Impact of nitric oxide-mediated vasodilation on outer medullary NaCl transport and oxygenation

Abstract

The present study aimed to elucidate the reciprocal interactions between oxygen (O(2)), nitric oxide (NO), and superoxide (O(2)(-)) and their effects on vascular and tubular function in the outer medulla. We expanded our region-based model of transport in the rat outer medulla (Edwards A, Layton AT. Am J Physiol Renal Physiol 301: F979-F996, 2011) to incorporate the effects of NO on descending vasa recta (DVR) diameter and blood flow. Our model predicts that the segregation of long DVR in the center of vascular bundles, away from tubular segments, gives rise to large radial NO concentration gradients that in turn result in differential regulation of vasoactivity in short and long DVR. The relative isolation of long DVR shields them from changes in the rate of NaCl reabsorption, and hence from changes in O(2) requirements, by medullary thick ascending limbs (mTALs), thereby preserving O(2) delivery to the inner medulla. The model also predicts that O(2)(-) can sufficiently decrease the bioavailability of NO in the interbundle region to affect the diameter of short DVR, suggesting that the experimentally observed effects of O(2)(-) on medullary blood flow may be at least partly mediated by NO. In addition, our results indicate that the tubulovascular cross talk of NO, that is, the diffusion of NO produced by mTAL epithelia toward adjacent DVR, helps to maintain blood flow and O(2) supply to the interbundle region even under basal conditions. NO also acts to preserve local O(2) availability by inhibiting the rate of active Na(+) transport, thereby reducing the O(2) requirements of mTALs. The dual regulation by NO of oxygen supply and demand is predicted to significantly attenuate the hypoxic effects of angiotensin II.

Fig. 1.

Postulated dependence of descending vasa recta (DVR) radius on nitric oxide (NO) concentration (C_NO) in DVR plasma, as described by Eq. 1. The radius of the vessel cannot fall below that of a single erythrocyte (∼4 μm).

Fig. 2.

Flow and pressure profiles in long DVR (LDV) and in the short DVR (SDV) that reach the outer-inner medullary junction, for scenario A. Results are similar for both scenarios. x: Position along the corticomedullary axis; x/L = 0 at the corticomedullary junction, and x/L = 1 at the outer-inner medullary junction. A: vessel radius. The radius is a function of luminal NO concentration (Eq. 1). B: blood flow rate. Blood flow variations along the corticomedullary axis are determined based upon the rate of water reabsorption. C: luminal pressure, calculated using the Poiseuille equation (Eq. 2). The pressure gradient is steeper in SDV than in LDV, because it is inversely proportional to the 4th power of the vessel radius.

Fig. 3.

Baseline concentration profiles for scenario A (vasoactive case). A: luminal Na⁺ concentrations (C_Na) in long (LAL) and short (SAL) ascending limbs. B: Po₂ in the interstitium of the 4 concentric regions (R1–R4). R1 corresponds to the center of the vascular bundle, and R4 is the outward-most region. C: NO concentrations (C_NO) in the interstitium of R1–R4. D: O₂⁻ concentrations (C_O2−) in the interstitium of R1–R4.

Fig. 4.

Baseline concentration profiles for scenario B (vasoactive case). A: luminal C_Na in LAL and SAL. B: interstitial Po₂ in R1–R4. C: interstitial C_NO in R1–R4. D: interstitial C_O2− in R1–R4.

Fig. 5.

Predicted rates of O₂ supply, O₂ consumption, and medullary thick ascending limb of Henle's loop (mTAL) NaCl reabsorption, in pmol·s⁻¹·vascular bundle⁻¹, for scenario A. Results are shown for different cases: baseline conditions (“basal”), in the absence of reaction between NO and O₂⁻ (“no rxn”), when the rate of NO synthesis by tubular epithelia (G_NO^ep) is 0, 2, or 5 times its baseline value (NO × 0, 2, or 5) , and/or when the rate of O₂⁻ synthesis by tubular epithelia (G_O2−^ep) is twice its baseline value (O₂⁻ × 2). Black bars, “vasoactive case”; grey bars, “fixed R case.”

Fig. 6.

Predicted rates of O₂ supply, O₂ consumption, and mTAL NaCl reabsorption, in pmol·s⁻¹·vascular bundle⁻¹, for scenario B. Results are shown for different cases: baseline conditions (basal), in the absence of reaction between NO and O₂⁻ (no rxn), when G_NO^ep is 0, 2, or 5 times its baseline value (NO × 0, 2, or 5) , and/or when G_O2−^ep is twice its baseline value (O₂⁻ × 2). Black bars, vasoactive case; grey bars, fixed R case.

Fig. 7.

Impact of the NO-O₂⁻ reaction on concentration profiles (scenario B, vasoactive case). Results are shown for the base case (basal) and assuming that the NO-O₂⁻ reaction rate is zero (no rxn). A: luminal C_Na in LAL and SAL. B: interstitial Po₂ in regions R2 and R4. C: interstitial C_NO in R2 and R4. D: interstitial C_O2- in R2 and R4. In the interbundle region, inhibition of the NO-O₂⁻ reaction has a larger impact on C_NO than on C_O2−. The subsequent increase in O₂ supply is accompanied by a significant decrease in the rate of NaCl reabsorption across LAL and SAL, and in the rate of O₂ consumption.

Fig. 8.

Impact of NO synthesis by tubular epithelia on Po₂ and C_NO in region R3, where most mTALs are located. Results are shown for scenario A. The rate of NO synthesis by tubular epithelia is either equal to its baseline value (basal), multiplied by 2 (G × 2), or 0 (G = 0). A and B: Po₂ and C_NO in the R3 interstitium, accounting for vasoactivity of DVR. C and D: Po₂ and C_NO in the R3 interstitium, assuming no vasoactivity of DVR. Results suggest that NO tubulovascular cross talk has a significant impact on O₂ balance in the outer medulla.

Fig. 9.

Impact of epithelial production of O₂⁻ (G_O2−^ep) and NO (G_NO^ep) on Po₂ and C_NO in region R3. Results are shown for scenario A. Basal denotes baseline profiles. In case 1, G_O2−^ep is multiplied by 2 (relative to its baseline value); in case 2, G_O2−^ep and G_NO^ep are both multiplied by 2. In case 3, G_O2−^ep is multiplied by 2, and G_NO^ep by 5. A and B: Po₂ and C_NO in the R3 interstitium, accounting for vasoactivity of DVR. C and D: Po₂ and C_NO in the R3 interstitium, assuming no vasoactivity of DVR. Results suggest that ANG II-induced stimulation of NO synthesis by mTAL counteracts the effects of oxidative stress.