Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet

Abstract

Activation of renal mechanosensory nerves is enhanced by high and suppressed by low sodium dietary intake. Afferent renal denervation results in salt-sensitive hypertension, suggesting that activation of the afferent renal nerves contributes to water and sodium balance. Another model of salt-sensitive hypertension is the endothelin B receptor (ETBR)-deficient rat. ET and its receptors are present in sensory nerves. Therefore, we examined whether ET receptor blockade altered the responsiveness of the renal sensory nerves. In anesthetized rats fed high-sodium diet, renal pelvic administration of the ETBR antagonist BQ-788 reduced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mmHg from 26+/-3 to 9+/-3% and the PGE2-mediated renal pelvic release of substance P from 9+/-1 to 3+/-1 pg/min. Conversely, in rats fed low-sodium diet, renal pelvic administration of the ETAR antagonist BQ-123 enhanced the ARNA response to increased renal pelvic pressure from 9+/-2 to 23+/-6% and the PGE2-mediated renal pelvic release of substance P from 0+/-0 to 6+/-1 pg/min. Adding the ETAR antagonist to ETBR-blocked renal pelvises restored the responsiveness of renal sensory nerves in rats fed a high-sodium diet. Adding the ETBR antagonist to ETAR-blocked pelvises suppressed the responsiveness of the renal sensory nerves in rats fed a low-sodium diet. In conclusion, activation of ETBR and ETAR contributes to the enhanced and suppressed responsiveness of renal sensory nerves in conditions of high- and low-sodium dietary intake, respectively. Impaired renorenal reflexes may contribute to the salt-sensitive hypertension in the ETBR-deficient rat.

Activation of Endothelin-A Receptors Contributes to Angiotensin-Induced Suppression of Renal Sensory Nerve Activation

“…Renal pelvic pressure was increased 7.5 mm Hg during the experimental periods. The renal pelvis was perfused with vehicle during the first part, losartan (0.44 mmol/L) 9 (nϭ10) or BQ123 (5 mol/L) 16 (nϭ8) during the second part and a mixture of losartan and BQ123 during the third part.…”

“…Whereas activation of ETB-R contributes to the enhanced responsiveness of the renal mechanosensory nerves in high-sodium diet, activation of ETA-R contributes to the impaired responsiveness of the renal mechanosensory nerves in low-sodium diet. 16 The similar effects of the Ang type I receptor (AT1-R) antagonist losartan and the ETA-R antagonist BQ123 18 to enhance the ARNA responses to increased renal pelvic pressure in vivo and the PGE 2 -mediated release of substance …”

“…16 ET-1 exerts its effects by activating 2 G protein-coupled receptors, ETA and ETB receptors (Rs). 17 Interestingly, the nature of effect of ET-1 on the renorenal reflexes depends on dietary sodium intake.…”

“…Whereas activation of ETB-R contributes to the enhanced responsiveness of the renal mechanosensory nerves in high-sodium diet, activation of ETA-R contributes to the impaired responsiveness of the renal mechanosensory nerves in low-sodium diet. 16 The similar effects of the Ang type I receptor (AT1-R) antagonist losartan and the ETA-R antagonist BQ123 18 to enhance the ARNA responses to increased renal pelvic pressure in vivo and the PGE 2 -mediated release of substance P from isolated renal pelvises in vitro in rats fed low-sodium diet 9,16 suggests an interaction between Ang II and ET-1 in the activation of renal mechanosensory nerves at the peripheral renal nerve endings. There is considerable evidence for such an interaction in the cardiovascular system.…”

“…31 Also, we have demonstrated the presence of both Ang II and ET-1 in the renal pelvic wall. 10,16 Because of the demonstrated interaction between Ang II and ET-1 in the cardiovascular system 20,22,24 -27 and the similar enhancements produced by the AT1-R and ETA-R antagonists of the responsiveness of renal mechanosensory nerves in rats on low-sodium diet, 9,16 we hypothesized that activation of ETA-R contributes to the Ang II-induced suppression of the renorenal reflexes. We tested this idea by comparing the effects of losartan and BQ123 alone and in combination on the activation of renal mechanosensory nerves in vivo and in vitro in rats fed low-sodium diet.…”