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ABSTRACT: The N(ω)-nitro-l-arginine methyl ester (l-NAME) model is widely employed to investigate the role of nitric oxide (NO) in renal injury. The present studies show that Sprague-Dawley rats from Harlan (H) and Charles River (CR) exhibit strikingly large differences in susceptibility to l-NAME nephropathy. After 4 wk of l-NAME (∼50 mg·kg(-1)·day(-1) in drinking water), H rats (n = 13) exhibited the expected hypertension [average radiotelemetric systolic blood pressure (BP), 180 ± 3 mmHg], proteinuria (136 ± 17 mg/24 h), and glomerular injury (GI) (12 ± 2%). By contrast, CR rats developed less hypertension (142 ± 4), but surprisingly no proteinuria or GI, indicating a lack of glomerular hypertension. Additional studies showed that conscious H, but not CR, rats exhibit dose-dependent renal vasoconstriction after l-NAME. To further investigate these susceptibility differences, l-NAME was given 2 wk after 3/4 normotensive nephrectomy (NX) and comparably impaired renal autoregulation in CR-NX and H-NX rats. CR-NX rats, nevertheless, still failed to develop proteinuria and GI despite moderate hypertension (144 ± 2 mmHg, n = 29). By contrast, despite an 80-90% l-NAME dose reduction and lesser BP increases (169 ± 4 mmHg), H-NX rats (n = 20) developed greater GI (26 ± 3%) compared with intact H rats. Linear regression analysis showed significant (P < 0.01) differences in the slope of the relationship between BP and GI between H-NX (slope 0.56 ± 0.14; r = 0.69; P < 0.008) and CR-NX (slope 0.09 ± 0.06; r = 0.29; P = 0.12) rats. These data indicate that blunted BP responses to l-NAME in the CR rats are associated with BP-independent resistance to nephropathy, possibly mediated by a resistance to the renal (efferent arteriolar) vasoconstrictive effects of NO inhibition.
AJP Renal Physiology 09/2011; 302(1):F173-82. · 4.42 Impact Factor
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ABSTRACT: The afferent arteriolar myogenic response contributes to the autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and plays an essential role in protecting the kidney against hypertensive injury. Systolic blood pressure (SBP) is most closely linked to renal injury, and a myogenic response coupled to this signal would facilitate renal protection, whereas mean blood pressure (MBP) influences RBF and GFR. The relative role of SBP vs. MBP as the primary determinant of myogenic tone is an area of current controversy. Here, we describe two mathematical models, Model-Avg and Model-Sys, that replicate the different delays and time constants of vasoconstrictor and vasodilator phases of the myogenic responses of the afferent arteriole. When oscillating pressures are applied, the MBP determines the magnitude of the myogenic response of Model-Avg, and the SBP determines the response of Model-Sys. Simulations evaluating the responses of both models to square-wave pressure oscillations and to narrow pressure pulses show decidedly better agreement between Model-Sys and afferent arteriolar responses observed in cortical nephrons in the in vitro hydronephrotic kidney model. Analysis showing that the difference in delay times of the vasoconstrictor and vasodilator phases determines the frequency range over which SBP triggers Model-Sys's response was confirmed with simulations using authentic blood pressure waveforms. These observations support the postulate that SBP is the primary determinant of the afferent arteriole's myogenic response and indicate that differences in the delays in initiation vs. termination of the response, rather than in time constants, are integral to this phenomenon.
AJP Regulatory Integrative and Comparative Physiology 09/2008; 295(5):R1502-11. · 3.34 Impact Factor
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ABSTRACT: Diabetes and increased blood pressure (BP) are believed to interact synergistically in the pathogenesis and progression of diabetic nephropathy. The present studies were performed to examine if there were differences in BP load and/or protective renal autoregulatory capacity between the obese diabetic Zucker fatty /spontaneously hypertensive heart failure F1 hybrid (ZSF1) (fa/fa cp) rats and their lean controls. By approximately 26 wk of age, ZSF1 (n = 13) but not their lean controls (n = 16) had developed substantial proteinuria (180 +/- 19 vs. 16 +/- 1.4 mg/24 h) and glomerulosclerosis (19 +/- 2.4 vs. 0.6 +/- 0.2%; P < 0.001). However, average ambient systolic BP by radiotelemetry (12-26 wk of age) was modestly lower in ZSF1 than in lean controls (130 +/- 1.4 vs. 137 +/- 1.7 mmHg, P < 0.002), although the 24-h BP power spectra showed a mild increase at frequencies <0.1 Hz in the ZSF1. Autoregulatory capacity under anesthesia in response to step changes in perfusion pressure between 100 and 140 mmHg was similarly well preserved in both ZSF1 and lean controls at 16-18 wk of age [autoregulatory indexes (AI) <0.1]. Similarly, differences were not observed for dynamic autoregulation in conscious rats [transfer functions between BP (input) and renal blood flow (output) using chronic Transonic flow probes]. Collectively, these data indicate that the pathogenesis of nephropathy in the ZSF1 model of type 2 diabetic nephropathy is largely independent of differences in systemic BP and/or its potential renal transmission. However, these data do not exclude the possibility that the diabetic milieu may alter the glomerular capillaries in the ZSF1, such that there is an enhanced local susceptibility to injury with even normal glomerular pressures.
American journal of physiology. Renal physiology 11/2007; 293(5):F1605-13. · 3.68 Impact Factor
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ABSTRACT: The dynamics of renal autoregulation are modeled using a modified Volterra representation called the fixed pole expansion technique (FPET). A data dependent procedure is proposed for selecting the pole locations in this expansion that enables a reduction in model complexity compared to standard Volterra models. Furthermore, a quantitative characterization of frequency dependent features of the renal autoregulatory response is enabled via the model's pole locations. The utility of this approach is demonstrated by applying the modeling technique to renal blood pressure and renal blood flow measurements in conscious rats. The model is used to characterize the myogenic autoregulatory response in control rats and rats whose renal autoregulation has been impaired by calcium channel blockers.
IEEE Transactions on Biomedical Engineering 12/2006; 53(11):2166-76. · 2.28 Impact Factor
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ABSTRACT: Salt-supplemented stroke-prone spontaneously hypertensive rats (SHRsp) develop more severe hypertension-induced renal damage (HIRD) compared with their progenitor SHR. The present studies were performed to examine whether in addition to increasing the severity of hypertension salt also enhanced the transmission of such hypertension to the renal vascular bed in the SHRsp. "Step" and "dynamic" renal blood flow (RBF) autoregulation (AR) were examined in approximately 12-wk-old SHR and SHRsp after 3-5 days of an 8% NaCl diet. During step AR under anesthesia (n = 8-11), RBF was significantly higher in the SHRsp at all perfusion pressures (P < 0.01), but AR capacity was not different. Similarly, in separate conscious chronically instrumented rats (n = 8 each), both blood pressure (BP) and RBF were modestly but significantly higher at baseline before salt in the SHRsp (P < 0.05). However, transfer function analysis did not show significant differences in the admittance gain parameters. However, after 3-5 days of salt, although average BP was not significantly altered in either strain, RBF increased further in the SHRsp and there was a significantly greater transfer of BP into RBF power in the SHRsp. This was reflected in the significantly higher admittance gain parameters at most frequencies including the heartbeat frequency (P < 0.05 maximum). These differential hemodynamic effects of salt have the potential to enhance BP transmission to the renal vascular bed and also contribute to the more severe HIRD observed in the salt-supplemented SHRsp.
American journal of physiology. Renal physiology 08/2005; 289(2):F305-13. · 3.68 Impact Factor
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ABSTRACT: Renal autoregulation (AR) mechanisms provide the primary protection against transmission of systemic pressures and hypertensive renal damage. However, the relative merits of the "step" change vs. "dynamic" methods for the assessment of AR capacity remain controversial. The effects of 48-72 h of orally administered amlodipine (L-type) and mibefradil (T-type) calcium channel blockers (CCBs) on step and dynamic AR in Sprague-Dawley rats were compared. Both CCBs significantly impaired "steady-state step" AR (autoregulatory indexes = approximately 0.5 vs. approximately 0.1 in controls, P < 0.05; n = 9-10/group). By contrast, dynamic AR compensation in separate conscious rats (n = 12) was not significantly altered by either amlodipine (n = 10) or mibefradil (n = 6; fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). However, both CCBs tended to attenuate the myogenic resonance peak along with shifting it to a significantly slower frequency (P < 0.001) during dynamic AR, but no consistent effects were observed on the tubuloglomerular feedback resonance peak. While the reasons for the insensitivity of dynamic vs. steady-state step AR capacity estimates to CCBs remain to be established, the present data indicate that dynamic AR methods may have a limited utility for assessing AR capacity but may provide potentially important insights into the operational characteristics of AR control mechanisms. A strong correlation was also observed between the average conductance and the admittance gain at the heart beat frequency (r = 0.77, P < 0.001), suggesting that such parameters may provide additional and possibly more meaningful indexes of BP transmission in conscious animals during dynamic AR.
American journal of physiology. Renal physiology 06/2004; 286(6):F1136-43. · 3.68 Impact Factor
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ABSTRACT: Renal autoregulatory (AR) mechanisms provide the primary protection against transmission of systemic pressures, and their impairment is believed to be responsible for the enhanced susceptibility to hypertensive renal damage in renal mass reduction (RMR) models. Assessment of AR capacity by the "step" change methodology under anesthesia was compared with that by "dynamic" methods in separate conscious control Sprague-Dawley rats and after uninephrectomy (UNX) and (3/4) RMR (RK-NX) (n = 7-10/group). Substantially less AR capacity was seen by the dynamic vs. the step methodology in control rats. Moreover, dynamic AR capacity did not differ among controls, UNX, and RK-NX rats (fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). By contrast, significant impairment of step AR was seen in RK-NX vs. control or UNX rats (AR indexes 0.7 +/- 0.1 vs. 0.1 +/- 0.02 and 0.2 +/- 0.04, respectively, P < 0.01). We propose that the step and dynamic methods evaluate the renal AR responses to different components of blood pressure (BP) power with the step AR assessing the ability to buffer large changes in average BP (DC power), whereas the present "dynamic" methods assess the AR ability to buffer slow BP fluctuations (<0.25 Hz) superimposed on the average BP (AC power), a substantially smaller component of total BP power. We further suggest that step but not dynamic AR methods as presently performed provide a valid index of the underlying susceptibility to hypertensive glomerular damage after RMR.
American journal of physiology. Renal physiology 07/2003; 285(1):F113-20. · 3.68 Impact Factor
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ABSTRACT: A broad class of nonlinear systems and filters can be modeled by the Volterra series representation. However, its practical use in nonlinear system identification is sometimes limited due to the large number of parameters associated with the Volterra filter′s structure. The parametric complexity also complicates design procedures based upon such a model. This limitation for system identification is addressed in this paper using a Fixed Pole Expansion Technique (FPET) within the Volterra model structure. The FPET approach employs orthonormal basis functions derived from fixed (real or complex) pole locations to expand the Volterra kernels and reduce the number of estimated parameters. That the performance of FPET can considerably reduce the number of estimated parameters is demonstrated by a digital satellite channel example in which we use the proposed method to identify the channel dynamics. Furthermore, a gradient-descent procedure that adaptively selects the pole locations in the FPET structure is developed in the paper.
EURASIP Journal on Advances in Signal Processing. 01/2001;
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IEEE Transactions on Signal Processing. 01/2000; 48:1467-1471.
