Volume expansion during NOS substrate donation with l-arginine: regulatory offsetting of renal response?

Abstract

Ϫ1 ⅐ min Ϫ1 ) and to slow volume expansion (saline 35 ml/kg for 90 min) alone and in combination were investigated in separate experiments. L-Arginine left blood pressure and plasma ANG II unaffected but decreased heart rate (6 Ϯ 2 beats/min) and urine osmolality, increased glomerular filtration rate (GFR) transiently, and caused sustained increases in sodium excretion (fourfold) and urine flow (0.2 Ϯ 0.0 to 0.7 Ϯ 0.1 ml/min). Volume expansion increased arterial blood pressure (102 Ϯ 3 to 114 Ϯ 3 mmHg), elevated GFR persistently by 24%, and enhanced sodium excretion to a peak of 251 Ϯ 31 mol/min, together with marked increases in urine flow, osmolar and free water clearances, whereas plasma ANG II decreased (8.1 Ϯ 1.7 to 1.6 Ϯ 0.3 pg/ml). Combined volume expansion and L-arginine infusion tended to increase arterial blood pressure and increased GFR by 31%, whereas peak sodium excretion was enhanced to 335 Ϯ 23 mol/min at plasma ANG II levels of 3.0 Ϯ 1.1 pg/ml; urine flow and osmolar clearance were increased at constant free water clearance. In conclusion, L-arginine 1) increases sodium excretion, 2) decreases basal urine osmolality, 3) exaggerates the natriuretic response to volume expansion by an average of 50% without persistent changes in GFR, and 4) abolishes the increase in free water clearance normally occurring during volume expansion. Thus L-arginine is a natriuretic substance compatible with a role of nitric oxide in sodium homeostasis, possibly by offsetting/shifting the renal response to sodium excess. sodium excretion; free water clearance; angiotensin PHYSICAL, NEURAL, AND HUMORAL mechanisms are involved in the control of renal sodium excretion. However, the relative influence of each of the components is still controversial, and the evaluation of the importance of the renin-angiotensin system vs. the role of nitric oxide (NO) in renal sodium homeostasis is particularly complex. The natriuretic effect of volume expansion is linked to a decrease in plasma levels of ANG II (e.g., 2, 5), and an intact NO synthesis is also a prerequisite for volume expansion natriuresis (e.g., 3). However, the relative importance and possible interaction between the two systems are poorly elucidated.NO is a potent renal vasodilator and natriuretic substance synthesized in the kidney (14,15,27,31,33,36). It has been shown that acute and chronic elevations in extracellular fluid volume lead to increased NO synthesis (9,16,26,29). Conversion of L-arginine into the vasorelaxant NO takes place in endothelial cells in response to a variety of stimuli by the enzyme NO synthase (NOS). In a recent study in dogs (3), we blocked the NOS unspecifically using the structural analog N G -nitro-L-arginine methyl ester (L-NAME) and demonstrated that this NOS inhibition is followed by increases in plasma ANG II, renal hypofiltration, and severe antinatriuresis that may be no more than returned to control levels by a sizeable volume expansion (3.5% body wt). Thus NOS inhibition virtually abolishes the volume expansion natriuresis, and thi...

Mechanisms of acute natriuresis in normal humans on low sodium diet

“…However, we recently demonstrated in conscious dogs that NOS inhibition effectively decreases the natriuresis in response to acute volume expansion and attenuates (> 85 %) the volume expansion induced by natriuresis observed during ANGII receptor blockade (Andersen et al 2002 a ). In agreement with these observations, NOS substrate donation was found to exaggerate the response to an identical volume expansion (Andersen et al 2002 b ). To our knowledge, data still do not exist on the influence of NOS inhibition or of an increased vascular NO release or vascular NOS expression during sodium loading in humans.…”

Body sodium and volume homeostasis

“…With a combination of NO synthase inhibition and AT 1 blockade, volume expansion induced only a very modest natriuresis. Consistent with these results, infusion of L-arginine as a substrate for NO synthase exaggerates the natriuretic response to volume expansion and counteracts the effect of NO synthase inhibition (2,3,25). These results indicate that NO synthase inhibition abolishes the natriuresis after volume expansion, in part by preventing the suppression of the renin-angiotensin-aldosterone system and show that the NO system plays a dominant role in the hierarchy of control systems that control salt excretion.…”

“…The interplay between the NO system and ANG II in the control of salt excretion during volume expansion in conscious dogs has been investigated in several studies (2,3,25). NO synthase inhibition increased plasma renin and ANG II concentrations and largely abolished natriuresis after volume expansion, whereas acute AT 1 blockade exaggerated the natriuresis.…”

Renal cortical and medullary blood flow during modest saline loading in humans

“…Adequate synthesis of NO seems to be a prerequisite for normal excretion of a sodium load (Andersen et al . ,b), but this mechanism is also difficult to place in a homeostatic context because stabilization of the availability of NO exaggerates rather than inhibits the response to sodium loading in normal man (Simonsen et al . ).…”