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Am J Physiol Heart Circ Physiol 282: H1592-H1602, 2002; doi:10.1152/ajpheart.00222.2001
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Vol. 282, Issue 5, H1592-H1602, May 2002

Central mechanisms of acute ANG II modulation of arterial baroreflex control of renal sympathetic nerve activity

Max G. Sanderford1 and Vernon S. Bishop2

1 Department of Biological Sciences, Tarleton State University, Stephenville 76401; and 2 Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229-3900


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Short-term intravenous infusion of angiotensin II (ANG II) into conscious rabbits reduces the range of renal sympathetic nerve activity (RSNA) by attenuating reflex disinhibition of RSNA. This action of ANG II to attenuate the arterial baroreflex range is exaggerated when ANG II is directed into the vertebral circulation, which suggests a mechanism involving the central nervous system. Because an intact area postrema (AP) is required for ANG II to attenuate arterial baroreflex-mediated bradycardia and is also required for maintenance of ANG II-dependent hypertension, we hypothesized that attenuation of maximum RSNA during infusion of ANG II involves the AP. In conscious AP-lesioned (APX) and AP-intact rabbits, we compared the effect of a 5-min intravenous infusion of ANG II (10 and 20 ng · kg-1 · min-1) on the relationship between mean arterial blood pressure (MAP) and RSNA. Intravenous infusion of ANG II into AP-intact rabbits resulted in a dose-related attenuation of maximum RSNA observed at low MAP. In contrast, ANG II had no effect on maximum RSNA in APX rabbits. To further localize the central site of ANG II action, its effect on the arterial baroreflex was assessed after a midcollicular decerebration. Decerebration did not alter arterial baroreflex control of RSNA compared with the control state, but as in APX, ANG II did not attenuate the maximum RSNA observed at low MAP. The results of this study indicate that central actions of peripheral ANG II to attenuate reflex disinhibition of RSNA not only involve the AP, but may also involve a neural interaction rostral to the level of decerebration.

circulating peptides; renal nerves; sympathetic nervous system; blood pressure; kidney


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

SHORT-TERM ELEVATION of peripheral angiotensin II (ANG II) may have a different effect on arterial baroreflex control of sympathetic nerve activity (SNA) than chronic elevation of ANG II. Chronic increases in ANG II are thought to reset arterial baroreflex control of SNA toward a higher mean arterial blood pressure (MAP). Evidence for this observation has been based on studies demonstrating that the depressor response to ganglionic blockade during chronic infusion of ANG II returns toward preinfusion levels despite sustained elevations in blood pressure (9, 13, 25, 43). This hypothesis has recently been tested in animal models with chronically high endogenous levels of circulating ANG II (20, 41, 42). In rats maintained on a low-sodium diet, administration of the AT1 receptor antagonist losartan reduces lumbar SNA relative to the level of MAP and resets arterial baroreflex control toward a lower MAP (42). Administration of converting enzyme inhibitors has a similar effect on arterial baroreflex control of renal SNA (RSNA) in one-kidney, one-clip hypertensive rats (20).

In contrast to the chronic effects of ANG II on arterial baroreflex control of SNA, acutely increasing peripheral ANG II does not appear to reset arterial baroreflex control of RSNA of the rabbit toward a higher MAP (24, 32, 34). Earlier studies that examined acute effects of ANG II on arterial baroreflex control of SNA focused their attention on whether or not ANG II altered the gain or the operating point of the arterial baroreflex (17, 29). Little attention, however, was given to possible effects of ANG II on the range or maximum level of sympathetic outflow. We recently demonstrated that acute, peripheral infusion of ANG II attenuates the range of RSNA observed during ramp changes in blood pressure by reducing the maximum level of RSNA that is achieved when MAP is lowered (32). This acute effect of ANG II on arterial baroreflex control of RSNA was not the integrated result of a sustained increase in MAP produced by peripheral actions of ANG II before arterial baroreflex assessment, nor was it due to actions of ANG II to elevate plasma arginine vasopressin (AVP), which would in turn attenuate maximum RSNA when blood pressure is lowered (34). This raised the possibility that acute modulation of arterial baroreflex control of RSNA by ANG II occurs through central actions of ANG II. Indeed, during intravertebral artery infusion of ANG II, the attenuated disinhibition of RSNA was greater than that observed when the same dose was infused into the jugular vein (34).

Although the mechanism by which peripheral ANG II chronically resets the arterial baroreflex is not well understood, it may include a hindbrain action of ANG II involving the area postrema (AP). Indeed, several studies have now shown that an intact AP is required for the chronic development of ANG II-dependent hypertension (9, 11) and that lesion of the AP attenuates hypertension in the DOCA-salt model (12), spontaneously hypertensive rats (27), and the transgenic rat carrying the Ren-2d gene (1). Furthermore, the ability of ANG II to reset arterial baroreflex control of heart rate (HR) to higher blood pressures, which occurs almost immediately on ANG II infusion, also involves the AP (9, 28). Located at the caudal end of the fourth ventricle, the AP is the only circumventricular organ in the hindbrain (36, 40). This makes it a logical target for mediating central effects of circulating peptides. It has neural connections with a number of central nuclei involved in cardiovascular regulation, including the nucleus tractus solitarius (NTS) (36, 40), the parabrachial nucleus (36, 40), and the rostral ventral medulla (4, 36).

It was recently reported that following administration of losartan to AP-lesioned rats maintained on a low-sodium diet, arterial baroreflex control of lumbar SNA still resets to lower pressures (42). However, these investigators observed that changes in the range and maximum SNA in response to losartan in AP-lesioned rats were attenuated compared with intact rats. These data suggest that ANG II, modulation of the range of arterial baroreflex control of SNA, involves the AP.

The purpose of the present study was to determine whether the attenuation of maximum RSNA observed on baroreceptor unloading during ANG II infusion requires an intact AP. To further localize the central areas involved in acute modulation of the arterial baroreflex by ANG II, an additional group of rabbits were decerebrated to determine whether integrity of neural connections between the hindbrain and higher-order cardiovascular control centers are required.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Preparation

New Zealand White rabbits of either gender weighing 2.5-3.2 kg were used in this study. Rabbits were anesthetized with a mixture of 43 mg ketamine, 3.6 mg chlorpromazine, and 8.6 mg xylazine per kilogram body weight; intubated; and mechanically ventilated with room air when necessary. With the use of sterile procedures, Teflon-tipped catheters were inserted into the descending aorta and inferior vena cava via a femoral artery and vein for direct measurement of arterial blood pressure and infusion of sodium nitroprusside (SNP; Sigma). A double-lumen Silastic catheter was inserted into the right external jugular vein for infusion of ANG II (Sigma) and phenylephrine (PE; Elkin-Sinn). Catheters were flushed with heparinized saline at least every other day to maintain patency. After at least a 6-day recovery period, two stainless steel, Teflon-coated wires (Medwire) were placed around a branch of the left or right renal nerve via a retroperitoneal incision. The electrodes were secured in place with silicone gel (Wacker Sil-Gel, 604A and 604B mixed at a ratio of 3:1). A ground wire was also secured to a nearby muscle before the incision was closed. Catheters, electrode wire, and ground wire were tunneled under the skin and exteriorized at the dorsal neck. A minimum recovery of 48 h was allowed before experimentation following implantation of nerve electrodes. Lesion of the AP was accomplished in anesthetized rabbits placed in a stereotaxic frame. Briefly, the atlantooccipital membrane was exposed through a dorsal, midcervical incision. The dorsal surface of the medulla at the level of the obex was then exposed by cutting a slit in the atlantooccipital membrane. The AP was removed using negative pressure applied through a 20-gauge cannula. Sham lesions were performed in an identical manner except that after the AP was exposed, no further action was taken. At least 14 days were allowed for recovery before any other procedures. Accounting for recovery periods after implantation of catheters and nerve electrodes, the minimum time between AP lesion and experimentation was 3 wk. To prevent infection, all rabbits were treated with an intramuscular injection of penicillin G procaine (Dura Pen) every other day for four doses after all surgeries. For analgesia, 2.0 mg/kg nalbuphine (Astra Pharmaceuticals) was administered intramuscularly immediately after all surgeries and 1.0 mg/kg was repeated on the following day. Additionally, all rabbits undergoing AP lesion were treated with 1 mg/kg dexamethasone intramuscularly immediately after the surgery to reduce inflammation.

Recording Procedure

Pulsatile arterial pressure and HR were monitored via the femoral artery catheter using a Cobe CDX III pressure transducer and a Beckman 9857B cardiotachometer triggered by the arterial pulse. A low-pass frequency filter was set at 0.08 Hz and used to obtain MAP from the pulsatile arterial pressure signal. RSNA, filtered between 30 and 3,000 Hz, was amplified using a Grass P511K preamplifier. Whole nerve activity was obtained by rectifying and integrating the recorded AC signals with a root mean square integrator (custom made) having a time constant of 28 ms. Whole nerve activity was filtered at 0.08 Hz to obtain mean RSNA. The level of background noise was determined when nerve activity was eliminated by increasing MAP with PE. Analog outputs from a Beckman R611 Dynograph recorder for pulsatile pressure, MAP, HR, RSNA, and mean RSNA were connected to an analog-to-digital converter (MacLab, ADI Australia). Digitized values were recorded and saved at 50 samples/s to an Apple Power PC using Chart software (ADI Australia).

Experimental Protocol

Rabbits were acclimated to the experimental environment by being placed in well-ventilated Plexiglas holding units (12 × 6 × 6 in.) on a daily basis before and throughout the preparation process. The rabbits were allowed to stabilize in the cage for 45 min before experimentation.

Experiment 1. The purpose of this experiment was to compare the effect of 10 and 20 ng · kg-1 · min-1 ANG II infusions on baseline MAP, RSNA, HR, and arterial baroreflex control of RSNA and HR in intact rabbits (n = 8) to AP-lesioned (APX) rabbits (n = 6). In intact or APX rabbits, the relationship between MAP and RSNA or HR was obtained during control and after a 5-min jugular vein infusion of 10 or 20 ng · kg-1 · min-1 ANG II (Sigma). An average of the last 30 s of the ANG II infusion before arterial baroreflex assessment was used to determine the effect of ANG II on baseline MAP, RSNA, and HR. The relationship between MAP and RSNA or HR under each condition was obtained by ramp increases and decreases in MAP produced by graded infusions of PE (1.24 to 22.0 µg · kg-1 · min-1) and SNP (2.5 to 75.0 µg · kg-1 · min-1), respectively. Approximately 5 min were allowed between the ramp infusion of PE and SNP to allow recovery of baseline values. In all cases, MAP was raised or lowered until an obvious upper or lower plateau in RSNA was observed and rate of change in MAP was manually controlled between 0.25 and 1.0 mmHg/s. By this method, ANG II was generally infused for no longer than 15 min. A minimum 30-min recovery period separated arterial baroreflex responses obtained under each condition. To alleviate potential problems associated with changes in arterial baroreflex responses over time, the order of baroreflex responses obtained under control conditions and during infusion of ANG II was randomized.

The lability of blood pressure was determined in each rabbit in intact and APX groups. Lability of MAP was determined by calculating the standard deviation of the average MAP at 5-s intervals over 10 min. This protocol has been reported by Schreihofer and Sved (35) to detect differences in lability of MAP among intact, sinoaortic-denervated, and partially sinoaortic-denervated rats.

Experiment 2. The purpose of this experiment was to determine the effect of 20 ng · kg-1 · min-1 ANG II on baseline MAP, HR, RSNA, and arterial baroreflex control of RSNA and HR in decerebrate rabbits. After experiment 1 was completed (see above), rabbits from the intact group were anesthetized with methoxyfluorane, intubated, and placed in a stereotaxic headframe. After an occipital craineotomy, the rabbits were ventilated with room air supplemented with oxygen and decerebrated at the midcollicular level with the use of a spatula. Localized bleeding was controlled with Gel-Foam (Upjohn), the incision was closed, and rabbits were removed form the stereotaxic frame. Positive pressure ventilation was maintained until rabbits had regained spontaneous breathing. At least 2 h of stabilization were allowed after rabbits had regained spontaneous breathing before repeating the arterial baroreflex protocol. End-tidal CO2 (Datex) and rectal temperature (Yellow Springs Instruments) were monitored periodically throughout the stabilization and experimental periods. Data were included in this study only from rabbits that breathed spontaneously, maintained a rectal temperature between 37 and 40°C, and maintained an end-tidal CO2 between 32 and 40 mmHg. Four rabbits met these criteria.

Histology

After completion of experiments in APX and decerebrate rabbits, the animals were euthanized with an overdose of pentobarbital sodium and perfused with normal saline followed by 20% formalin. Coronal sections (40 µm) through the medulla of APX rabbits were stained with cresyl violet and examined under a light microscope to verify lesion of the AP. To more accurately show the level of decerebration, 80-µm sections in the saggittal plane were obtained from decerebrate animals and stained with cresyl violet.

Analysis of Arterial Baroreflex Function Curves

Digitized values for MAP, HR, and mean RSNA obtained during ramp changes in pressure were averaged in 0.5-s intervals with the use of a macro written on Chart software (ADI). Values for RSNA or HR were averaged into 1-mmHg bins of MAP with the use of a macro written on Microsoft Excel. All RSNA values were recalculated as RSNA × 100/(maximum RSNA obtained in the control curve). The data were then displayed graphically, analyzed, and fitted with a logistic sigmoid curve function (23) as described previously (3). Briefly, RSNA or HR = P4 + {P1/1 + exp[P2(MAP - P3)]}, where P1 is the range of RSNA or HR, P2 is the coefficient to calculate the gain as a function of pressure, P3 is the pressure at midrange of the curve, P4 is the minimum RSNA or HR, and P1 + P4 is the maximum value of RSNA or HR. The gain of the function at any given MAP was calculated from the derivative of the above equation. The maximum gain was calculated as -(P1 · P2/4).

Statistical Analysis

Differences in baseline MAP, HR, RSNA, and arterial baroreflex parameters among values of 0, 10, and 20 ng · kg-1 · min-1 ANG II and between intact and APX or decerebrate groups was determined using one- or two-way analysis of variance with repeated measure. Significant differences determined by ANOVA were evaluated with the Newman-Keuls multiple-range test. All data are expressed as means ± SE.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Experiment 1

Because sham lesion of the AP (n = 3) did not alter baseline MAP, HR, RSNA, or arterial baroreflex control of HR and RSNA, and because it did not affect the response of these variables to ANG II compared with rabbits that did not undergo sham surgery, we have grouped these animals together and collectively refer to them as the intact group. There was no difference in baseline MAP, HR, and RSNA among control in both intact and APX groups (Table 1). In the intact group (n = 8), infusion of 10 and 20 ng · kg-1 · min-1 ANG II significantly increased MAP and decreased RSNA from control. Although the increase in MAP from control tended to be greater during infusion of 20 ng · kg-1 · min-1 ANG II compared with 10 ng · kg-1 · min-1, it did not reach statistical significance. In contrast, neither dose of ANG II changed HR from control in the intact group. In the APX group (n = 6), the pressor response to ANG II was blunted. Only 20 ng · kg-1 · min-1 ANG II significantly increased MAP above the control level. Furthermore, the level of MAP attained during infusion of both 10 and 20 ng · kg-1 · min-1 in APX rabbits was significantly less than the level of MAP attained during infusion of the same doses in intact rabbits (Table 1). Even though the pressor response to ANG II was blunted in APX, RSNA was significantly reduced by each dose of ANG II to levels that were not different from intact rabbits. In contrast to the intact, each dose of ANG II significantly decreased HR in APX rabbits.

                              
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  		Table 1.   Effect of treatment on MAP, HR, and RSNA

Figure 1 shows representative data illustrating the relationship of RSNA or HR to MAP from one rabbit in the intact group (Fig. 1, A and C) and from one rabbit in the APX group (Fig. 1, B and D). Data from the intact rabbit indicate that ANG II acutely attenuates the range of RSNA by reducing maximum RSNA during unloading of baroreceptors (Fig. 1A) and resets arterial baroreflex control of HR toward a higher MAP without altering the maximum or range (Fig. 1C). Data from the APX rabbit indicate that an intact AP is required for peripheral ANG II to acutely attenuate the range of RSNA (Fig. 1B ) and reset the operating point of arterial baroreflex control of HR toward higher pressures (Fig. 1D).


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  		Fig. 1.   Representative renal sympathetic nerve activity (RSNA) (A and B) and heart rate (HR) (C and D) arterial baroreflex curves produced during a control response (+) and during acute jugular vein infusion of angiotensin II (ANG II) at rate of 20 ng · kg-1 · min-1 (-) from 1 area postrema-intact rabbit (A and C) and 1 rabbit with lesion of the area postrema (B and D). Note that an intact area postrema is required for ANG II to attenuate maximum RSNA and shift the relationship between mean arterial blood pressure (MAP) and HR to a higher MAP. bpm, Beats per minute.

On the basis of the sigmoid logistic model, the range (P1), maximum (P1 + P4), minimum (P4), MAP at midrange (P3), and gain were determined using the best fit to a sigmoid logistic function. The average data for the individual parameters used to describe arterial baroreflex control of RSNA are shown in Table 2. In the intact group, ANG II infusion resulted in an attenuation of the RSNA range. The reduction in the range was due to a decrease in maximum RSNA from 100.1 ± 1.2 to 79.5 ± 3.3% of the control maximum in response to 10 ng · kg-1 · min-1 ANG II (P < 0.05 compared with control) and from 99.3 ± 0.6 to 70.1 ± 3.4% of the control maximum in response to 20 ng · kg-1 · min-1 ANG II (P < 0.05 compared with control). Furthermore, 10 and 20 ng · kg-1 · min-1 ANG II significantly increased P3 compared with control values from 76.6 ± 1.1 to 81.1 ± 1.7 mmHg and from 74.2 ± 2.0 to 82.5 ± 1.5 mmHg, respectively. In contrast to the intact group, the range and maximum RSNA were not reduced from control values during infusion of either dose of ANG II in the APX group. In both intact and APX groups, infusing ANG II had no effect on P4 or the gain.

                              
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  		Table 2.   Parameters describing arterial baroreflex control of RSNA

The average data for the individual parameters used to describe arterial baroreflex control of HR in intact and APX rabbits are shown in Table 3. Neither dose of ANG II affected P1, P4, P1 + P4, or the gain. Note, however, that 20 ng · kg-1 · min-1 significantly increased P3 from 74.4 ± 2.4 to 83.2 ± 1.9 mmHg in intact rabbits. In APX rabbits, neither dose of ANG II altered any parameter describing arterial baroreflex control of HR. In contrast to its lack of effect on control parameters describing arterial baroreflex regulation of RSNA, APX alone significantly reduced the control value of P4 for HR compared with the intact group (P < 0.05). However, because of variability in responses, this was not reflected as a significantly increased range of HR in the APX group compared with intact.

                              
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  		Table 3.   Parameters describing arterial baroreflex control of HR

Using the parameter values describing arterial baroreflex control of RSNA and HR from Tables 2 and 3, we reconstructed average arterial baroreflex function curves according to the logistic equation. Because the two control values within each group for both RSNA and HR were not different, we averaged these values for the purpose of illustration. The averaged control values are shown in Tables 2 and 3. Figure 2 illustrates the average logistic relationship between MAP and RSNA or HR in the intact group. The filled symbols on this figure indicate the baseline relationship between MAP and RSNA or HR before arterial baroreflex assessment. Note in Fig. 2A that because the range (or maximum) is reduced, the curves during ANG II are not shifted to higher pressures despite significant increases in P3. In Fig. 2B, because ANG II did not significantly affect the range, a shift in P3 to higher pressures during ANG II infusion is reflected as a shift in arterial baroreflex control of HR to higher pressures.


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  		Fig. 2.   Average logistic relationship between MAP and RSNA (A) and MAP and HR (B) illustrating arterial baroreflex function during acute jugular vein infusion of ANG II at rates of 0 (heavy solid line), 10 (light solid line), and 20 (light dashed line) ng · kg-1 · min-1 in area postrema-intact rabbits (n = 8). Filled symbols represent the average relationship between MAP and RSNA or HR during infusion of ANG II at rates of 0 (), 10 (), and 20 ng · kg-1 · min-1 (black-lozenge ) just before arterial baroreflex assessment. Error bars indicate SE. * P < 0.05 compared with internal control; dagger P < 0.05 compared with previous dose.

Figure 3 illustrates the average logistic relationship between MAP and RSNA or HR in the APX group. The filled symbols in Fig. 3 indicate the baseline relationship between MAP and RSNA or HR before arterial baroreflex assessment. APX not only eliminated attenuation of the range and maximum RSNA by ANG II (Fig. 3A), but also prevented resetting of arterial baroreflex control of HR to higher pressures (Fig. 3B).


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  		Fig. 3.   Average logistic relationship between MAP and RSNA (A) and MAP and HR (B) illustrating arterial baroreflex function during acute jugular vein infusion of ANG II at rates of 0 (heavy solid line), 10 (light solid line), and 20 ng · kg-1 · min-1 (light dashed line) in rabbits with lesion of the area postrema (n = 6). Filled symbols represent the average relationship between MAP and RSNA or HR during infusion of ANG II at rates of 0 (), 10 (), and 20 ng · kg-1 · min-1 (black-lozenge ) just before baroreflex assessment. Error bars indicate SE.

Visual comparison of coronal sections through the medulla of intact and APX rabbits showed no AP lesion resulted in no observable damage to the adjacent NTS. Furthermore, lability of blood pressure, as measured by the standard deviation of arterial blood pressure, in intact rabbits (2.3 ± 0.2 SD) was not different from APX rabbits (2.4 ± 0.2 SD).

Experiment 2

The baseline values for MAP, HR, and RSNA in the four rabbits from the intact group that were included in the decerebration study are shown in Table 4. Note that all RSNA values were normalized to the maximum and minimum values obtained in the control response before decerebration. The control values for MAP and RSNA were not different before and after decerebration. In contrast, control HR was significantly reduced by decerebration.

                              
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  		Table 4.   Effect of treatments on MAP, HR, and RSNA

Before decerebration, 20 ng · kg-1 · min-1 ANG II significantly increased MAP from 82.7 ± 6.2 to 94.3 ± 3.2 mmHg (P < 0.05), decreased RSNA from 22.6 ± 2.5% control maximum to 3.2 ± 0.6% control maximum (P < 0.05), and caused a small but significant decrease in HR from 229 ± 12 to 207 ± 8 beats/min (P < 0.05). After decerebration, infusing ANG II at 20 ng · kg-1 · min-1 did not significantly affect MAP (82.2 ± 5.9 vs. 88.2 ± 4.2 mmHg). Furthermore, the level of MAP during infusion of ANG II was significantly lower than the level observed during infusion of ANG II before decerebration. Infusing ANG II did not affect HR in the decerebrate state (204 ± 8 vs. 193 ± 8 beats/min), but significantly decreased RSNA from 23.8 ± 6.4 to 6.3 ± 4.3% control maximum (P < 0.05).

The average parameters describing arterial baroreflex function before and after decerebration are shown in Table 5. Infusing ANG II at 20 ng · kg-1 · min-1 significantly attenuated the range and maximum RSNA and increased P3 before decerebration. In these animals, ANG II did not significantly affect any parameter describing arterial baroreflex control of HR, although there was a tendency to shift P3 to higher pressures. Decerebration alone did not alter parameters used to describe arterial baroreflex control of RSNA compared with those observed before decerebration. However, decerebration completely eliminated ANG II-induced modulation of P1 and P1 + P4.

                              
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  		Table 5.   Parameters describing arterial baroreflex control of RSNA and HR before and after decerebration

Although decerebration alone did not affect arterial baroreflex control of RSNA, it did significantly affect reflex control of HR. Decerebration resulted in a significant reduction in P1, P1 + P4, and the gain of HR without altering P4 or P3 (Table 5). When ANG II was infused following decerebration, it did not alter any parameter describing arterial baroreflex control of HR. Using the average parameters describing arterial baroreflex control of RSNA and HR, we reconstructed arterial baroreflex function curves using the logistic equation. These curves, illustrating the effect of ANG II on arterial baroreflex regulation of RSNA and HR before decerebration, are shown in Fig. 4. Figure 5 illustrates the effect of ANG II on arterial baroreflex control of RSNA and HR after decerebration. The filled symbols superimposed on the curves illustrate the baseline relationship between MAP and RSNA or HR just before arterial baroreflex assessment.


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  		Fig. 4.   Average logistic relationship between MAP and RSNA (A) and MAP and HR (B) in 4 rabbits before decerebration during a control response (solid line) and during infusion of ANG II at a rate of 20 ng · kg-1 · min-1. Symbols illustrate the relationship between MAP and RSNA or HR during the control () and during infusion of 20 ng · kg-1 · min-1 ANG II () just before arterial baroreflex assessment. Error bars indicate SE. * P < 0.05 compared with control.



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  		Fig. 5.   Average logistic relationship between MAP and RSNA (A) and MAP and HR (B) in 4 rabbits after decerebration during a control response (solid line) and during infusion of ANG II at a rate of 20 ng · kg-1 · min-1. Symbols illustrate the relationship between MAP and RSNA or HR the control response () and during infusion of 20 ng · kg-1 · min-1 ANG II (open circle ) just before arterial baroreflex assessment. Error bars indicate SE.

The decerebration was produced in the dorsal to ventral direction. Light microscope examination of sagittal sections through the brain of decerebrate rabbits showed that decerebration began at the midcollicular level and angled slightly in the rostral to caudal direction. This cut resulted in a midpontine decerebration that eliminated the rostral pons. In all cases the decerebration was complete.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The primary objective of the present study was to determine the effect of ANG II on arterial baroreflex control of RSNA and to localize the site of action of ANG II in the central nervous system. Three conclusions were drawn from this study: 1) acute increases in peripheral ANG II attenuate the maximum rise in RSNA in response to unloading baroreceptors and reset arterial baroreflex control of HR toward a higher blood pressure; 2) arterial baroreflex control of RSNA and HR during infusion of ANG II is normalized to control by lesioning the AP; and 3) arterial baroreflex control of RSNA during infusion of ANG II is normalized to control by decerebration.

Our observation that ANG II alters the maximum increase in SNA in response to baroreceptor unloading is consistent with results of previous studies (32, 34). Furthermore, results from other laboratories using animal models with high levels of endogenous ANG II suggest that ANG II alters the maximum level of RSNA during baroreceptor unloading. Heesch and co-workers (20) observed in the one-kidney, one-clip hypertensive rat that inhibition of ANG II synthesis with captopril not only reset arterial baroreflex control of lumbar SNA (LSNA) toward lower pressures, but also increased the maximum LSNA that was observed during baroreceptor unloading. These data suggest that chronic increases in ANG II not only reset the arterial baroreflex toward higher operating pressures, but also chronically attenuate the maximum increase in SNA that is under arterial baroreflex control. In contrast, administration of losartan to rats maintained on a low-sodium diet shifts the arterial baroreflex to lower pressures as expected, but reduces the maximum LSNA observed when blood pressure is lowered (42). In these animals, it appears that chronic elevations in ANG II increase the maximum the level of SNA. Although it is not clear why acutely blocking ANG II in these two studies results in different effects on maximum SNA, the difference might be related to the sodium and/or volume status of the animals. In this regard, rabbits used in the present study were maintained on a normal sodium diet as were the animals used by Heesch and co-workers. Thus it appears that, depending on the experimental circumstances, the range and operating point of the arterial baroreflex can be independently affected by ANG II.

The results of the present study differ from conclusions drawn by other researchers who have investigated acute effects of ANG II on arterial baroreflex control of SNA (17, 24, 29). The reason for these differences may be related to experimental protocol, dose of ANG II, duration of ANG II infusion, and/or the presence of anesthesia. Kumagai and Reid (24) concluded that acutely increasing peripheral ANG II with a dose similar to doses used in this study had little effect on arterial baroreflex control of RSNA in conscious rabbits. In that study, reflex data were based on steady-state responses to four doses (3-5 min each) of PE and SNP to raise and lower MAP, respectively. Gou and Abboud (17), using anesthetized rabbits, and Matsumura and co-workers (29), using conscious rabbits, also concluded that ANG II has little effect on reflex disinhibition of sympathetic outflow. These studies, however, were focused on the slope of the MAP-SNA relationship. Because each curve was normalized to itself rather than to the control response, there was no attempt to analyze the effect of ANG II on maximum SNA in these animals. Our data, normalized to the maximum and minimum levels observed in the control response, allow us to demonstrate in absolute terms how ANG II acutely affects arterial baroreflex control of RSNA throughout its entire range.

A number of investigators have suggested that peripheral ANG II acts at a central site to modulate autonomic regulation. Early studies demonstrated that intravertebral infusion of ANG II increased MAP more than the same dose administered peripherally (10, 26). Additional support for a central action of ANG II has developed from studies that have examined the effect of ANG II on reflex control of HR. Pressor doses of peripheral ANG II attenuate the slope of the MAP-HR relationship compared with PE (24, 28, 29), and intravertebral artery infusion of ANG II results in an even greater attenuation (29). Recent evidence suggests that hindbrain actions of ANG II can attenuate the range of RSNA (15, 16, 34). Gaudet and co-workers (15, 16) demonstrated that infusion of losartan or enalapril into the fourth ventricle increases the maximum RSNA response to baroreceptor unloading. These data suggest that hindbrain ANG II tonically alters arterial baroreflex control of RSNA by reducing the maximum RSNA that can be achieved when MAP is lowered. Because the AP is the only hindbrain structure devoid a blood-brain barrier, it has been hypothesized that the central actions of ANG II involve the AP. Not only does lesion of the AP normalize the relationship between MAP and HR during peripheral infusion of ANG II to that of PE (28), but it also attenuates chronic ANG II-dependent hypertension (11) and reduces blood pressure in the mRen-2d transgenic rat (1).

In the present study, we observed that ANG II did not attenuate maximum RSNA at low blood pressure in APX rabbits. It appears then that APX normalized the maximum RSNA response at low blood pressure to that of control. This interpretation is limited due to the use of whole nerve activity measurement as an index of sympathetic outflow because placement of electrodes and the number of nerve fibers make absolute comparisons between animals difficult. It is possible that absolute sympathetic outflow could be different between intact and APX animals and not detected by these methods. However, coupled with the fact that baseline MAP and HR were not different from intact groups, and that previous studies have shown that plasma catecholamines are similar to intact animals after recovery from AP lesion (9, 33), it is unlikely that sympathetic outflow was different between the groups. It could also be argued that damage to the NTS tract during AP lesion altered the regulation of the arterial baroreflex such that effects of ANG II were masked. However, this also seems an unlikely explanation for the differences observed between intact and APX rabbits. First, there was no difference in the sensitivity of the arterial baroreflex between the groups. Second, there was no visible evidence that lesion of the AP resulted in damage to the NTS. Finally, an increase in lability of MAP, which would be expected if significant damage to the NTS had occurred (7), was not observed in APX rabbits compared with intact rabbits.

It is unclear why AP lesion resulted in a significant reduction in P4 of HR. In rats maintained on a low-sodium diet, AP lesion did not affect the minimum plateau of HR (42). However, direct comparisons between these two studies are difficult due to differences in species and diet. It might be reasoned that AP lesion removed a low level tonic influence of circulating ANG II on parasympathetic control of HR; however, losartan administration to conscious rabbits on a regular diet did not affect the minimum plateau of HR even though it shifted the relationship between MAP and HR toward lower pressures (24).

The acute pressor response to ANG II was accompanied by a reflex bradycardia in APX rabbits; a response not observed in intact rabbits. Furthermore, subsequent assessment of arterial baroreflex control of HR revealed that the relationship between MAP and HR was not reset toward higher pressures in APX rabbits. These observations are in agreement with previous studies that have concluded that central actions of ANG II to attenuate reflex bradycardia involve the AP (9, 28). The enhanced bradycardia in APX rabbits during infusion of ANG II may contribute to the reduced pressor response to ANG II infusion. Moreover, APX might also have prevented an acute shift in arterial baroreflex control of SNA toward higher pressures, which could also attenuate an acute pressor response to ANG II. In this regard, the small, but significant, increase in P3 that we observed in intact rabbits in response to ANG II infusion was not evident in APX rabbits.

A secondary objective of the present study was to determine whether acute modulation of arterial baroreflex control of RSNA by ANG II could be localized to medullary neural circuits involved in cardiovascular regulation. In decerebrate rabbits, the effect of ANG II to attenuate maximum RSNA in response to baroreceptor unloading was abolished suggesting that supramedullary structures are indeed involved. It is possible, however, that some uncontrolled variable arising from the decerebration procedure itself affected the results. For example, surgical stress of decerebration potentially elevated endogenous ANG II to levels that completely masked any effect of exogenously infused ANG II. We cannot rule out this possibility because neither plasma renin nor ANG II concentrations were measured. However, decerebration did not alter baseline MAP, RSNA, or arterial baroreflex control of RSNA, which might have been expected if ANG II levels were high. Note that unlike the limitation of comparing whole nerve recordings as a measure of SNA between APX and intact rabbits, RSNA measurements before and after decerebration were made in the same animal and normalized to the control maximum before decerebration. These results are supported by earlier studies that showed in cats that the pressor response to carotid occlusion was not significantly affected by decerebration (8, 22). Although decerebration did not change baseline MAP or RSNA, it resulted in a significant reduction in HR. Furthermore, arterial baroreflex control of HR was greatly attenuated as indicated by a significantly reduced range (P1), maximum (P1 + P4), and gain. The present results are similar to our previous observations in rabbits, which showed that decerebration reduced baseline HR and attenuated the slope of the relationship between MAP and HR during ramp increases in pressure (39). Histological verification in our rabbits demonstrated that decerebration involved the rostral portion of the pons. This level of decerebration may explain the dramatic fall in HR observed in the present study following decerebration. An early study in dogs demonstrated that the effect of decerebration on HR depended on the level of decerebration (21). These investigators showed that when ether-anesthetized dogs were decerebrated at the midpontine level following midcollicular decerebration, HR significantly decreased. They attributed the effect of midpontine decerebration to a disruption in the balance between facilitory and inhibitory influences on parasympathetic outflow. Similar observations have been made in anesthetized cats (14).

Previous work from our laboratory showed that decerebration did not alter the ability of AVP to facilitate reflex inhibition of SNA (39). Because transection of the brain at this level interrupts neural connections to the hindbrain originating from forebrain circumventricular organs, the authors hypothesized that the action of AVP to influence the arterial baroreflex occurred through a direct action on AP neurons. Data in the present study indicate that, while involving the AP, the ability of ANG II to attenuate reflex disinhibition of RSNA involves additional neural mechanisms rostral to the decerebration. It was recently reported that acute, lateral ventricle infusion of ANG II in conscious sheep inhibited RSNA independent of a change in blood pressure (30). This raises the possibility that forebrain structures, in addition to the AP, are involved in the acute effects of ANG II on arterial baroreflex control of RSNA. The mechanisms and pathways through which this interaction might occur are not known. Single-unit recordings obtained from AP neurons show that these neurons can be influenced by stimulation of the paraventricular nucleus (37). Additionally, studies using a brain slice preparation have shown that a small percentage of AP neurons that increased their activity in response to ANG II did not respond after low calcium/high magnesium blockade of synaptic transmission (38). Together, these studies raise the possibility that descending inputs from the forebrain may influence the response of AP neurons to circulating peptides.

Because decerebration in the present study involved the rostral portion of the pons, which includes the parabrachial nucleus (PBN), we cannot limit the discussion to an elimination of interactions between the forebrain and hindbrain. Electrical stimulation of the PBN influences both MAP and HR (2, 18, 19). Because the AP and PBN make reciprocal neural connections (36), it is reasonable to think that the acute effects of ANG II on reflex control of RSNA might depend on both of these structures. Fink and co-workers (13), reporting that bilateral lesion of the lateral PBN in rats attenuates the chronic pressor response to ANG II, have provided evidence for such an interaction. However, whether lesion of the PBN also eliminates acute actions of ANG II to attenuate sympathetic disinhibition is not known.

Although decerebration did not alter baseline MAP, the pressor response to ANG II infusion was attenuated in decerebrate rabbits. It is possible that the surgical stress of decerebration increased endogenous ANG II to levels that competed for receptor binding with exogenously infused ANG II. Because neither plasma renin activity nor plasma ANG II were measured in the present study, this possibility cannot be ruled out. Another possibility, however, relates to our observation that during infusion of ANG II, RSNA decreased to levels similar to that observed in control even though the pressor response was attenuated. This suggests that decerebration may facilitate arterial baroreflex inhibition of RSNA during infusion of ANG II.

In conclusion, this study demonstrates that the attenuated disinhibition of RSNA during acute infusion of ANG II involves the AP. However, this action of ANG II cannot be localized to central sites caudal to the level of decerebration. In fact, the data indicate that supramedullary sites may be necessary. The nature of any neural interactions between medullary and supramedullary sites in the acute effect of ANG II on arterial baroreflex control of RSNA remains to be determined.


    ACKNOWLEDGEMENTS

We thank Linda Stahl and Matt Riley for technical assistance and Sue Garner for help in preparing this manuscript.


    FOOTNOTES

This study was supported by National Heart, Lung, and Blood Institute Grants HL-36080, HL-12415, and HL-59326.

Address for reprint requests and other correspondence: V. S. Bishop, Dept. of Physiology, MC 7756, Univ. of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900 (E-mail: Bishop{at}uthscsa.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpheart.00222.2001

Received 21 March 2001; accepted in final form 18 December 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 282(5):H1592-H1602
0363-6135/02 $5.00 Copyright © 2002 the American Physiological Society


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