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Am J Physiol Heart Circ Physiol 279: H1804-H1812, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 4, H1804-H1812, October 2000

Angiotensin II acutely attenuates range of arterial baroreflex control of renal sympathetic nerve activity

Max G. Sanderford and Vernon S. Bishop

Department of Physiology-7756, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Acutely increasing peripheral angiotensin II (ANG II) reduces the maximum renal sympathetic nerve activity (RSNA) observed at low mean arterial blood pressures (MAPs). We postulated that this observation could be explained by the action of ANG II to acutely increase arterial blood pressure or increase circulating arginine vasopressin (AVP). Sustained increases in MAP and increases in circulating AVP have previously been shown to attenuate maximum RSNA at low MAP. In conscious rabbits pretreated with an AVP V1 receptor antagonist, 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 MAP and RSNA when the acute pressor action of ANG II was left unopposed with that when the acute pressor action of ANG II was opposed by a simultaneous infusion of sodium nitroprusside (SNP). Intravenous infusion of ANG II resulted in a dose-related attenuation of the maximum RSNA observed at low MAP. When the acute pressor action of ANG II was prevented by SNP, maximum RSNA at low MAP was attenuated, similar to that observed when ANG II acutely increased MAP. In contrast, intravertebral infusion of ANG II attenuated maximum RSNA at low MAP significantly more than when administered intravenously. The results of this study suggest that ANG II may act within the central nervous system to acutely attenuate the maximum RSNA observed at low MAP.

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


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE PRESSOR RESPONSE TO ACUTE INFUSION of angiotensin II (ANG II) involves a different mechanism than the pressor response observed during chronic infusion of ANG II. Increases in mean arterial pressure (MAP) during acute infusion involve vasoconstrictor actions of ANG II on peripheral ANG II type I (AT1) receptors (34). The rise in MAP in response to activation of these peripheral receptors initiates a reflex reduction in sympathetic nerve activity (SNA), thereby reducing the contribution of the sympathetic nervous system to the maintenance of blood pressure. This has been observed as a reduced depressor response to ganglionic blockade after short-term elevations in circulating ANG II (10, 21, 36). Furthermore, comparable decreases in renal sympathetic nerve activity (RSNA) have been observed when arterial pressure is increased to similar levels using either ANG II or phenylephrine (PE), suggesting that reflex-mediated sympathoinhibition is not acutely altered by ANG II (20, 25).

Hypertension resulting from chronic infusion of ANG II increases the contribution of the sympathetic nervous system to the maintenance of blood pressure (10, 15, 21, 36). In these studies, the depressor response to ganglionic blockade returns toward the preinfusion level despite a sustained elevation in MAP. This apparent increase in sympathetic neural outflow relative to the level of MAP is thought to involve an upward resetting of the operating point of the arterial baroreflex toward higher arterial blood pressures. Although the mechanism(s) by which chronic ANG II increases sympathetic neural outflow relative to the level of MAP remains poorly understood, data suggest that this effect of ANG II may involve circumventricular organs such as the area postrema (AP) (10, 14). This is in contrast to observations concerning the effect of ANG II on arterial baroreflex control of heart rate (HR), where acute infusion of ANG II in conscious animals resets arterial baroreflex control of HR to higher blood pressures almost immediately (7, 20, 28, 30). Although the resetting of the MAP-HR relationship to a higher blood pressure involves the parasympathetic nervous system (23, 29, 30), it still requires an intact AP (10, 24).

In investigating the acute effects of ANG II on arterial baroreflex control of SNA, the focus of prior studies has been to evaluate the effects of ANG II on the sensitivity of the reflex and whether the reflex has been reset to higher blood pressures (17, 20). We recently observed that acute infusion of ANG II, while not altering the gain or the operating point of arterial baroreflex control of RSNA, reduced the maximum increase in RSNA in response to a decrease in MAP (28). This observation raised the possibility that the acute effect of circulating ANG II attenuates the range of RSNA observed during changes in arterial blood pressure. The integrative mechanisms that underlie this observation are not known.

The reduced RSNA range may result from several actions of ANG II. One possible mechanism may be related to the acute, sustained pressor effect of ANG II. Previous studies have demonstrated that a short-term elevation in MAP alters the ability to reflexly increase SNA (12, 33). A second mechanism may relate to the ability of ANG II to increase circulating levels of arginine vasopressin (AVP) (6, 8, 31). AVP has been shown to reduce the maximum RSNA at low MAP and reset the MAP-RSNA relationship toward a lower MAP through central actions involving the AP (27, 32). Consequently, it was hypothesized that acute modulation of arterial baroreflex control of RSNA by ANG II occurs secondary to reflex modulation produced by acute, sustained hypertension and/or increased circulating AVP. Thus the goal of the present study was to compare the effect of ANG II on arterial baroreflex control of RSNA and HR when the pressor action of ANG II was opposed, or not, by sodium nitroprusside (SNP) in conscious rabbits pretreated with the vasopressin V1 receptor antagonist.


    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 kg body wt; intubated; and mechanically ventilated with room air when necessary. With the use of sterile surgical 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 SNP (Sigma). A double-lumen catheter was inserted into the right external jugular vein for infusion of ANG II (Sigma) and PE (Elkin-Sinn). Catheters were flushed with heparinized saline at least every other day to maintain patency. After at least a 6-day recovery from catheter implantation, rabbits were anesthetized as described above, and 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. At least 2 days were allowed for rabbits to recover from surgical implantation of renal nerve electrodes before experimentation. Catheters, electrode wire, and ground wire were tunneled under the skin and exteriorized at the dorsal neck. For infusion of ANG II into the vertebral circulation, a Teflon-tipped catheter was inserted into the right common carotid artery as previously described (28). The tip of the catheter was advanced to the junction of the right carotid and brachiocephalic arteries. The right subclavian artery was ligated in these animals to increase direction of blood flow into the vertebral artery. 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.

Recording Procedure

Pulsatile arterial pressure and HR were monitored via the femoral arterial catheter by use of 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 with the use of a Grass P511K preamplifier. Whole nerve activity was obtained by rectifying and integrating the recorded alternating current 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 computer with 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. After all electrode and catheter leads were connected on the day of the experiment, 3 mU · kg-1 · min-1 AVP (Sigma) were infused intravenously for 3 min, and changes in MAP, HR, and RSNA were recorded. The rabbits were then allowed to stabilize for 45 min before experimentation. Ten minutes before collection of all arterial baroreflex function data, each rabbit was treated with a 15 µg/kg intravenous dose of the AVP V1 receptor antagonist, [d(CH2)51,O-Me-D-Tyr2,Val4,Arg8]-vasopressin (Bachem), to eliminate effects of endogenous AVP. At the end of the experiment, the infusion of AVP was repeated. Only data from animals in which there was no change in MAP, HR, or RSNA in response to infusion of AVP were included in the study.

Experiment 1. The purpose of this experiment was to determine the effect of 10 and 20 ng · kg-1 · min-1 ANG II on baseline MAP, RSNA, and HR and arterial baroreflex control of RSNA and HR in rabbits pretreated with an AVP V1 receptor antagonist when the acute pressor action of ANG II was prevented. For this study, rabbits were divided into two groups. In the ANG II group (n = 8), the relationship between MAP and RSNA or HR was obtained during 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. MAP was raised or lowered until an obvious upper or lower plateau in RSNA was observed. Rate of MAP change was manually controlled between 0.25 and 1.0 mmHg/s. After at least a 30-min recovery period, 10 or 20 ng · kg-1 · min-1 ANG II (Sigma) were infused into the jugular vein. The effect of ANG II on baseline MAP, RSNA, and HR was determined by comparing a 30-s average of these values recorded before and after infusion of ANG II for 5 min. At this point, while the infusion of ANG II was maintained, the relationship between MAP and RSNA or HR was again obtained. This time point after ANG II infusion was chosen because we have previously observed that infusion of ANG II for 5 min attenuates maximum RSNA at low MAP compared with a control response (28). The order of baroreflex responses that were obtained under resting conditions and during infusion of ANG II was randomized. In the ANG II + SNP group (n = 6), the acute pressor effect of ANG II was prevented by simultaneously infusing SNP via the femoral venous catheter. In all other aspects, the protocol was the same as that described for the ANG II group.

Experiment 2. The purpose of this experiment was to determine the effect of raising MAP, with PE, to a similar level and for a similar duration as that produced by 20 ng · kg-1 · min-1 ANG II on baseline MAP, RSNA, and HR and arterial baroreflex control of RSNA. In five rabbits, PE was variably infused into the jugular vein for 5 min to produce a 15-mmHg increase in MAP. The protocol to determine the effect of PE on baseline MAP, RSNA, and HR and arterial baroreflex control of RSNA was the same as that for the ANG II group in experiment 1.

Experiment 3. In this experiment, the effects of intravertebral artery (IVA) infusion of 10 ng · kg-1 · min-1 ANG II for 5 min on baseline MAP, RSNA, and HR and arterial baroreflex control of RSNA were determined. The protocol for the IVA group (n = 4) was the same as that for the ANG II group in experiment 1.

Analysis of Arterial Baroreflex Function Curves

Digitized values for MAP, HR, and mean RSNA obtained during ramp changes in pressure were averaged at 0.5-s intervals with the use of a macro written on Chart software. 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 at low MAP in the control curve). The value for maximum RSNA was obtained by taking a 5-s average of RSNA after RSNA had reached a maximum plateau. The data were then fitted with a logistic sigmoid curve function (19) 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 ANG II and ANG II + SNP groups or ANG II and IVA groups were determined with the use of two-way ANOVA with repeated measures. Significant differences determined by ANOVA were evaluated with the Newman-Keuls multiple-range test. Significant effects of PE on MAP, HR, RSNA, and arterial baroreflex control of RSNA and HR were determined by a paired t-test. The change in MAP, HR, and RSNA from baseline during infusion of ANG II at a rate of 20 ng · kg-1 · min-1 was compared with the change in these variables produced by infusion of PE with the use of an unpaired t-test. P < 0.05 was considered significant. All data are expressed as means ± SE.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Experiment 1

There were no differences in MAP, HR, and RSNA among the control values within or between the ANG II and ANG II + SNP groups (Table 1). In the ANG II 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 tended to be greater during infusion of 20 compared with 10 ng · kg-1 · min-1 ANG II, it did not reach statistical significance. In contrast, neither dose of ANG II altered HR in the ANG II group. In the ANG II + SNP group, simultaneous infusion of SNP with ANG II resulted in no change in MAP compared with the internal control values (Table 1). When the increase in MAP during infusion of ANG II was opposed by SNP, RSNA did not change; however, a dose-related increase in HR was observed. In these animals, HR increased from 211 ± 13 to 264 ± 9 beats/min in response to 10 ng · kg-1 · min-1 ANG II (P < 0.05 compared with control and same dose in ANG II group) and from 221 ± 10 to 300 ± 10 beats/min in response to infusion of 20 ng · kg-1 · min-1 ANG II (P < 0.05 compared with control, previous dose, and same dose in ANG II group).

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

Figure 1 shows representative data illustrating the relationship of RSNA and HR to MAP from one rabbit in the ANG II group (Fig. 1, A and C) and from one rabbit in the ANG II + SNP group (Fig. 1, B and D). These data indicate that ANG II acutely attenuates maximum RSNA in AVP V1 receptor-blocked rabbits during unloading of baroreceptors while having little effect on the operating point (defined as the pressure at midrange) or gain. These data also show a tendency to reset arterial baroreflex control of HR toward a higher MAP without alteration of the maximum or range. In addition, these data indicate that attenuation of maximum RSNA does not depend on the acute, sustained pressor effect of ANG II. On the basis of the sigmoid logistic model, the range (P1), maximum (P1 + P4), minimum (P4), MAP at midrange (P3), and gain were determined by use of the best fit to a sigmoid logistic function. The average data for the individual parameters used to describe arterial baroreflex control of RSNA and HR are shown in Tables 2 and 3, respectively. In the ANG II group, infusion of ANG II resulted in a dose-related attenuation of the RSNA range. The reduction in the range was due to a dose-related decrease in maximum RSNA at low MAP from 101.8 ± 1.0 to 78.5 ± 2.8% of the control maximum in response to 10 ng · kg-1 · min-1 ANG II (P < 0.05 compared with control) and from 100.8 ± 1.4 to 66.1 ± 3.8% of the control maximum in response to 20 ng · kg-1 · min-1 ANG II (P < 0.05 compared with control and previous dose). Similar to the ANG II group, the range of and maximum RSNA were reduced during infusion of both doses of ANG II in the ANG II + SNP group (P < 0.05 compared with control). In this group, ANG II delivered at a rate of 20 ng · kg-1 · min-1 tended to cause a greater attenuation than 10 ng · kg-1 · min-1 ANG II, but it did not reach statistical significance. In both ANG II and ANG II + SNP groups, infusion of ANG II had no effect on P3, P4, or gain. Arterial baroreflex control of HR as described by the four-parameter logistic function was not altered by either dose of ANG II in the ANG II group. However, 20 ng · kg-1 · min-1 ANG II in the ANG II + SNP group resulted in a significant increase in P3 of HR compared with both control and the lower dose of ANG II (P < 0.05). Furthermore, both doses of ANG II in the ANG II + SNP group significantly reduced the gain of HR compared with control responses (P < 0.05). After the experiment, no changes in MAP, RSNA, or HR were observed in response to infusion of AVP, indicating that vasopressin V1 receptors were completely antagonized.


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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 venous infusion of ANG II at rate of 20 ng · kg-1 · min-1 () from 1 rabbit in which ANG II increased blood pressure (A and C) and 1 rabbit in which the acute pressor response to ANG II was opposed by a simultaneous infusion of sodium nitroprusside (SNP; B and D). Note that ANG II attenuated maximum RSNA at low blood pressure in both rabbits and caused a shift in arterial baroreflex control of HR to higher pressures. MAP, mean arterial pressure; bpm, beats/min; max, maximum.


                              
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  		Table 2.   Parameters describing arterial baroreflex control of RSNA


                              
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  		Table 3.   Parameters describing arterial baroreflex control of HR

With the use of the parameter values describing arterial baroreflex control of RSNA and HR, average arterial baroreflex function curves were constructed according to the logistic equation. Because the two control values within each group were not different, these values were averaged 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 (Fig. 1, A and B) or HR (Fig. 1, C and D) for both ANG II-treated (Fig. 1, A and C) and ANG II + SNP-treated (Fig. 1, B and D) groups. The solid symbols in Fig. 2 indicate the baseline relationship between MAP and RSNA or HR before baroreflex assessment.


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  		Fig. 2.   Average logistic relationship between MAP and RSNA (A and B) and MAP and HR (C and D) illustrating arterial baroreflex function during acute jugular venous infusion of ANG II at rates of 0 (thick solid line, control), 10 (thin solid line), and 20 ng · kg-1 · min-1 (beaded line) in the ANG II group (A and C, n = 8) and in the ANG II + SNP group (B and D, n = 6). Solid 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.

Experiment 2

Baseline MAP, HR, and RSNA (%control maximum) during control and infusion of PE are shown in Table 1. With the use of the ANG II (20 ng · kg-1 · min-1) data from the ANG II group (n = 8), the changes in MAP, RSNA, and HR were compared with changes in these parameters in the PE group (n = 5). For this comparison, RSNA at baseline MAP was normalized to 100%. Figure 3 shows the change in MAP, RSNA (%baseline), and HR in response to infusion of 20 ng · kg-1 · min-1 ANG II and PE. ANG II and PE similarly increased MAP and similarly decreased RSNA. In contrast, the effect of PE to reduce baseline HR by 28.7 beats/min was significantly greater (P < 0.05) than the change produced by ANG II. The average parameters describing arterial baroreflex control of RSNA during a control response and during PE infusion are shown in Table 2. Note that increasing MAP with PE to a similar level as that produced by 20 ng · kg-1 · min-1 ANG II had no effect on the arterial baroreflex range or maximum RSNA recorded at low MAP. Furthermore, PE did not alter any other parameter. The average logistic relationship between MAP and RSNA during control and infusion of PE is shown in Fig. 4.


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  		Fig. 3.   Average change in (Delta ) MAP (top), RSNA (middle), and HR (bottom) in response to jugular venous infusion of 20 ng · kg-1 · min-1 ANG II (n = 6) and phenylephrine (PE; n = 5). Error bars indicate SE. * P < 0.05 compared with ANG II (20 ng · kg-1 · min-1). Note that for this comparison, RSNA at resting MAP was normalized to 100%. Also note that the Delta MAP produced by PE was similar to that produced by ANG II (20 ng · kg-1 · min-1).



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  		Fig. 4.   Average logistic relationship between MAP and RSNA (n = 5) illustrating arterial baroreflex function during control (solid line) and during a jugular venous infusion of PE that produced a 15-mmHg increase in MAP for 5 min before arterial baroreflex assessment (beaded line). Symbols represent the average relationship between MAP and RSNA during control () and during infusion of PE () just before arterial baroreflex assessment. Error bars indicate SE.

Experiment 3

Baseline MAP, HR, and RSNA during control and infusion of 10 ng · kg-1 · min-1 ANG II for the IVA group (n = 4) are shown in Table 1. In these rabbits, infusion of ANG II significantly increased MAP and significantly decreased RSNA without changing baseline HR. When these values were compared with those of control and ANG II (10 ng · kg-1 · min-1) for the ANG II group, no differences were observed between these values during control or during infusion of ANG II. Table 2 shows the average logistic parameters describing baroreflex regulation of RSNA during control and IVA infusion of 10 ng · kg-1 · min-1 ANG II. IVA infusion of ANG II significantly reduced the range (P1) from 102.0 ± 3.4 to 61.7 ± 5.0% of the control maximum. The reduced range was due to a significant reduction in maximum (P1 + P4) RSNA from 102.2 ± 2.6 to 64.0 ± 4.3% of the control maximum recorded during reductions in MAP. Furthermore, the reduction in RSNA range and maximum observed during IVA infusion of 10 ng · kg-1 · min-1 ANG II was significantly decreased compared with the value observed during jugular venous infusion of 10 ng · kg-1 · min-1 ANG II in the ANG II group. With the use of the average baroreflex parameters obtained from rabbits in the IVA group and from the ANG II group of rabbits receiving 10 ng · kg-1 · min-1 ANG II, the average logistic relationship between MAP and RSNA was reconstructed. These curves, with baseline values indicated by the superimposed symbols, are illustrated in Fig. 5. These data indicate that directing the infusion of ANG II toward the hindbrain results in a greater attenuation of maximum RSNA.


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  		Fig. 5.   Average logistic relationship between MAP and RSNA illustrating arterial baroreflex function during acute jugular venous (solid lines, n = 8) and intravertebral arterial (beaded lines, n = 4) infusion of ANG II at rates of 0 (dark, thick lines) and 10 ng · kg-1 · min-1 (light, thin lines). Symbols indicate the relationship between MAP and RSNA just before arterial baroreflex assessment: , jugular vein control; , during jugular venous infusion of ANG II; , intravertebral artery control; open circle , during intravertebral arterial infusion of ANG II. Error bars indicate SE. * P < 0.05 compared with internal control. dagger  P < 0.05 compared with jugular venous infusion of ANG II at 10 ng · kg-1 · min-1.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present study sought to determine integrative mechanisms involved in modulation of arterial baroreflex control of RSNA during acute increases in peripheral ANG II. The major finding was that maximum RSNA was similarly reduced in conscious rabbits pretreated with an AVP V1 receptor antagonist regardless of the acute pressor action of ANG II. Furthermore, directing the infusion of ANG II toward the vertebral circulation resulted in a greater attenuation of maximum RSNA than when it was infused into the jugular vein. We previously observed that infusion of 20 ng · kg-1 · min-1 ANG II into the vertebral artery of conscious rabbits for 5 min significantly reduced maximum RSNA in response to arterial baroreceptor unloading (28). Because a number of studies have generally concluded that central actions of ANG II are sympathoexcitatory (10, 15, 36), it seemed likely that acute attenuation of maximum RSNA by ANG II was due to secondary actions. Observations made under the conditions of these experiments, however, suggest that ANG II acts centrally to attenuate the range of arterial baroreflex control of RSNA by reducing the maximum response to arterial baroreceptor unloading.

Studies concerning acute effects of ANG II on arterial baroreflex regulation have consistently used doses of ANG II that cause a rapid and sustained increase in MAP (17, 20, 25, 28). On the basis of studies showing that arterial baroreceptor activity quickly adapts to sustained increases in blood pressure (1, 11), it is generally believed that arterial baroreflex control of efferent sympathetic activity will quickly adapt to the prevailing level of blood pressure. However, data from conscious animals provide little support for this hypothesis. While testing the pressure-dependent resetting hypothesis, Undesser and co-workers (33) observed that when blood pressure was quickly returned to control levels after a short-term hypertension, RSNA was slow to recover back to control levels. In fact, the time required for return of RSNA to control levels was dependent on the duration and magnitude of the pressor stimulus. In contrast to increasing SNA relative to MAP, as would be predicted by the pressure-dependent resetting hypothesis, these data suggest that a sustained increase in baroreceptor activation will interfere with mechanisms involved in disinhibition of SNA. Dorward et al. (12) determined the effect of acute hypertension on the entire arterial baroreflex range of RSNA. They found that short-term elevations in arterial blood pressure (15 min) resulted in a reduction of maximum RSNA observed during baroreceptor unloading. This attenuated sympathetic disinhibition was dependent on the magnitude of the pressor stimulus and only partially involves activation of cardiac afferents. Together, these two studies raised the possibility that the rapid and sustained increase in MAP produced by peripheral actions of ANG II before assessment of arterial baroreflex function underlies the attenuation of maximum RSNA that is observed when MAP is subsequently lowered. Results presented in this study demonstrate that this is not the case. First, when SNP was simultaneously infused with ANG II to maintain MAP at control levels, maximum RSNA was reduced to levels similar to those observed when blood pressure was allowed to increase. Second, increasing blood pressure with PE for a similar duration and magnitude as that produced by 20 ng · kg-1 · min-1 ANG II did not alter maximum RSNA. On the basis of these observations, it is concluded that the attenuated sympathetic disinhibition during increases in peripheral ANG II does not result from sustained loading of arterial baroreceptors.

A second mechanism by which increases in peripheral ANG II might secondarily alter arterial baroreflex control of RSNA is through central actions of ANG II to increase circulating AVP, which could, in turn, modulate the arterial baroreflex. An early study showed direct evidence that peripheral ANG II stimulates AVP release (6). However, the effect of ANG II to increase plasma AVP appears to be blunted by arterial baroreceptor afferent input, because the ability of ANG II to increase plasma AVP is much greater when the acute pressor action of ANG II is prevented (8, 31). In these conscious dogs, when the acute pressor action of ANG II is opposed by infusion of SNP, plasma AVP increases to levels that potentially influence arterial baroreflex regulation. Previous studies have demonstrated that circulating AVP facilitates arterial baroreflex-mediated inhibition of RSNA through central actions involving the AP (5, 18, 32). This effect of AVP on the regulation of arterial baroreflex function is characterized by a reduced sensitivity, a resetting of the arterial baroreflexes to a lower blood pressure, and a dose-dependent attenuation of maximum RSNA observed at low MAP (27). To eliminate this possibility, all rabbits in this study were pretreated with an AVP V1 receptor antagonist. Although this study was not designed to determine a specific contribution of AVP to changes in arterial baroreflex control of RSNA during ANG II infusion, the data presented indicate that ANG II reduces the maximum RSNA recorded in response to arterial baroreceptor unloading when possible interactions with AVP are eliminated.

Our results confirm and extend previous observations from our laboratory concerning the effect of acute increases in peripheral ANG II on arterial baroreflex control of RSNA. However, our results differ from conclusions drawn by other investigators (17, 20, 25). 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. Using conscious rabbits, Kumagai and Reid (20) concluded that acutely increasing peripheral ANG II has little effect on arterial baroreflex control of RSNA. These investigators based their reflex data on steady-state responses to four doses of PE and SNP to raise and lower MAP, respectively. Close inspection of their data shows that during ANG II infusion, the largest dose of SNP lowered MAP to only ~65 mmHg. This level of blood pressure closely corresponds to the level at which we observed the upper plateau effect on RSNA during ANG II infusion. Our data are in agreement with theirs in that we observed little effect of ANG II on the gain or the operating point (pressure at midrange) or the MAP-RSNA relationship.

Guo and Abboud (17), using anesthetized rabbits, and Matsumura and co-workers (25), using conscious rabbits, both 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. Although the slope of the MAP-RSNA relationship was not affected by ANG II in these studies, baseline SNA was always normalized to 100%. Because the absolute level of SNA during infusion of ANG II was actually much lower than control, it is difficult to draw straightforward conclusions about maximum RSNA from these studies. 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.

In contrast to the effects of ANG II on RSNA, HR was unaltered when arterial blood pressure increased during infusion of ANG II but increased when the pressor action of ANG II was opposed by SNP. These observations are in agreement with previous studies concluding that ANG II resets arterial baroreflex control of HR to higher pressures by increasing HR relative to the level of MAP (8, 20, 28, 34). The tendency for ANG II to reset the MAP-HR relationship to a higher blood pressure in the present study was more apparent during ANG II infusion, when its pressor action was opposed by SNP. Infusion of 20 ng · kg-1 · min-1 ANG II significantly shifted the curve relating MAP to HR to a higher blood pressure compared with both control and 10 ng · kg-1 · min-1 ANG II in the ANG II + SNP group. It is unlikely that this was a nonspecific effect of SNP to lower central venous pressure (CVP). Previous studies in dogs showed that although SNP alone will lower CVP, coinfusion of SNP and ANG II does not change CVP from the control level (8). The results of the present study suggest that an increase in MAP produced by infusion of ANG II may oppose the central effect of ANG II to reset arterial baroreflex control of HR to higher blood pressures.

The present study was primarily aimed at determining whether the baroreceptor loading that accompanies peripheral ANG II infusion contributes to the integrated effect of ANG II on arterial baroreflex control of RSNA. It is possible that a direct action of ANG II on baroreceptor endings could have contributed to the observed alterations in arterial baroreflex regulation of RSNA and HR. However, this seems unlikely for several reasons. Similar effects of ANG II on arterial baroreflex control of RSNA and HR would have been expected if ANG II was acting this early in the reflex loop. In contrast, we observed qualitatively different effects on arterial baroreflex control of RSNA and HR. Furthermore, a number of earlier studies concluded that ANG II does not change the relationship between MAP and baroreceptor activity (17, 23, 26). Recording from single-unit aortic nerve fibers in an in vitro aortic arch/aortic nerve preparation, Yang and Andresen (35) more recently concluded that several vasoactive agents, including ANG II, do not change arterial baroreceptor activity, independent of their effect on vessel tone. They suggested that increased arch tone produced by ANG II and other vasoactive agents limits pressure-induced stretch of afferent endings and results in lower afferent activity relative to the distending pressure. On the basis of these observations, we would have expected, if anything, for RSNA to be higher at any given MAP during infusion of ANG II compared with control. We observed a similar relationship between MAP and RSNA throughout a wide range of pressures. It was only when MAP was low that ANG II significantly affected the relationship between MAP and RSNA, and this effect was to reduce RSNA relative to MAP. Finally, if peripheral ANG II significantly affected baroreceptor afferent activity through a mechanism sufficient to alter efferent RSNA, a change in the relationship between MAP and RSNA at all levels of MAP would have been expected. This was not observed.

ANG II acutely increases MAP when administration is directed centrally at doses that have little or no effect on arterial blood pressure when administration is directed peripherally (13, 22, 36). Furthermore, increasing MAP with a progressive IVA infusion of ANG II results in greater attenuation of the slope of the relationship between MAP and HR than peripheral infusion (25). These observations suggest that central structures capable of sensing circulating peptides mediate some of the cardiovascular responses to circulating ANG II. Indeed, the physiological significance of this action of ANG II may lie in its ability to interact with other sensory inputs to regulate outflow of the sympathetic nervous system. It was recently shown that fourth ventricle administration of losartan or enalapril enhances sympathetic disinhibition during decreases in MAP in conscious rabbits (2, 16). Although these authors speculated that ANG II mechanisms in the hindbrain tonically attenuate sympathetic disinhibition, the central site involved in this observation was not examined. Because attenuation of the maximum RSNA recorded at low MAP was observed in rabbits pretreated with the AVP V1 receptor antagonist regardless of initial baroreceptor loading conditions, we postulated that peripheral ANG II acts centrally to alter arterial baroreflex control of RSNA. We observed that IVA infusion of ANG II resulted in greater attenuation of the maximum RSNA recorded at low MAP compared with the same dose infused into the jugular vein. Although IVA infusion of ANG II resulted in greater attenuation of maximum RSNA than peripheral infusion, we did not determine the area in the central nervous system that mediates attenuated sympathetic responses to lowering blood pressure in the presence of ANG II. The AP is the only site in the hindbrain that is capable of sensing circulating peptides. Ablation studies in both rats and rabbits have demonstrated that maintenance of ANG II hypertension is dependent on the AP (4, 10, 14). Additionally, an intact AP is required for ANG II to acutely modulate arterial baroreflex control of HR (24). Together, these studies provide evidence to suggest that the AP might be involved in the action of peripheral ANG II to attenuate maximum RSNA at low MAP.

In summary, ANG II attenuated the maximum RSNA observed during baroreceptor unloading when its acute pressor action was opposed in conscious rabbits pretreated with the AVP V1 receptor antagonist. This attenuation of maximum RSNA appears to involve hindbrain mechanisms, because IVA infusion of ANG II resulted in greater attenuation of maximum RSNA at low MAP. Because the AP is the only site in hindbrain lacking a blood-brain barrier, circulating ANG II may act at this site to acutely influence arterial baroreflex control of RSNA.


    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-59326, and HL12415.

Address for reprint requests and other correspondence: V. S. Bishop, Dept. of Physiology-MC 7756, The 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.

Received 30 July 1999; accepted in final form 9 May 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 279(4):H1804-H1812
0363-6135/00 $5.00 Copyright © 2000 the American Physiological Society


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