Effect of reduction of nitric oxide on plasma and kidney tissue angiotensin II levels.

Nitric oxide synthase (NOS) blockade increases blood pressure (BP) and modifies glomerular and tubular function. Angiotensin II (AII) blockade restores glomerular and tubular function but does not lower BP. We measured plasma renin activity (PRA), plasma (AIIp), and kidney tissue (AIIk) AII with radioimmunoassay to investigate the dissociation between renal and systemic effects of NOS blockade. Two period clearance studies followed by plasma and renal tissue harvesting were performed in seven groups of rats. Groups 1 and 1A served as controls. Groups 2 and 2A received NaCl-NaHCO3 during the first period and N(G)-monomethyl-L-arginine (L-NMMA, 0.5 mg/kg/min) during the second period. Group 3 was similar to group 2 but renal perfusion pressure (RPP) was maintained constant by using an aortic snare. Groups 4 and 4A received N(G)-nitro-L-arginine-methyl ester (L-NAME, 5 mg/100 mL of drinking water) for 2 weeks. NOS blockers decreased AIIp (group 1, 74 +/- 7 pg/mL; group 2, 22 +/- 1 pg/mL; group 3, 26 +/- 1 pg/mL; group 4, 19 +/- 3 pg/mL). The decrease in AIIp was a direct effect of L-NMMA independent of changes in perfusion pressure, as AIIp was similar in group 3 (normal RPP) and groups 2 and 4 (increased RPP). Measurements of PRA and AIIp demonstrated a similar reduction in PRA and AIIp in rats treated with NOS blocker. Although NOS blockers decreased AIIp, acute or chronic administration of NOS blockers did not modify AIIk (group 1, 1,192 +/- 51; group 2, 1,354 +/- 85; group 3, 1,348 +/- 180; group 4, 1,276 +/- 172 pg/kidney). Our findings demonstrate that NO blockers produce a dissociation between plasma and kidney AII levels. This dissociation can explain the beneficial effects of AII blockers on renal function and their lack of antihypertensive effects in anesthetized rats treated with NOS blockers.

Effect of chronic salt loading on kidney function in early and established diabetes mellitus in rats.

Glomerular hyperfiltration and renal hypertrophy are among the events that characterize the early course of diabetes mellitus in rats and human patients. Previous studies from this laboratory demonstrated that salt restriction paradoxically reduces total renal vascular resistance (RVR) and increases glomerular filtration rate (GFR) in diabetic rats (J Am Soc Nephrol 1995;5:1761-7). In the present study we examined the converse condition by testing the effects of chronic salt loading on kidney function in moderately hyperglycemic insulin-treated rats with early and established streptozotocin diabetes. Salt loading was accomplished by adding 1% NaCl to the drinking water 1 day or 35 days after diabetes was induced. The high-salt diet appropriately increased salt excretion in diabetic rats and nondiabetic controls. GFR and renal plasma flow were determined by inulin and para-amino hippuric acid (PAH) clearance 7 days after salt loading was started. Diabetic rats receiving tap water exhibited hyperfiltration with no change in renal blood flow (RBF). In nondiabetic rats, salt loading caused a reduction in total RVR and proportional increases in RBF, GFR, and kidney weight (KW). Salt loading in early diabetes did not affect RVR, RBF, or KW and caused a paradoxical reduction in GFR. In established diabetes, salt loading reduced RVR and increased RBF, similar to results in nondiabetic rats, but as in rats with early diabetes, it did not increase GFR or KW. In summary, although the response in RVR and RBF to chronic salt loading depends on the duration of diabetes, the increase in GFR and KW as seen in nondiabetic rats is blunted in the early and established state of insulin-treated diabetes in rats. These findings further support the notion that the renal response to variation in salt intake is altered in insulin-treated diabetes in rats.

Effect of angiotensin II on the renal response to amino acid in rats.

Administration of the nitric oxide (NO) synthase blocker, N(G)-monomethyl L-arginine prevents the increase in glomerular filtration rate (GFR) normally observed with glycine, an effect that is restored by angiotensin II (AII) blockers. These findings suggest that changes in NO and AII dictate the presence or absence of renal vasodilation during amino acid (AA) infusion. We examined the effect of branched-chain (BCAA) and non-branched-chain (NBCAA) AA on GFR, NO, and AII to determine if abnormal NO or AII responses could explain the absence of vasodilation with BCAA. Our findings demonstrated that NBCAA increased GFR and NO and did not modify AII, either plasma (AIIp) or kidney (AIIk) AII. The response with BCAA was strikingly different. L-Valine increased GFR without modifying NO or AII. L-Leucine increased AIIk and NO but did not increase GFR. Administration of AII blockers (captopril or losartan) was associated with an increase in GFR during infusion of leucine. Single nephron studies demonstrated that increased AIIk with L-leucine was associated with decreased absolute proximal reabsorption and probably activation of the tubuloglomerular feedback. An AA-specific increase in AIIk is critical to inhibition of the normal renal response to AA infusion. NO generation is an important mediator but not the sole mechanism that determines the increase in GFR during amino acid infusion.

Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: effect of sodium and salt restriction.

Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats, the effect of a low-sodium (LNa) and a low-salt (LNaCl) diet on renal function and on plasma and kidney tissue angiotensin II (AIIp, AIIk) was tested. Clearance experiments were performed in anesthetized rats 7 days after starting on LNa or LNaCl. On a control diet, STZ exhibited an increase in GFR, RBF, and kidney weight (KW) and a reduction in renal vascular resistance (RVR) and AIIk, but no change in AIIp, compared with nondiabetic normal rats (CON). Although sodium restriction reduced and salt restriction increased AIIk in CON, both diets increased AIIp without affecting renal hemodynamics or KW. In diabetic rats, both salt and sodium restriction further increased GFR and RBF by reducing RVR, increased KW, and changed AIIk and AIIp in a similar pattern, but at significantly lower values compared with CON. Daily treatment of STZ-LNa with the AII-receptor blocker losartan (20 mg/L, in drinking water) did not affect the reduction in RVR and the increase in KW but slightly reduced RBF because of a decrease in mean arterial blood pressure and further increased GFR. It was concluded that (1) AIIk but not AIIp is affected differently by LNa compared with LNaCl in both CON and STZ; (2) LNaCl and LNa change AIIp and AIIk in a similar pattern but at significant lower values in STZ compared with CON; and (3) with regard to renal hemodynamics and KW, the response to LNa and LNaCl is different in CON compared with rats 6 wk after the onset of diabetes mellitus, the latter exhibiting a further increase in renal hyperfiltration and KW by a mechanism that is not directly AII receptor dependent.

Arginine feeding modifies cyclosporine nephrotoxicity in rats.

Glycine (G) infusion causes renal vasodilation mediated by nitric oxide (NO). Cyclosporine A (CsA) nephrotoxicity is characterized by preglomerular vasoconstriction and decreased efferent arteriolar tone probably related to reduced NO and angiotensin II, respectively. L-Arginine (ARG) is a precursor to NO. To test the hypothesis that chronic CsA decreases renal NO activity, we compared the glomerular hemodynamic response to glycine infusion in rats after 8 d of CsA (30 mg/kg per d s.c.), CsA and ARG (1.6 g/kg per d p.o.) (A/CsA), and in two groups of pair-fed controls (CON, A/CON). Single nephron GFR (SNGFR), single nephron plasma flow (SNPF), glomerular capillary hydrostatic pressure gradient (delta P), proximal tubular reabsorption (APR), and kidney tissue angiotensin II (AIIk) were measured before and during G. CsA was associated with baseline decrements in SNGFR, SNPF, delta P, and AIIk, and with a blunted hemodynamic response to G. In CON, ARG did not affect baseline hemodynamics or modify the response to G. In CsA, ARG decreased baseline preglomerular resistance and restored the glomerular hemodynamic response to G. G was associated with a significant increase in AIIk in both CON and CsA. These findings suggest that (a) CsA is associated with decreased AIIk, and (b) CsA may diminish NO activity within the kidney, and that this capacity may be partially restored by arginine feeding.