possible that the association between triglycerides and renal failure could have arisen because higher triglycerides are associated with higher concentrations of non-esterified fatty acids (NEFA). Non-esterified fatty acids have been shown to impair endothelial function, probably by inhibiting nitric oxide production [41,42] and decreased nitric oxide production is associated with the development of diabetic nephropathy in diabetic spontaneously hypertensive rats [43]. Thus it is possible to speculate that high triglycerides could be a marker of impaired nitric oxide production with consequent renal damage.…”

Aldosterone Antagonism Ameliorates Proteinuria and Nephrosclerosis Independent of Glomerular Dynamics in <i>L</i>-NAME/SHR Model

“…Prolonged nitric oxide synthase inhibition has been demonstrated to activate both the systemic and local renal renin-angiotensin systems [4, 5, 6, 7, 8], which may be the major pathogenic mechanism of L -NAME-induced renal damage. Our previous studies demonstrated that ACE inhibitors or AT1 receptor antagonists produced dramatic renal protective effects by inhibiting local renal angiotensin II generation or by antagonizing its effect on the renal AT1 receptor sites [9, 10, 11].…”

“…Moreover, prolonged nitric oxide synthase inhibition has been shown to activate both the systemic and local renal renin-angiotensin systems [4, 5, 6, 7, 8]. Previous studies from our laboratory have shown that angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT1) receptor antagonists confer dramatic pathophysiological renoprotection through inhibition of local renal angiotensin II generation or by antagonizing its effect on the renal AT1 receptor sites in the experimental model of SHR with 3-week L -NAME treatment [9, 10, 11].…”

Differential Effects of Antihypertensive Drugs on Renal and Glomerular Hemodynamics and Injury in the Chronic Nitric-Oxide-Suppressed Rat

“…Therefore, existing data suggest that aldosterone plays a deleterious role in the progression of L- NAME-induced SHR nephrosclerosis, although angiotensin II may be considered as an essential determinant of inducing the advanced hemodynamic consequences such as systemic and glomerular hypertension as well as renal damage during chronic NOS inhibition [10,11,12,13]. Eplerenone, the selective mineralocorticoid receptor antagonist, has afforded favorable renal actions in the experimental model of chronic NOS inhibition.…”

“…It plays a critical role in regulating endothelial function [4, 5], systemic, renal and coronary hemodynamics [4,5,6], platelet adhesion and aggregation [7], cardiomyocyte hypertrophy [8] and vascular smooth muscle cell proliferation and fibrosis [9]. Chronic NOS inhibition with N ω -nitro- L -arginine methylester ( L- NAME) has been shown to activate both the systemic and local renal renin-angiotensin systems [10,11,12,13] and to increase sympathetic nerve activity [11, 14], thereby promoting persistent hypertension through cardiovascular and renal damage. In normotensive rats, prolonged NOS inhibition results in sustained systemic and glomerular hypertension with proteinuria and focal glomerular sclerosis [15], marked renal vasoconstriction, arteriolar hypertrophy and focal arteriolar obliteration, and renal interstitial inflammatory responses [16].…”