Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O₂⁻ dismutation on renal autoregulation in the time and frequency domains

Abstract

Moss NG, Gentle TK, Arendshorst WJ. Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O 2 Ϫ dismutation on renal autoregulation in the time and frequency domains. Am J Physiol Renal Physiol 310: F832-F845, 2016. First published January 28, 2016 doi:10.1152/ajprenal.00461.2015.-Renal blood flow autoregulation was investigated in anesthetized C57Bl6 mice using time-and frequency-domain analyses. Autoregulation was reestablished by 15 s in two stages after a 25-mmHg step increase in renal perfusion pressure (RPP). The renal vascular resistance (RVR) response did not include a contribution from the macula densa tubuloglomerular feedback mechanism. Inhibition of nitric oxide (NO) synthase [N G -nitro-L-arginine methyl ester (L-NAME)] reduced the time for complete autoregulation to 2 s and induced 0.25-Hz oscillations in RVR. Quenching of superoxide (SOD mimetic tempol) during L-NAME normalized the speed and strength of stage 1 of the RVR increase and abolished oscillations. The slope of stage 2 was unaffected by L-NAME or tempol. These effects of L-NAME and tempol were evaluated in the frequency domain during random fluctuations in RPP. NO synthase inhibition amplified the resonance peak in admittance gain at 0.25 Hz and markedly increased the gain slope at the upper myogenic frequency range (0.06 -0.25 Hz, identified as stage 1), with reversal by tempol. The slope of admittance gain in the lower half of the myogenic frequency range (equated with stage 2) was not affected by L-NAME or tempol. Our data show that the myogenic mechanism alone can achieve complete renal blood flow autoregulation in the mouse kidney following a step increase in RPP. They suggest also that the principal inhibitory action of NO is quenching of superoxide, which otherwise potentiates dynamic components of the myogenic constriction in vivo. This primarily involves the first stage of a two-stage myogenic response. renal circulation; perfusion pressure; renal vascular resistance; admittance gain; afferent arteriole MOST VASCULAR BEDS REGULATE blood flow according to metabolic conditions to provide adequate nutrient delivery and effective waste removal. Control of renal blood flow (RBF) is unique among peripheral vascular beds, as the principal goal is not to satisfy metabolic demands, but rather to stabilize glomerular capillary pressure at a level that provides an adequate glomerular filtration rate. This is achieved by an efficient autoregulatory mechanism(s) that adjusts glomerular afferent arteriolar diameter in response to fluctuations in renal perfusion pressure (RPP). Of equal importance, this process protects glomerular capillaries from excessive pressures that can cause barotrauma, glomerular injury, and renal failure. Several intrinsic mechanisms regulate renal vascular resistance (RVR) in response to changes in RPP (3, 13). In common with most organs, changes in RPP invoke an intrinsic myogenic mechanism in the vascular smooth muscle cells (VSMC) of renal resistance vessels, which stabilizes dow...

A dynamic computational network model for the role of nitric oxide and the myogenic response in microvascular flow regulation

“…As in the MAP = 100 mm Hg case, increasing R NO slightly increases flow, while decreasing R NO decreases network flow at the simulated pressures. The time response for the change in total blood flow with MAP is also faster in the absence of NO, which is consistent with recent experimental mouse renal studies showing the effects of NOS inhibition …”

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“…A second peak, located in 30–60 mHz, is also present in most of the experimental transfer functions. This peak is attributed to the operation of TGF and is missing from preparation in which TGF is inhibited by either ureteral obstruction (e.g., Daniels et al 1990; Moss et al 2016), administration of furosemide (e.g., Shi et al 2006; Just et al 1998; Ajikobi et al 1996), or induced hydronephrosis (e.g., Cupples and Loutzenhiser 1998). Similarly, such peak is present in every model that includes an active TGF and is missing from all models in which TGF is inhibited.…”

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“…Other known mediators of septic renal microcirculatory dysfunction include reactive oxygen species (ROS) and endothelin-1. Studies have yielded conflicting results, with ROS shown to enhance the myogenic response [ 67 ] and regulate TGF [ 68 ], but also to abolish autoregulation in juxtamedullary afferent arterioles [ 69 ]. Conversely, renal hypoxanthine/xanthine oxidase-generated superoxide production in rats did not affect autoregulation of RBF [ 70 ].…”