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Am J Physiol Regul Integr Comp Physiol 279: R1910-R1921, 2000;
0363-6119/00 $5.00
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Vol. 279, Issue 5, R1910-R1921, November 2000

Carotid and aortic baroreflexes of the rat: I. Open-loop steady-state properties and blood pressure variability

Barry R. Dworkin1,2, Susan Dworkin1, and Xiaorui Tang1

1 Department of Behavioral Science and 2 The Neuroscience Program, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

To characterize the baroreflex in central nervous system-intact neuromuscular-blocked rats, we measured the vascular and cardiac responses and compared direct stimulation of the aortic depressor nerve (ADN) with a capacitance electrode (differentially activating either A or A + C fibers) to carotid sinus pressure with a micro-balloon (SINUS). One-thousand-two-hundred-ninety-seven open-loop measurements of systolic blood pressure (SBP), heart rate, venous pressure (VBP), and mesenteric (msBF), femoral (fmBF), and skin (skBF) blood flow were completed; the linear range of the effects was determined for each response and stimulus mode. The rats were sinoaortic denervated (SAD). The open-loop stimulation effect was very stable; e.g., the mean effect of 790 ADN stimulations during >7 days was -9.8 mmHg, with an average drift of +0.001 mmHg/h. In contrast, there was large variability of the SBP baseline (e.g., SD = ±10.9), which was due to SAD (±6.3 to ±16.3 mmHg, t = -13.9, df = 4, P < 0.0002) and was reversed by ganglionic block (±10.8 to ± 2.9 mmHg, t = -12.9, df = 3, P < 0.001). The ADN stimuli produced larger depressor responses than sinus stimuli (-66 vs. -45 mmHg); all component responses paralleled the magnitude of the SBP effect, except interbeat interval (IBI), for which the ADN Delta IBI was approx 10 times that of SINUS. For all stimuli, fmBF increased and msBF did not. Mesenteric and femoral vascular conductance both increased, whereas VBP decreased and skBF followed SBP. We found that for all baroreflex response components, with the exception of SINUS-elicited Delta IBI, there was an orderly, substantially linear, relationship between stimulus strength and response magnitude.

baroreceptors; aortic depressor nerve; carotid sinus; sinoaortic denervation; noise; baroafferent stimulation


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

THE BAROREFLEXES ARE THE MAJOR mechanism of blood pressure (BP) stabilization and are probably the most thoroughly studied example of a regulatory reflex. Two of the central observations in the reflex control of the circulation are that stimulation of the baroreceptors decreases BP (21, 30, 33) and that with destruction of the baroreceptors [sinoaortic denervation (SAD)], there is greatly increased BP variability (2, 4, 5, 20, 23, 32, 36, 38). It is likely that these phenomena are immediately related, but there have been no studies, within the same subjects, that actually reconcile the quantitative properties of the baroreflex with the effects of denervation. There is ample theory to support such an analysis: the mathematical relationship between the input and output spectra and transfer function are well defined for approximately linear systems. What is needed is an appropriate experimental model. The rat is increasingly an important species in the study of cardiovascular regulation; however, although the rat literature on SAD variability is extensive, the only detailed open-loop measurements of baroreflex properties have been acute with surgical-level anesthesia or in animals that were just operated (6). Previously, we described classical conditioning of cardiovascular responses (7, 8), including discriminative auditory conditioning of the aortic depressor nerve (ADN)-elicited baroreflex (8), in intensively maintained, unanesthetized, neuromuscular-blocked (NMB) rats. Because with NMB there is no skeletal muscle function and ventilation is mechanical, cardiovascular effects are not influenced by respiration or general activity. During 10-35 days of a typical NMB experiment, the rats have basal endocrine levels,1 normal vital signs, and typical patterns of BP variability, including diurnal rhythms and sleep cycles (7, 8). NMB rats can be instrumented for a full range of cardiovascular measurements as well as carotid sinus (SINUS) and ADN barostimulation. The ADN stimulation uses a special noncorrosive capacitance electrode, and the SINUS stimulation uses a volumetric balloon in a vascularly isolated sinus. Both methods are capable of exact and reproducible open-loop activation of baroreflex mechanisms, hundreds of times, over many days or weeks.

We exploited the stability and robustness of the stimulation methods and the preparation to repeatedly compare, within the same subject, the linearity and general properties of the various response components at many levels of both SINUS and ADN stimulation. We determined the open-loop baroreflex effects of ADN and SINUS for systolic (SBP) and diastolic (DBP) BP; interbeat interval (IBI); intestinal (mesenteric artery, msBF), skeletal muscle (femoral artery, fmBF), and skin (paw, laser Doppler, skBF) blood flow; venous pressure (VBP); and vagus and peroneal nerve activity. The NMB rats were SAD, and the experimental procedures were entirely automated: barostimulation was prescheduled and administered at random. Thus over hours and days, the experimental stimuli interacted with the unattenuated (by the baroreflexes) effects of natural sources of BP variability. The mechanical SINUS and electrical ADN stimuli were related to one another using Delta SBP as an index of reflex activation and then comparing the subsidiary responses that produced similar Delta SBP. [In the companion paper (10), we give a new method for calibration of the SINUS balloon and ADN electrode stimuli to equivalent vascular pressure.] We found that for NMB rats 1) the patterns and determinants of variability were similar to what has been reported for freely moving rats, indicating that the sources of variability are endogenous to the central nervous outflow and not dependent on general behavior, 2) the variability was unattenuated by averaging in a way that indicated that it is not entirely random in time, and 3) for all baroreflex response components, with the exception of SINUS-elicited heart rate (HR) changes, there was an orderly, substantially linear, relationship between stimulus strength and response magnitude.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

Subjects

Fourteen female Long-Evans rats (CDBS-VAF, Charles River, Wilmington, MA), weighing 225-275 g, were obtained 3-4 wk before the start of an experiment and, after quarantine and examination by a veterinarian, they were housed in groups of four to six in an isolation cubicle at the Central Animal Facilities. The ventilated, central nervous system-intact, NMB rats were individually and carefully maintained with the use of monitoring, life support, and analgesic protocols as stringent as those that are accepted as adequate for critical care of human adults and infants. All actual surgery or physical manipulation was done under precisely controlled and carefully monitored, deep isoflurane anesthesia. The protocol is certified to be in compliance with National Institutes of Health Guidelines by the Pennsylvania State University College of Medicine Institutional Animal Use and Care Committee. The NMB rats are studied one at a time and attended around the clock.

General Procedures

All surgery and instrumentation was done with sterile techniques. During surgery, the anesthetic level was >1.5% isoflurane, which maintained the following states: 1) the electroencephalogram (EEG) was synchronized and dominated by high-voltage slow-wave (delta ) activity; 2) mean arterial pressure <100 mmHg, HR <420 beats/min; and 3) no evident EEG, BP, or IBI responses to manipulation. Isoflurane was delivered into the inspiratory gas stream by a precision mass-flow controller. A low (analgesic 0.15-0.3%) level was maintained between surgical days, for 3- to 4-days postsurgery, and gradually reduced to zero on day 5, when the incisions were completely healed. During the experimental protocols, the rats were ventilated through a per os coaxial tracheal cannula at 72 breaths/min with an inspiratory and expiratory ratio of 1:2 and a minute volume of 180-200 ml and gas concentrations of 50% O2, 47% N2, and 3% CO2, delivered by a precision (±1%/wk) volumetric respirator. Intermittent hyperinflations (6 per hour at 15 cmH2O), positive end-expiratory pressure (1.5 cmH2O), and expiratory CO2 monitoring were continuous.

Surgery

Day 1. Under deep isoflurane anesthesia, the following procedures were performed. Precordial silver wire electrocardiogram (ECG) electrodes were implanted subcutaneously. An abdominal aortic catheter (28-gauge Teflon) was inserted via the left femoral artery, and to administer parenteral solutions and to record VBP, a 0.9-mm Renathane catheter was threaded into the inferior vena cava from the left femoral vein. Pulse transit time (PTT) flow probes (AP01RS, Transonic Systems, Ithaca, NY) were applied to the right femoral artery and to the superior mesenteric artery or the caudal aorta. An ABLF21 laser Doppler flow probe was attached to the right paw. Two 0-80 screws were placed into the skull at lambda and bregma for EEG. Temperature was measured by an implanted intra-abdominal thermistor and servo-regulated at 37°C. Bipolar silver recording electrodes were applied to the cervical vagus and right peroneal nerve. A silicone cannula was inserted in the urethra to continuously record urine output. For the duration of the experiment, nutrition was maintained by infusion of high-nitrogen Vivonex (Vivonex TEN Novartis, Minneapolis, MN) through a surgically placed gastroduodenal feeding cannula (0.030 × 0.065 medical grade silicone).

Induction of NMB

Once a continuous display of IBI, BP, respiratory rate, and expired CO2 had been established, the vital signs stabilized within normal limits and computer alarm routines were set to monitor the depth of anesthesia, 100 µg of alpha -cobrotoxin (Biotoxins, Miami, FL), a specific neuromuscular-blocking agent, were injected intra-arterially. Within 20-30 min, as the drug took effect, mechanical ventilation was begun. NMB was maintained by continuous infusion of alpha -cobrotoxin (250 µg/day).

Parenteral Solutions

For the duration of the experiment, the following solutions were infused intra-arterially (0.37 ml/h): 50 ml H2O, 50 ml 0.5 N lactated Ringer, 500 IU heparin Na, 1.25 g oxacillin Na, 2.8 mg alpha -cobrotoxin, 0.3 mg vitamin K (Synkavite), and 20 meq K+ (as KCl). The following solutions were infused intravenously (0.45 ml/h): 50 ml H2O, 50 ml 0.5 N lactated Ringer, 300 IU heparin Na, 1.25 g oxacillin Na, and 0.5 g ticarcillin disodium.

Baroreceptor Surgery

Day 2. The left ADN was identified, and the Ta-Ta2O5 capacitance electrode was affixed; the left sinus was denervated, the right ADN was cut, and the stainless steel and silicone balloon was inserted into the right carotid sinus (See APPENDIX).

ADN Stimulation

Stimulus trains were generated by a computer-controlled pulse generator (Master-8vp, A.M.P.I., Jerulsalem, Israel).

Electrical parameters. Fan and Andresen (12) described parameters that differentially activate A and A + C fibers; our implementation was as follows. On day 6, thresholds were determined by measuring Delta SBP to 60 s 2- and 40-impulses/s test stimuli of progressively increasing strength presented at six per hour until the Delta SBP of a five-trial average was at least -10 mmHg for three successive replications.

Current and duration. For all rats, A-fiber parameters were 15-50 µA and 100-µs pulse width (PW). A + C-fiber parameters were 80-100 µA and 300-µs PW; thus the A-to-A + C power ratio was approx 1:6, which is comparable to what was described (12, 27). The rate for A was 1-50 impulses/s, whereas the rate for A + C was 1-16 impulses/s.

Sinus Stimulation

The maximum depressor effect was at a volume of <3.5 µl. Because >4 µl could permanently damage the sinus and statistically reliable differences in depressor effect occurred with 0.25-µl increments, test volumes were limited to 0.5 µl greater than a maximum depressor effect.

Schedules

Stimulus presentations were automated and, except during routine maintenance, continuous (stimulation did not affect sleep patterns, and hyperinflations were postponed during trials).

Timing and sequence. Each of the six randomized trials per hour had the following pattern: 2-min baseline, 1-min stimulation, and 2-min baseline. The trials were separated by a pseudorandom (mean = 5 min) intertrial period. The last 30 s of the prestimulus baseline and the first 30 s of stimulus were used for the response calculations.

Stimuli

For SINUS, initially, only <2.25-µl stimuli were presented; the magnitude was gradually increased to identify the maximum test volume. Finally, a random sequence of volumes, of 1 µl to the maximum, was presented. For ADN, the stimuli were initially presented at widely spaced frequencies; then, additional rates were interpolated to locate the maximum depressor effect and to define the linear region (see Fig. 8). Where applicable, ADN-A, ADN-A + C, and SINUS stimuli were intermixed within the same hour to minimize bias in cross-modal comparisons. Complete determinations for all three stimulus modes required ~7-9 days for each rat.

Data Acquisition

Single-beat and 2.5-s resolution data were acquired continuously throughout the experiment; 6-kHz digital audio tape (DAT) recordings of all raw signals (see Fig. 5) were acquired during all stimulation trials. SBP, DBP, VBP, urine flow, and temperature were directly processed in the data acquisition computers; low-level signals (ECG, EEG, peroneal nerve, vagus nerve) were preprocessed by AC preamplifiers (XCELL-3 × 4 40-#40-8B, FHC, Bowdoinham, ME). Additionally, ECG was conditioned by an amplifier-rectifier-integrator circuit. EEG was analyzed online into four power bands: delta  (0.5-3 Hz), theta  (6.5-7.5 Hz), alpha  (8.5-18 Hz), and beta  (20-45 Hz) (#79-78-5, FHC).

Protocols

Response stability. An ADN of two NMB rats was repeatedly stimulated over extended time. To optimize sensitivity to changes in the threshold and response magnitude, the current strength and impulse rate of the test stimuli were set well below saturation; but, to stringently test for fatigue or long-term damage, maximal stimuli were intermixed.

Effects of denervation on variability. In five NMB rats, SBP variability was assessed before and after denervating the baroreceptors.

Effects of ganglionic block on variability. In four chronically SAD NMB rats, SBP variability was assessed before and during 2.5-mg · kg-1 · h-1 infusions of chlorisondamine.

Cardiovascular mechanisms of baroreceptor stimulation. Five NMB rats were implanted with ADN electrodes, of these three also had balloons inserted into an isolated carotid sinus. Graded electrical and hydraulic stimuli were applied. With each kind of stimulation, Delta SBP, Delta msBF, Delta fmBF, Delta skBF, Delta IBI, and Delta VBP were simultaneously measured. The ADN was stimulated to differentially select A or A + C fibers.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

Response Stability

The response measure was the Delta SBP between the 30-s baseline mean and 30-s stimulation mean. In the first rat, during 109 h, the mean baroreflex SBP response (Delta SBP) to a 4-impulses/s stimulus (40 µA, 1 ms, 120 s) was -4.8 ± 11.9, and to a 100-impulses/s (maximal) stimulus, it was -39.0 ± 14.7 mmHg. [LANOVA 4 impulses/s: m = -0.009 mmHg/h, r2 = 0.001, not significant (NS); 100 impulses/s: m = 0.014 mmHg/h; r2 = 0.001, NS]. In the second rat (see Fig. 1A), there were 496 stimulations at 100 µA, 300 µs, 20 impulses/s; and there were 294 stimulations at 100 impulses/s during 173 h. The 20-impulses/s response changed from -9.9 to -9.7 mmHg (LANOVA: 0.001 mmHg/h, r2 = 0.000, NS).


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  		Fig. 1.   Top: the systolic blood pressure (SBP) responses to repeated stimulation with a Ta-Ta2O5 electrode at 100 µA, 300 µs, and 20 impulses/s. The measure is the difference between the mean SBP during 30 s of baseline and 30 s of stimulation. There were 496 stimulations at 100 µA, 300 µs, and 20 impulses/s; and 294 stimulations at 100 impulses/s during 173 h. The 20-impulses/s response changed from -9.9 to -9.7 mmHg (LANOVA: 0.001 mmHg/h, r2 = 0.000, not significant). Bottom: mean SBP differences between successive 30-s null trials. When translated to µ = 0 and evaluated by a Kolmogorov-Smirnov 2-sample test, the distributions are not different (df = 2, chi 2 = 0.600, P > 0.9999).

The stability of the mean change contrasted with its large variance; thus, to measure the variability of the baseline, interleaved null "trials" were also analyzed. In these trials, no stimulus was administered, but the effect was calculated exactly as in the actual test trials. Null trials thus show the unbiased sampling properties of the measurement procedure. For the first rat, the null trial SD was ±11.8 mmHg (compared with ±11.9 for the 4-impulses/s stimulus); for the second rat (Fig. 1B), SD (null) = ±10.9 (compared with ±8.7 mmHg for the 20-impulses/s stimulus). This result indicates that the large variability score was due to baseline variability not to erratically generated stimuli or variability of the baroreflex.

For the SINUS, stimulations at fixed volume also yield consistent average responses even when separated by hundreds of inflations. For example, for a 3.5-µl stimulus, the initial response was -43.2 ± 20.07 mmHg. After 225 h of two 1.5- to 3.5-µl peak-to-peak 5-min sinusoidal inflations per hour (total = 2,250 min), the mean response was -41.8 ± 23.9 mmHg (LANOVA: 0.007 mmHg/h, r2 = 0.00, NS). However, the SD of the SINUS responses was twice that of the ADN, whereas the SINUS SD (null), ±8.98, was similar. Thus, unlike the ADN, the additional variability from the SINUS-elicited baroreflex response increased the overall Delta SBP variance.

Effects of Denervation

Denervation increases variability, and the above rats were effectively SAD (no pulse synchronous activity rostral to the ADN cuff and no detectable bradycardia to 10 µg phenylephrine). Figure 2 shows the effect of SAD on SBP variability in five additional rats. The mean SBP SD before surgery was 6.3 ± 3.5, and after surgery it was 16.3 ± 2.4 mmHg.


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  		Fig. 2.   The effect of sinoaortic denervation (SAD) on SBP variability as measured in 100 random 30-s null difference trials per rat (Delta SD = 9.96, df = 4, t = -13.9, P < 0.0002). The mean SD before surgery was 6.3 ± 3.5, and after it was 16.3 ± 2.4 mmHg. Pre-data were collected between the first and second surgical days, after completion of all general procedures; post-data were collected from the third day after the baroreflex surgery. All measurements were at analgesic (0.15%) levels of isoflurane. At 0.15%, undisturbed neuromuscular-blocked (NMB) rats have normal electroencephalogram (EEG) and baseline interbeat interval (IBI) and SBP levels, but IBI and SBP increase and EEG desynchronizes to loud noise or light touch (see Fig. 2 of Ref. 10). The 2-letter codes identify individual NMB rats; the inserted pre- and postSAD sample records are from EH.

Effects of Ganglionic Block

The result in Fig. 3 suggests that much of the increased SBP variability is related to neural control. The observations were made on four additional surgically similar rats that were given 2.5 mg · kg-1 · h-1 infusions of chlorisondamine, which blocks both the parasympathetic and sympathetic ganglia. The measurements were made more than 5 days after the surgery was completed; thus without isoflurane. The mean preblock baseline SBP of 140.2 decreased to 84.7 mmHg during the block; the mean baseline SBP SD of ±10.8 decreased to ±2.9 mmHg.


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  		Fig. 3.   The effect of ganglionic block on SBP variability. The SD measure was the same as in Figs. 1 and 2; for each rat, there were 200 samples before and 200 samples during the block. The measurements were made more than 5 days after the surgery was completed; thus without isoflurane anesthesia. The mean baseline SD of ±10.8 decreased to ±2.9 mmHg (Delta SD -7.9 mmHg, t = -12.9, df = 3, P < 0.001).

Statistical Analysis of the Variability

For NMB rats, respiration, temperature, and general environmental stimuli are tightly controlled. For example, over the entire 7 days of Fig. 1, baseline SBP was 107.8 ± 16.5 mmHg, core temperature was 37.13 ± 0.06°C, inspiratory pressure was 5.27 ± 2.70 cmH2O, and expired CO2 was 43.88 ± 0.90 mmHg. Variation in these and other recorded variables were not statistically related to the null trial or baroreflex-induced Delta SBP. Typical of all rats described, absolute SBP and absolute arousal level, as estimated by EEG (delta ) power, were correlated, but the 30-s difference samples were not [>36% of the baseline SBP variance could be accounted for by EEG (delta ); only 8% of Delta SBP could be accounted for by Delta EEG (delta )]. The relationship between variance and mean, evident in Fig. 1, characterizes all of the subjects that we have studied, and in addition to Delta SBP, all component response measures and all modes of stimulation. Figure 4 gives the baseline coefficient of variation for major baroreflex mechanisms for the rats in Table 1. The only measure that appears substantially more stable than SBP is IBI; however, this is misleading, because the physiological range of the IBI scale is comparatively constrained, and, relative to the baseline, the baroreflex-Delta IBI effects are much smaller.


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  		Fig. 4.   The baseline coefficient of variation for the major baroreflex mechanisms for all rats in Table 1. The IBI appears more stable; however, the baroreflex-IBI change, relative to baseline, is smaller than the other variables. The 3 right bars are regional flows, and the error bars give the SD. None of the differences are statistically significant.


                              
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  		Table 1.   Summary of the component response effects

Extensive regression and factor analytic exploration have not identified a combination of baseline measures that, when applied to the baroreflex-response data, substantially reduced the variance. For example, for the rat shown in Fig. 1, with the use of a stepwise regression analysis of nine baseline variables, an optimum model was identified that included SBP, IBI, fmBF, and EEG (delta ) power. When the model was applied to the Delta SBP responses in Fig. 1A and the distributions before and after regression correction, compared with the use of a Kolmogorov-Smirnov test, no difference was found (chi 2 = 0.581, df = 2, P > 0.9999). In a parallel analysis for a second rat, an independent stepwise regression procedure identified the same suite of variables, and the result of applying the regression-correction procedure was also similar (chi 2 = 1.03, df = 2, P > 0.9999). The results with four additional rats and other regression methods were comparable; thus so far, we have been unable to identify any variable, or linear combination, or multiplicative dyad of variables that attenuates the Delta SBP SD by >10%.

Analysis of the Effects of Barostimulation

The individual component responses including mesenteric vascular conductance (msVC), femoral vascular conductance (fmVC), skBF, IBI, and VBP were measured in the same subjects during each kind of stimulation. A typical high-resolution record of the initial 6 s of a 3.25-µl SINUS trial is shown in Fig. 5. The maximum response effects are in Table 1; the averages of the maximums over all rats are in the last two columns. For all three SINUS and ADN rats, the maximal ADN stimulus was substantially more effective than the maximal SINUS stimulus in producing SBP decreases; the individual component responses, with the exception of Delta IBI, generally reflect the magnitude of the Delta SBP. Although for strong SINUS stimulation a small Delta IBI was evident in all rats, the maximum Delta IBI to ADN-A was on average five times of that to SINUS.


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  		Fig. 5.   Signals and calculated variables during the initial 6 s of a 3.5-µl (larger Delta IBI; see Fig. 7) carotid sinus pressure (SINUS) trial (The balloon is inflated at the vertical cursor). The instantaneous conductances were calculated at each (6 kHz) sample point; the nerve firing rate traces are the discriminator-counter outputs that were used for the nerve data (#74-60-3A1, FHC) presented in Figs. 6 and 7. The heart rate (beats/min) trace was generated by software detection of the R wave [from the electrocardiogram (ECG) shown] and interpolation of the interbeat time (for other data in the paper, IBI was measured directly by a 10-µs resolution hardware discriminator timer). Venous pressure was measured in the abdominal vena cava; the respiratory variations are from the restraint of venous return by the inspiratory peak of the positive pressure ventilator. The burst pattern of vagus activity, including the initial interburst acceleration, is typical. The decrease in the diastolic flow signals after stimulus onset (which is probably due to vascular capacitance effects) is genuine and highly reproducible.

Because of ceiling effects, for an accurate comparison across stimulation modes, the strengths must be equated and restricted to physiologically realistic values. To do this, we used the Delta SBP as a criterion and modulus for two different response-normalization procedures. For the first procedure, to qualitatively compare response mechanisms across modes, we found a magnitude for both SINUS and ADN-A stimuli that produced a similar (approx -40 mmHg) Delta SBP, and ensemble averaged 20 trials of each stimulus. Figure 6 shows the result for rat EF (similar results were obtained for each of the three rats with both SINUS and ADN). Most perspicuously, compared with the SINUS, the ADN produced a much larger Delta IBI. To visualize the relationship between vagus firing and Delta IBI, 20 maximal volume SINUS trials were split at the median Delta IBI response, and for each subset, the ensemble averages of Delta IBI and vagus firing rate were computed. Larger Delta IBI was accompanied by a larger increase in nerve activity, and the nerve firing anticipated the IBI response (Fig. 7; also see Ref. 10).


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  		Fig. 6.   An ensemble average of 20 stimulations comparing the IBI and right-limb vascular mechanisms for aortic depressor nerve and A fiber (ADN-A) (top) or SINUS (bottom). The stimulus levels were chosen to produce approximately equal Delta SBP. Skin blood flow (skBF) is from a laser Doppler flow meter on the right hindpaw [mTPU = 10-3 tissue perfusion units]; femoral vascular conductance (fmVC) is derived from a femoral artery pulse transit time (PTT) probe. Peroneal and vagus are counts of hardware discriminated >10-µV spikes. Note that the SINUS-Delta IBI scale is expanded and that the ADN-Delta IBI effect is much larger than the SINUS effect. The ADN vagus trace is not shown because stimulus artifact obliterates the recordings.



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  		Fig. 7.   The vagus-IBI relationship. Twenty 3.5-µl SINUS trials were split at the median Delta IBI response; ensemble average of the Delta vagus and Delta IBI for the 10 smaller (A) Delta IBI and 10 larger (B) Delta IBI.

A second, more general normalization procedure was used for quantifying the relative contribution of each response mechanism by stimulus mode. For each of the five rats and for all completed stimulus sets, we determined the linear range of the SBP effect, mapped the stimulus domain corresponding to this range onto a standard scale, and used the scale to systematically compare the maximum size and linearity of the individual component responses. The linear range was determined as follows. The stimulus-response data were least-squares fit with first-, second-, and third-order polynomial functions (see Fig. 8). The ANOVA model-corrected regression coefficients for these expressions were calculated, and the order-of-fit that yielded the largest model-corrected squared coefficient was determined. For all of the SINUS data, probably because of combined stimulus and receptor mechanical factors, the best fit was cubic; for the ADN data in all cases, a quadratic fit was best. The obtained regression equations were differentiated, set to zero, and solved. For the SINUS, the two roots were taken as the minimum and maximum extent of the linear range; for the ADN, the minimum was defined as a stimulus of zero and the maximum as the single root.


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  		Fig. 8.   Polynomial curve fits for SBP vs. SINUS, ADN-A, and ADN-A + C magnitude; the regression coefficients are 0.56, 0.54, and 0.64 (rat EF). For all rats, the best fits to the SINUS data were with third order, and to the ADN data with second-order functions. The polynomial curve fits were used to define the stimulus domain of the linear SBP effect. The large scatter of measurements at each stimulus level is typical and chiefly due to baseline variability (see Fig. 1). In contrast to the individual measurement variability, the means at each stimulus level are consistent; e.g., for these same data, the coefficients for the linear regression of mean values, within the threshold-to-saturation stimulus range, are 0.88, 0.88, and 0.96 (see Table 1).

To calculate the linearity and comparative sensitivity of the component-response effects for each rat and each stimulus mode, the minimum stimulus strength within the previously defined linear Delta SBP range was assigned a value of zero and the maximum a value of 100. (The scale is used in Ref. 10 to define the amplitude and offset of the modulation stimulus within the linear range.) Each response, including Delta SBP, was linear fit with respect to this standardized "percent of Delta SBP linear range" scale, slope, R2, and ANOVA reliability entered in Table 1.

The slope directly compares the efficacy with which different stimulus modes activate particular component responses, and the regression statistics measure the consistency of the effect. Because percentage transformation of the stimulus scale is linear, R2 measures the degree to which each baroreflex-component response is proportional to stimulus magnitude within the threshold-saturation limits of the Delta SBP. Figure 9 shows Delta IBI for ADN-A and SINUS, plotted on the corresponding standardized stimulus scale.


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  		Fig. 9.   SINUS and ADN-A linear regression for Delta IBI (rats EF and EH). Comparing the ordinates shows that the SINUS-Delta IBI effect is far smaller; but, the graphs further show that, for the ADN-A, the Delta IBI has a more consistent relationship to stimulus magnitude. Table 1 gives this "dose-response" relationship for each rat and each component response; e.g., the R2 values for Delta SBP are nearly the same for SINUS or ADN-A.

Comparison Between Balloon and Open SINUS

McKeown and Shoukas (26) described a chronic method for directly applying hydraulic stimulation to the carotid sinus. To compare volumetric (balloon) and hydraulic stimulation, we prepared two chronic NMB rats with isolated and cannulated sinuses. With the use of a saline column, the maximum Delta SBP (at 170-200 mmHg) were -30.1 and -40.4 mmHg (which were similar to those in Ref. 26 and to the balloon maximums in Table 1). The slope for the first rat was -0.22 mmHg/mmHg, and for the second rat it was -0.20 mmHg/mmHg (Fig. 10), which are both similar to approx -0.22 mmHg/mmHg reported for a double-open sinus in conscious Sprague-Dawley rats (26).


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  		Fig. 10.   The relationship between carotid sinus pressure (CSP) and Delta SBP in a rat with an open (without balloon), isolated sinus (LANOVA: m = -0.20 mmHg/mmHg, R2 = 0.96, P < 0.003). The preparation followed McKeown and Shoukas (26).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

Baroreflex-Stimulation Methods

ADN. A silicone-embedded Ta-Ta2O5 electrode is an accurate and consistent method to chronically stimulate the ADN. Of the 13 NMB rats that had Ta-Ta2O5 electrodes, the median functional time for the electrode was 18 days (8-67 days), and 9 of the rats had stretches of >10 days during which the stimulation effects were constant to less than ±10%. Thus the electrode is practical for repeated quantitative stimulation of baroreflex pathways in complicated within-subjects experimental designs.

SINUS. Unlike the dog chronic reversible sinus (34, 35), rat sinus preparations do not restore the intramural circulation between sessions. The baroreceptors themselves have a stable blood supply from small vessels that travel with the glossopharyngeal and sinus nerve and are not rendered ischemic by sinus isolation (24, 25); however, with isolation, ischemia of the vessel wall causes degenerative changes, including necrosis, revascularization, and scar formation, which almost certainly affect elasticity and thus compliance. As the compliance of the isolated sinus changes with time, the proximal stimulus, i.e., receptor stretch, at a designated pressure also changes. Although balloon stimulation lacks ostensible BP equivalence, it also does not depend on the vessel modulus of elasticity, and thus in practice, the stimulus can be more accurately and repeatably applied.

Baroreflex Mechanisms

The skeletal, visceral, and cutaneous circulations subserve separate functions and are potentially differently affected by various modes or intensities of baroreceptor input. Within the technical constraints of one laser Doppler and two PTT channels, we chose representative vascular fields and measured changes in flow to barostimulation. In four of five of the subjects, we measured superior msBF. However, preliminary analysis of the data showed that although msVC increased substantially, the actual flow increment was negligible; consequently, in the fifth rat (EH), we placed the second PTT probe on the aorta, caudal to the superior mesenteric artery. This location, which included the femoral, inferior mesenteric, iliolumbar, and caudal arteries, gave a broad sample of skeletal and visceral abdominal flow, which together increased substantially to baroreceptor stimulation (Table 1). In anesthetized rats, the observations of Faber and Brody (11), using the entire superior laryngeal nerve, and Hebert and Marshall (16, 17), using strong carotid inflation (approx 250 mmHg), closely accord with ours. With the use of ADN stimulation, Machado et al. (22) found msVC substantially decreased in anesthetized rats and slightly decreased in semichronic awake (24- to 48-h postsurgery) rats (6). Assuming that the plantar flow of the paw approximately represents skin, taken together, our results indicate that in the NMB rat, the skeletal circulation has a large, probably dominant role in the baroreflex regulation of BP.

Baroreceptor Mode

We use the terms "A fiber" and "A + C fiber" to describe low-current, high-rate and high-current, low-rate stimulation of the ADN (12, 27). Others have reported that A or C fibers could be differentially stimulated [Fan and Andresen (12) confirmed this by capsaicin block of the C fibers]. However, in fact, there is no straightforward way of entirely avoiding stimulation of A fibers [Fan et al. (14) describe the use of anodal block to prevent A-fiber activation, but the block duration is limited.] However, at C fiber effective rates, A fiber activation is probably minimal. With the use of parameters similar to Fan and Andresen (12), we obtained similar response curves, with high-current effects asymptotic at ~10 impulses/s (Fig. 8) and low-current effects continuing to increase up to ~40 impulses/s.

There were no obvious differences between the A and A + C fiber baroreflex-response patterns, and the SINUS vascular patterns were also similar. However, the SINUS and ADN-Delta IBI effects were quite different. Table 1 shows that the ADN maximum Delta IBI is from 2 to 25 times larger than that of the SINUS; and the Delta IBI is disproportionately larger than Delta SBP, which is 1.5 to 2 times larger for ADN than SINUS (Table 1). Figure 9 shows the relationship between the Delta IBI change and stimulus magnitude. Whereas the ADN effects are orderly and linear, the SINUS effects are scattered. However, in contrast to Delta IBI, the R2 values for SINUS and ADN-Delta SBP effects are similar (Table 1). Fan et al. (13) reported differences in the Delta IBI for ADN and carotid sinus nerve in anesthetized rats (compare with their Figs. 3 and 6), and unanesthetized ADN-transected (sinus intact) rats show greatly attenuated Delta IBI responses to phenylephrine (3). Compared with vascular conductance changes, baroreflex-Delta IBI effects are quite small and are probably of little regulatory significance; however, because Delta IBI responses to vasoactive drugs are used extensively to measure baroreflex gain and to confirm denervation, they are of importance: we have relied on the "phenylephrine test" in the past (9), and in the present studies, so have others. Schreihofer and Sved (32) have cautioned that taking the absence of Delta IBI as evidence of denervation is potentially misleading, and it seems increasingly clear that, under some circumstances, sinus stimulation can produce a substantial depressor response with practically no Delta IBI and, correlatively, rats with almost no Delta IBI to pharmacologically induced BP change can have completely intact carotid sinus innervation.

Properties of BP Variability

The large random SBP variability, evident in Fig. 1, is not peculiar to NMB but is generally characteristic of unanesthetized SAD rats (see Refs. 13 and 29 for the effects of anesthetics). In freely moving SAD rats, Jacob et al. (20) reported that SAD increased the SBP SD by a factor of three over controls. Schreihofer and Sved (32) reported preSAD SD approx ±4 and postSAD SD approx ±12 mmHg; Machado et al. (23) reported preSAD SD ±3.6 and postSAD SD ±13.6 mmHg; Trapani et al. (38) reported preSAD SD approx ±5 and postSAD SD approx ±15 mmHg; Buchholz et al. (4) reported preSAD SD ±6.2 and postSAD SD ±22.5 mmHg; and Alper et al. (2) reported preSAD SD ±6.5 and postSAD SD ±19.6 mmHg. These results compare with our values of ±6.3 ± 3.5 and ±16.3 ± 2.4 mmHg for pre- and post-SAD SD. [For historical reference in 1973, Cowley et al. (5) obtained values of ±10.9 for normal and ±20.6 for SAD dogs.]

That equivalent variability persists with NMB indicates that the variability is not a trivial artifact of, for example, respiration, skeletal movement, or thermoregulation; whereas ganglionic block (see Fig. 3) confirms that a major constituent depends on neural activity, again similar to freely moving rats, where Jacob et al. (20) found that chlorisondamine reduced postSAD variability by a factor of approx 3 and Alper et al. (2) found that it decreased from approx ±17 to approx ±7 mmHg. (In intact rats, with block, there is somewhat increased variability; consistent with a fraction of the increased variability being due to nonneural mechanisms that are buffered by an intact baroreflex.)

Consequences of BP Variability

Because noise confounds experimental observations, the greatly increased variability with SAD has practical consequences for open-loop baroreflex studies. Our response measure, the difference between a 30-s baseline mean and a 30-s baroreceptor-stimulation mean, is similar to that used by many others (11-13, 16, 17, 28, 29, 37) and was chosen to allow the response to asymptote but not fatigue. For this measure, fluctuations of period <10 s are subsumed in each average, and of >120 s, canceled in the difference (see Ref. 10); but, in fact, we found that postSAD variability was relatively unaffected by this within-response averaging, and a mean of many separate responses was needed to accurately estimate baroreflex effects.

More fundamentally, it appears likely that the variability that emerges postSAD is normally attenuated by the negative feedback of the baroreflex. In a companion paper (10), we consider whether the frequency spectrum of the variability and the transfer function of the baroreflex are mutually consistent with this interpretation.

Perspectives

In explaining to medical students his and Cowley's classic observations of the effects of the baroreceptors on BP variability, Guyton (15) wrote, "Note the extreme variability of pressure in the denervated dog caused by simple events of the day such as lying down, standing, excitement, eating, defecation, noises, and so forth." Guyton's explanation reflects the conventional notion of baroreflex operation; the baroreflex is engaged on those particular occasions when BP regulation is directly challenged by extrinsic demands, such as postural adjustments, exercise, or digestion. However, if the variability that emerges after SAD is, in an intact animal, normally attenuated by the negative feedback effects of the baroreflex, then it follows that the usual conception is not correct. Instead, the baroreflex is engaged frequently, repeatedly, usually randomly, and as the data from NMB rats presented here show, without any need of skeletal activity.


    APPENDIX
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

Isolation of the ADN

We located the SLN at the thyroid cartilage and, at approx 20×, dissected toward the bifurcation to approx 5 mm from the cartilage, where the ADN enters the main trunk of the SLN via a small "delta" of nerve and connective tissue.

Verification. Stimulation (30-70 µA, 300-µs pulses at 2-50 impulses/s) under (approx 1.5% isoflurane) anesthesia elicits a gradual (30-90 s to asymptote) monotonic impulses/s and current-dependent depressor response, which includes bradycardia, hypotension, and vasodilatation and does not convert to a pressor pattern with very strong (>500 µA) stimulation.

ADN electrode. The anodized Ta-Ta2O5 electrode (Fig. 11) is polarized and was driven by the positive terminal of an optical isolator (CCIU-8, FHC), and the cathode was 2-cm s/s wire and imbedded in an adjacent muscle. (Electrochemical reaction products at the cathode disburse harmlessly in the muscle.)


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  		Fig. 11.   The ADN electrode. Noncorrosive Ta-Ta2O5 capacitance electrode constructed from a commercially produced high-density capacitor slug. The electrode is a semiconductor diode with a low-forward impedance and an extremely high-back capacitance (~1.7 µF, 40-V breakdown). To allow discharge between stimulation pulses, the isolator had a switched interpulse output shunt. The stem of a Ta capacitor slug (a) (PML, Tokyo, Japan) and a 15-cm flexible lead wire of 0.1-mm vacuum annealed Ta wire (c) (California Fine Wire, Grover Beach, CA) were crimped into a 2-mm section of Ta tubing (b) (Uniform Tubes, South Plainfield, NJ) and anodized at 40 V (8). (The wire was enclosed in a silicone jacket.) The device shown has been implanted in several different NMB rats and used for hundreds of total hours of stimulation. Arrow shows the ADN location.

Embedding. After testing, s/s wing-shaped microhooks were placed in the neck muscle surrounding the electrode site to stabilize and prevent twisting of the nerve. The electrode was then repositioned under the nerve, approx 800 µm above the muscle, and the field was thoroughly dried. The embedding compound (KWIK-CAST, WPI, Sarasota, FL), which was injected through a 25-gauge tip directly under the electrode, rises to engulf the electrode and nerve and seal to the silicone jacket.

Isolation of the SINUS and Insertion of the Balloon

A threader was passed through the caudal aspect of the right bifurcation; and 7-0 silk suture captured, pulled through the bifurcation, and tied, ligating the external carotid, caudal to the carotid body artery. An s/s cannula was introduced into the common carotid and preloaded with a pair of 0.635-mm 316 s/s balls (Salem Specialty Ball, Canton, CT), which were flushed in toward the bifurcation. The balls, which can pass the pterygopalatine and cervical portion of the internal carotid but not the posterior lacerated foramen or carotid canal, lodge snugly in each of the branches and isolate the sinus. After the cannula was removed, the balloon (Fig. 12) was introduced and gradually advanced to where the front of the back ferrule was adjacent to the external carotid ligature. A 4-0 suture was passed under the artery and secured behind the ferrule; the 7-0 suture was then tied to the 4-0 suture, accurately and permanently fixing the balloon position relative to the bifurcation. Typically, the SINUS response is depressed for 12-24 h after the surgery, and it reaches asymptotic sensitivity and stability within 3 days.


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  		Fig. 12.   The sinus balloon. At ~3.5 µl, the expansion is almost entirely radial and uniform over the length. Fabrication was with s/s Tubing and compression fittings, without any adhesive seals. The shaft is 26-gauge s/s tubing, and the balloon is 0.037 × 0.025 RenaSil (Braintree Scientific). The balloon shown was used for >1,000 inflations. The inflation pressure at 2.5 µl is >1,000 mmHg; thus the balloon is effectively volumetric.

Balloon stimulus control. The volume was controlled by a servo, constructed from an (-3 dB at 7 Hz) analog plotter. Linear motion of the plotter was hydraulically transmitted, from the plunger of a rigidly fixed 10-µl syringe (Hamilton gastight 1700 series, Reno, NV) mechanically coupled to the x-axis via rigid Teflon tubing, to the balloon.


    ACKNOWLEDGEMENTS

We thank K. P. McKeown and A. A. Shoukas for generously sharing expertise and knowledge. We also thank L. H. Beltz of EMI (Pottstown, PA) and T. Takemura of PML (Tokyo, Japan) for supplying raw capacitor slugs and technical advice. Isoflurane was generously provided by Ohmeda (Murray Hill, NJ).


    FOOTNOTES

The studies were supported by Grant HL-40837 to B. R. Dworkin from the National Heart, Lung, and Blood Institute, Division of Heart and Vascular Diseases.

Address for reprint requests and other correspondence: B. R. Dworkin, Pennsylvania State Univ. College of Medicine, Hershey, PA 17033 (E-mail: brd1{at}psu.edu).

1 Basal (BL) corticosterone levels are normal and rise in response to auditory disturbance showing that secretory function is not impaired. For two of the rats: BL = 7.88 µg/dl, and it increased to 32.3 µg/dl; BL = 3.9 µg/dl, and it increased to 20.1 µg/dl.

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 31 January 2000; accepted in final form 7 June 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 279(5):R1910-R1921
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