Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback

Abstract

This rat renal blood flow (RBF) study quantified the impact of nitric oxide synthase (NOS) inhibition on the myogenic response and the balance of autoregulatory mechanisms in the time domain following a 20 mmHg-step increase or decrease in renal arterial pressure (RAP). When RAP was increased, the myogenic component of renal vascular resistance (RVR) rapidly rose within the initial 7-10 s, exhibiting an ∼5 s time constant and providing ∼36% of perfect autoregulation. A secondary rise between 10 and 40 s brought RVR to 95% total autoregulatory efficiency, reflecting tubuloglomerular feedback (TGF) and possibly one or two additional mechanisms. The kinetics were similar after the RAP decrease. Inhibition of NOS (by L-NAME) increased RAP, enhanced the strength (79% autoregulation) and doubled the speed of the myogenic response, and promoted the emergence of RVR oscillations (∼0.2 Hz); the strength (52%) was lower at control RAP. An equi-pressor dose of angiotensin II had no effect on myogenic or total autoregulation. Inhibition of TGF (by furosemide) abolished the L-NAME effect on the myogenic response. RVR responses during furosemide treatment, assuming complete inhibition of TGF, suggest a third mechanism that contributes 10-20% and is independent of TGF, slower than the myogenic response, and abolished by NOS inhibition. The hindlimb circulation displayed a solitary myogenic response similar to the kidney (35% autoregulation) that was not enhanced by L-NAME. We conclude that NO normally restrains the strength and speed of the myogenic response in RBF but not hindlimb autoregulation, an action dependent on TGF, thereby allowing more and slow RAP fluctuations to reach glomerular capillaries.

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

“…The myogenic response is much faster, with a natural frequency of 0.1-0.2 Hz in the anaesthetized rats and 0.2-0.3 Hz in conscious animals (2,32,36,38,56,76,122,165,166). Essentially similar data regarding the kinetics of these mechanisms have been obtained through analyses of RBF responses to step changes in BP (84,85,102,175). These natural frequencies imply that the myogenic response can prevent changes in RBF in response to BP fluctuations that occur at intervals greater than 3-4 s, whereas TGF responds to slower BP fluctuations over intervals of 20 s or longer.…”

Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation

“…15 Ang II levels also do not seem to modulate the relative contributions of MR and TGF. 27,38 We and others have shown that NO exerts a strong attenuating influence on the MR in the renal but not nonrenal circulations. 27,28 Importantly, this NO influence depends on functional TGF, 27,28 suggesting neuronal NOS in macula densa cells as the source.…”

“…27,38 We and others have shown that NO exerts a strong attenuating influence on the MR in the renal but not nonrenal circulations. 27,28 Importantly, this NO influence depends on functional TGF, 27,28 suggesting neuronal NOS in macula densa cells as the source. Given the probable role of Cx40 in TGF signal transduction and the possibility of NO modulation of connexin conductance, 25,39 we postulated that the absence of Cx40 impacts on NO effects on the renal MR.…”

“…The autoregulatory response of RBF to a rapid step increase in RAP within the autoregulatory pressure range was investigated as described previously. 16,27,30 The RAP increase was produced after reducing RAP 20 mmHg below the resting level for 60 to 70 s. This procedure was repeated every 5 min, thus allowing 4 min for recovery between RAP steps. Several steps were induced in each experimental period.…”

“…26 In addition, NO blunts the strength of the pressure-induced MR in RBF autoregulation, an effect specific to the kidney and dependent on JGA function and TGF. 27,28 Considering the possible involvement of Cx40 in JGA function, we postulated that Cx40 is critical for NO modulation of agonist-induced renal vascular responses and pressure-induced RBF autoregulation.…”