Question

Furosemide: Relative to normal, what would happen if the drug furosemide inhibits Na^+/K⁺ and Na^+/Cl^- symport channels in the thick segment of the ascending limb of the nephron tubule? Explain your reasoning for each.

1. What would happen to water loss from the descending limb? Why.

2. What would happen to the osmolarity of the filtrate inside the bottom of the nephron loop? Why?

3. What would happen to the loss of salt (NaCl) from the thin segment of the ascending limb. Why?

Answer 1

Normal physiology and mechanism of Furosemide:

Loop diuretics (e.g. furosemide) act on the loop of Henle to reabsorb Na+ and water to the blood. In thick ascending limb, Na+, K+ and Cl- ions are actively transported from the filtrate into the cell by the membrane co-transporter protein Na+/K+/2Cl- pump and then to the interstitial fluid by Na+/K+ symporter and Na+/Cl- symporter. Hence in the descending limb, the water molecules diffuses out from the low solute concentration region to the higher solute concentration region of interstitial fluid. This makes the filtrate more concentrated as it moves down the descending limb. It becomes less concentrated as it moves to the ascending limb. Since Na+, K+ and Cl- are left from the ascending limb to the interstitial fluid. the overall effect is reabsorption of the Na+.-,K+, Cl- and water molecules into the blood. This is known as counter current mechanism.

Furosemide act on the thick ascending limb by blocking the co-transporter Na+/K+/2Cl- protein on the thick ascending limb of the loop of Henle. So, it prevents the Na+ to be pumped from the filtrate into the interstitial fluid of medulla of kidney. Hence water is not drawn out of the descending limb and remains in the filtrate. The overall effect is more Na+, K+ ,Cl- and water are still remains in the filtrate and excreted out in the urine. So the urine output is significantly increased and consequently blood pressure decreases.

In this case furosemide act on Na+/K+ symport cannel and Na+/Cl- symport channel. Since the Na+/K+/2Cl- co-Transporter channel on the lumen side of the cell is not blocked, those ions will be actively transported into the cell. But, since the Na+/K+ symport cannels and Na+/Cl- symport channels are blocked, there won't be pumping out of these ions into the interstitial space. Those ions will remain inside the cell itself. Consequently the concentration of these ions will be reduced in the ascending limb when compared to the interstitial space interstitial space. i.e. the thick ascending limb lumen will be hypotonic. Consequently medullary interstitial space of the loop of Henle won't be hypertonic. Hence diffusion of water molecules into interstitial space will not occur in the descending loop.

Since the ion concentration of interstitial space is lesser than that of the filtrate in the descending limb, there will be movement of water molecules from in the reverse order. i.e. from the interstitial space to the descending limb. Hence filtrate become more diluted as it comes down. i.e. osmolarity decreases down,

The osmolarity of the filtrate in the descending loop will be least at  base of the loop. Because of water movement from the interstitial space into the lumen along the concentration gradient.

Normally the thin ascending limb is impermeable to water; It is permeable to ions allowing for some Na+ reabsorption. Na/K-ATPase is expressed at very low levels in this segment. This this reabsorption is likely through passive diffusion. Salt moves out of the tubule and into the interstitial space due to osmotic pressure created by the countercurrent system. Since the counter current system is impaired here, there won't be salt excretion to interstitial space occurring in the thin ascending limb.