Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron

Abstract

Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (−7.9 ± 0.2 mmHg) was blocked by furosemide (−0.4 ± 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: −0.2 ± 0.1 vs. furosemide+benzamil: −4.3 ± 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 ± 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: −1.1 ± 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors.

Tubule-vascular feedback in renal autoregulation

“…2B) (38). We confirmed this in a later study using a more specific ENaC inhibitor, benzamil (51). These studies indicate that there is cross talk between CNTs and Af-Arts and that the presence of high NaCl levels induces Af-Art vasodilation by activating ENaCs.…”

How Do Antihypertensive Drugs Work? Insights from Studies of the Renal Regulation of Arterial Blood Pressure

“…The observation that the chronic action of diuretics is primarily as afferent arteriolar dilators (Table 4 , Figure 3 ) is perhaps most surprising of all, given that their main associations are with tubular sodium uptake mechanisms. Relevant here may be the known inhibition of macular densa cell function in the tubulo-arteriolar (also known as tubulo-glomerular) feedback mechanism by furosemide (Schnermann, 2003 ; Orlov and Mongin, 2007 ) and the recent elucidation of a more distal tubulo-arteriolar feedback mechanism that can be affected by inhibitors of the epithelial sodium channel (ENaC), such as amiloride (Ren et al, 2013 ; Wang et al, 2015 ). If the main long-term action of diuretics were via their inhibition of tubulo-arteriolar feedback, we would anticipate that the effect would depend upon sodium flux, with greater dilatation being evident at higher levels of urinary sodium excretion rate.…”

Trimethoprim-sulfamethoxazole-induced hyponatremia in an elderly lady with Achromobacter xylosoxidans pneumonia

“…Dynamic effects of sympathetic nerves and circulating mediators on renal blood flow [ 51 – 53 ] may convergently modify proximal convoluted tubular reabsorption of sodium [ 54 ] and prove culprit in drug-induced hyponatremia. Sympathetic nerve fibers innervate vascular smooth muscle cells of renal arteries and arterioles and renin-secreting cells of the juxtaglomerular apparatus.…”