Volume expansion during acute angiotensin II receptor (AT₁) blockade and NOS inhibition in conscious dogs

Abstract

The responses to AT1-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) ) were investigated in separate experiments in normal dogs. AT1 blockade decreased arterial pressure (106 Ϯ 4 to 96 Ϯ 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 Ϯ 3 to 116 Ϯ 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1 blockade and NOS inhibition (21 Ϯ 4 mmHg). Volume expansion during AT 1 blockade elicited marked natriuresis (26 Ϯ 11 to 274 Ϯ 55 mol/min) that was severely reduced by concomitant NOS inhibition (10 Ϯ 3 to 45 Ϯ 11 mol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 Ϯ 1 to 23 Ϯ 7 mol/min). Volume expansion during AT 1 blockade increased GFR (ϩ30%), less so during combined AT1 blockade and NOS inhibition (ϩ13%), but it did not increase GFR significantly (P ϭ 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT 1 blockade and doubled with NOS inhibition (paired t-test, P Ͻ 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute AT 1 blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are Ͼ85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system. sodium excretion; blood pressure; glomerular filtration rate; N G -nitro-L-arginine methyl ester; candesartan THE CONTROL OF RENAL SODIUM excretion is multifactorial, involving physical, neural, and humoral mechanisms. However, the relative contributions of the individual components are still unclear, e.g., 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., 3, 32), and an intact NO synthesis is also a prerequisite for volume expansion natriuresis (21, 26). However, the relative importance and possible interaction between the two systems are poorly elucidated in conscious animals. We recently demonstrated (2) that a slow, moderate volume expansion in the absence of ANG II (due to converting enzyme inhibition) elicited a marked exaggeration of the natriuresis seen in control dogs, although blo...

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.…”

Efficacy and Tolerability of Candesartan Cilexetil and Amlodipine in Patients with Poorly Controlled Essential Hypertension

“…Amlodipine and candesartan cilexetil significantl crease in urine flow, renal sodium, chloride and potassium excretion. [16,17] The present study demonstrate that serum chloride in the amlodipine group was lower than that in the candesartan group and serum sodium at follow up was lower than that at baseline in the candesartan group. However, values of serum sodium and serum chloride were within the normal range.…”

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

“…The observation that NOS substrate donation alone did not change GFR is also compatible with the findings of Salazar's group (1,25,30), who showed repeatedly that blockade of NO synthesis did not induce changes in renal hemodynamics. Several groups including our own, however, reported that NOS inhibition results in a decrease in GFR (3,24,28). Thus the effects of NO on GFR are still unclear.…”

“…We previously showed that even modest increases in renal sodium excretion are preceded by and to a large extent regulated by a decrease in the level of activity of the renin system and that an intact NO system is required for this system to be fully operative (2,3). Neither our previous nor our present studies demonstrate definitively whether NO exerts a permissive effect on renal sodium handling, i.e., a certain activity is a necessary prerequisite for regulatory systems to be fully operative, or whether it works as a control system playing in concert with other control systems.…”