Autonomic cardiovascular control was characterized in conscious, chronically catheterized mice by spectral analysis of arterial pressure (AP) and heart rate (HR) during autonomic blockade or baroreflex modulation of autonomic tone. Both spectra were similar to those obtained in humans, but at approximately 10x higher frequencies. The 1/f relation of the AP spectrum changed to a more shallow slope below 0.1-0.2 Hz. Coherence between AP and HR reached 0.5 or higher below 0.3-0.4 Hz and also above 2.5 Hz. Muscarinic blockade (atropine) or beta-adrenergic blockade (atenolol) did not significantly affect the AP spectrum. Atropine reduced HR variability at all frequencies, but this effect waned above 1 Hz. beta-Adrenergic blockade (atenolol) slightly enhanced the HR variability only above 1 Hz. alpha-Adrenergic blockade (prazosin) reduced AP variability between 0.05 and 3 Hz, most prominently at 0. 15-0.7 Hz. A shift of the autonomic nervous tone by a hypertensive stimulus (phenylephrine) enhanced, whereas a hypotensive stimulus (nitroprusside) depressed AP variability at 1-3 Hz; other frequency ranges of the AP spectrum were not affected except for a reduction below 0.4 Hz after nitroprusside. Variability of HR was enhanced after phenylephrine at all frequencies and reduced after nitroprusside. As with atropine, the reduction with nitroprusside waned above 1 Hz. In conclusion, in mice HR variability is dominated by parasympathetic tone at all frequencies, during both blockade and physiological modulation of autonomic tone. There is a limitation for further reduction but not for augmentation of HR variability from the resting state above 1 Hz. The impact of HR on AP variability in mice is confined to frequencies higher than 1 Hz. Limits between frequency ranges are proposed as 0.15 Hz between VLF (very low frequency range) and LF (low frequency range) and 1.5 Hz between LF and HF (high frequency range).

Autoregulation of renal blood flow (RBF) is caused by the myogenic response (MR), tubuloglomerular feedback (TGF), and a third regulatory mechanism that is independent of TGF but slower than MR. The underlying cause of the third regulatory mechanism remains unclear; possibilities include ATP, ANG II, or a slow component of MR. Other mechanisms, which, however, exert their action through modulation of MR and TGF are pressure-dependent change of proximal tubular reabsorption, resetting of RBF and TGF, as well as modulating influences of ANG II and nitric oxide (NO). MR requires < 10 s for completion in the kidney and normally follows first-order kinetics without rate-sensitive components. TGF takes 30–60 s and shows spontaneous oscillations at 0.025–0.033 Hz. The third regulatory component requires 30–60 s; changes in proximal tubular reabsorption develop over 5 min and more slowly for up to 30 min, while RBF and TGF resetting stretch out over 20–60 min. Due to these kinetic differences, the relative contribution of the autoregulatory mechanisms determines the amount and spectrum of pressure fluctuations reaching glomerular and postglomerular capillaries and thereby potentially impinge on filtration, reabsorption, medullary perfusion, and hypertensive renal damage. Under resting conditions, MR contributes ∼50% to overall RBF autoregulation, TGF 35–50%, and the third mechanism < 15%. NO attenuates the strength, speed, and contribution of MR, whereas ANG II does not modify the balance of the autoregulatory mechanisms.

-We investigated dynamic characteristics of renal blood flow (RBF) autoregulation and relative contribution of underlying mechanisms within the autoregulatory pressure range in rats. Renal arterial pressure (RAP) was reduced by suprarenal aortic constriction for 60 s and then rapidly released. Changes in renal vascular resistance (RVR) were assessed following rapid step reduction and RAP rise. In response to rise, RVR initially fell 5-10% and subsequently increased ϳ20%, reflecting 93% autoregulatory efficiency (AE). Within the initial 7-9 s, RVR rose to 55% of total response providing 37% AE, reaching maximum speed at 2.2 s. A secondary RVR increase began at 7-9 s and reached maximum speed at 10-15 s. Response times suggest that the initial RVR reflects the myogenic response and the secondary tubuloglomerular feedback (TGF). During TGF inhibition by furosemide, AE was 64%. The initial RVR rise was accelerated and enhanced, providing 49% AE, but it represented only 88% of total. The remaining 12% indicates a third regulatory component. The latter contributed up to 50% when the RAP increase began below the autoregulatory range. TGF augmentation by acetazolamide affected neither AE nor relative myogenic contribution. Diltiazem infusion markedly inhibited AE and the primary and secondary RVR increases but left a slow component. In response to RAP reduction, initial vasodilation constituted 73% of total response but was not affected by furosemide. The third component's contribution was 9%. Therefore, RBF autoregulation is primarily due to myogenic response and TGF, contributing 55% and 33-45% in response to RAP rise and 73% and 18-27% to RAP reduction. The data imply interaction between TGF and myogenic response affecting strength and speed of myogenic response during RAP rises. The data suggest a third regulatory system contributing Ͻ12% normally but up to 50% at low RAP; its nature awaits further investigation. renal circulation; afferent arteriole; glomerular arterioles; myogenic mechanism; tubuloglomerular feedback; vascular smooth muscle cells; macula densa cells; calcium channel blocker; furosemide; acetazolamide AUTOREGULATION OF RENAL blood flow (RBF) has been well characterized under steady-state conditions (2, 28, 36).Less is known about the dynamics and the relative contribution of the responsible mechanisms. Since the underlying mechanisms differ in their response times, the relative contributions affect the speed of overall regulation. Because of the continuous fluctuations of arterial pressure over a wide range of frequencies (33), the efficiency of autoregulation determines the size and range of pressure changes reaching glomeruli, peritubular capillaries, and medullary perfusion and will thus have an important bearing on fluid homeostasis and hypertensive renal damage.There is general agreement that renal autoregulation is mediated by at least two mechanisms, the tubuloglomerular feedback (TGF) and the myogenic response (36), and perhaps by a third (24). Although TGF participates, it appears that a d...

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.

The aim of this study was to investigate the autoregulation of renal blood flow under physiological conditions, when challenged by the normal pressure fluctuations, and the contribution of the tubuloglomerular feedback (TGF). The transfer function between 0.0018 and 0.5 Hz was calculated from the spontaneous fluctuations in renal arterial blood pressure (RABP) and renal blood flow (RBF) in conscious resting dogs. The response of RBF to stepwise artificially induced reductions in RABP was also studied (stepwise autoregulation). Under control conditions (n= 12 dogs), the gain of the transfer function started to decrease, indicating improving autoregulation, below 0.06‐0.15 Hz (t= 7‐17 s). At 0.027 Hz a prominent peak of high gain was found. Below 0.01 Hz (t> 100 s), the gain reached a minimum (maximal autoregulation) of ‐6.3 ± 0.6 dB. The stepwise autoregulation (n= 4) was much stronger (‐19.5 dB). The time delay of the transfer function was remarkably constant from 0.03 to 0.08 Hz (high frequency (HF) range) at 1.7 s and from 0.0034 to 0.01 Hz (low frequency (LF) range) at 14.3 s, respectively. Nifedipine, infused into the renal artery, abolished the stepwise autoregulation (‐2.0 ± 1.1 dB, n= 3). The gain of the transfer function (n= 4) remained high down to 0.0034 Hz; in the LF range it was higher than in the control (0.3 ± 1.0 dB, P< 0.05). The time delay in the HF range was reduced to 0.5 s (P < 0.05). After ganglionic blockade (n= 7) no major changes in the transfer function were observed. Under furosemide (frusemide) (40 mg + 10 mg h−1 or 300 mg + 300 mg h−1 i.v.) the stepwise autoregulation was impaired to ‐7.8 ± 0.3 or ‐6.7 ± 1.9 dB, respectively (n= 4). In the transfer function (n= 7 or n= 4) the peak at 0.027 Hz was abolished. The delay in the LF range was reduced to ‐1.1 or ‐1.6 s, respectively. The transfer gain in the LF range (‐5.5 ± 1.2 or ‐3.8 ± 0.8 dB, respectively) did not differ from the control but was smaller than that under nifedipine (P < 0.05). It is concluded that the ample capacity for regulation of RBF is only partially employed under physiological conditions. The abolition by nifedipine and the negligible effect of ganglionic blockade show that above 0.0034 Hz it is almost exclusively due to autoregulation by the kidney itself. TGF contributes to the maximum autoregulatory capacity, but it is not required for the level of autoregulation expended under physiological conditions. Around 0.027 Hz, TGF even reduces the degree of autoregulation.

The time course of the autoregulatory response of renal blood flow (RBF) to a step increase in renal arterial pressure (RAP) was studied in conscious dogs. After RAP was reduced to 50 mmHg for 60 s, renal vascular resistance (RVR) decreased by 50%. When RAP was suddenly increased again, RVR returned to baseline with a characteristic time course (control; n = 15): within the first 10 s, it rose rapidly to 70% of baseline ( response 1), thus already comprising 40% of the total RVR response. Thereafter, it increased at a much slower rate until it started to rise rapidly again at 20–30 s after the pressure step ( response 2). After passing an overshoot of 117% at 43 s, RVR returned to baseline values. Similar responses were observed after RAP reduction for 5 min or after complete occlusions for 60 s. When tubuloglomerular feedback (TGF) was inhibited by furosemide (40 mg iv, n = 12), response 1 was enhanced, providing 60% of the total response, whereas response 2 was completely abolished. Instead, RVR slowly rose to reach the baseline at 60 s ( response 3). The same pattern was observed when furosemide was given at a much higher dose (>600 mg iv; n = 6) or in combination with clamping of the plasma levels of nitric oxide ( n = 6). In contrast to RVR, vascular resistance in the external iliac artery after a 60-s complete occlusion started to rise with a delay of 4 s and returned to baseline within 30 s. It is concluded that, in addition to the myogenic response and the TGF, a third regulatory mechanism significantly contributes to RBF autoregulation, independently of nitric oxide. The three mechanisms contribute about equally to resting RVR. The myogenic response is faster in the kidney than in the hindlimb.

The vascular actions of endothelin-1 (ET-1) reflect the combination of vasoconstrictor ETA and ETB receptors on smooth muscle cells and vasodilator ETB receptors on endothelial cells. The present study investigated the contribution of ET receptor subtypes using a comprehensive battery of agonists and antagonists infused directly into the renal artery of anesthetized rats to evaluate the actions of each receptor class alone and their interactions. ET-1 (5 pmol) reduced renal blood flow (RBF) 25 Ϯ 1%. ETA antagonist BQ-123 attenuated this response to a 15 Ϯ 1% decrease in RBF (P Ͻ 0.01), indicating net constriction by ETB receptors. Combined receptor blockade (BQ-123ϩBQ-788) resulted in a renal vasoconstriction of 7 Ϯ 1% (P ϭ 0.001 vs. BQ-123), supporting a constrictor action of ET B receptors. In marked contrast, the ETB antagonist BQ-788 enhanced the ET-1 RBF response to 60 Ϯ 5% (P Ͻ 0.001), suggesting ET B-mediated net dilation. Consistent with ET A blockade, the ETB agonist sarafotoxin 6C (S6C) produced vasoconstriction, reducing RBF by 23 Ϯ 5%. Dose-response curves for ET-1 and S6C showed similar degrees of constriction between 0.2 and 100 pmol. Both antagonists (BQ-123, BQ-788) were equally effective at threefold lower than the standard doses, suggesting complete inhibition. We conclude that ET B receptors alone exert a net constrictor effect but cause a net dilator influence when costimulated with ET A receptors. Such opposing actions indicate more complex than additive interaction between receptor subtypes. Model analysis suggests ET A-mediated constriction is appreciably greater without than with costimulation of ET B receptors. Possible explanations include ET-1 clearance by ET B receptors and/or a dilator ETB receptor function that counteracts constriction. vascular smooth muscle cells; endothelial cells; renal vascular resistance; nitric oxide ENDOTHELIN-1 (ET-1) PLAYS an important role in the regulation of renal hemodynamics and salt and water excretion (38). Under physiological conditions the vascular endothelium constitutively produces ET-1. Although endogenous ET-1 normally has a minor influence on renal hemodynamics (37), it gains more importance in disease states such as hypertension, acute and chronic renal failure, and congestive heart failure (38). ET-1 is capable of constricting or dilating the renal vasculature depending on the relative distribution and influence of ET A and ET B receptors. In the vascular wall, ET A receptors are limited to smooth muscle cells, whereas ET B receptors are expressed in both endothelial and smooth muscle cells (38). Both receptor types are coupled to Gq proteins, thereby activating several signaling pathways including phospholipase C and intracellular calcium concentration (38), which leads to constriction of smooth muscle cells. Activation of endothelial ET B receptors by the same signaling pathways produces vasodilation mediated by nitric oxide and possibly eicosanoids (14).There is general agreement that administration of ET-1 produces renal vasoconstrictio...

In this work absolute values of regional renal blood volume (rRBV) and flow (rRBF) are assessed by means of contrastenhanced (CE) MRI using an intravascular superparamagnetic contrast agent. In an animal study, eight foxhounds underwent dynamic susceptibility-weighted MRI upon injection of contrast agent. Using principles of indicator dilution theory and deconvolution analysis, parametric images of rRBV, rRBF, and mean transit time (MTT) were computed. For comparison, wholeorgan blood flow was determined invasively by means of an implanted flow probe, and the weight of the kidneys was evaluated postmortem. A mean rBV value of 28 ml/100 g was found in the renal cortex, with a corresponding mean rBF value of 524 ml/100 g/min and an average MTT of about 3.4 s. Although there was a systematic difference between the absolute blood flow values determined by MRI and the ultrasonic probe, a significant correlation (r s ‫؍‬ 0.72, P < 0.05) was established. The influence of the arterial input function (AIF), T 1 relaxation effects, and repeated measurements on the precision of the perfusion quantitation is discussed.Magn Key words: kidney; perfusion; susceptibility contrast; intravascular contrast agent; dynamic T* 2 -weighted imaging; time series deconvolutionIt has been shown that absolute values of regional cerebral blood volume and flow can be determined from T* 2 -weighted dynamic MR images acquired during the passage of a paramagnetic contrast agent (1-4). However, with the use of a conventional diffusible MR contrast agent (such as Gd-DTPA), this method is limited to tissue regions with an intact blood-brain barrier, wherein the contrast agent remains within the intravascular space (5). Recently, ultrasmall superparamagnetic iron oxide (USPIO) particles, which can be employed as intravascular contrast agents, have become available (6). These agents generate a strong transient decrease in signal intensity when delivered as a bolus, and enable determination of both blood flow and volume in extracranial tissues (7).Absolute quantification of tissue perfusion by dynamic MRI appears to be highly promising in the evaluation of diseases of the kidney, since MRI has already been established as a valuable tool for the assessment of renovascular disease through the combination of morphologic and functional imaging (8,9). As renoparenchymal damage is often caused by a long-standing renal artery stenosis, the challenge for an MR perfusion technique is to differentiate hemodynamically significant stenoses from nonsignificant stenoses. Renoparenchymal perfusion would provide a valuable parameter for deciding whether a stenosis is hemodynamically relevant, in the context of a reduction in renal blood flow.The primary objective of this study was to investigate whether quantification of regional renal blood flow (rRBF) and regional renal blood volume (rRBV) is feasible by means of T* 2 -weighted dynamic MRI with an intravascular contrast agent. To this end, eight foxhounds under physiologic conditions underwent dynamic MRI upon in...