ATTENUATION OF A PULSATILE PRESSURE COMPONENT IN THE NEURAL ARC OF THE ARTERIAL BAROREFLEX

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1 ATTEUATIO OF A PULATILE PREURE COMPOET I TE EURAL ARC OF TE ARTERIAL BAROREFLEX T. Kawada, M. ugimachi, K. unagawa Department o Cardiovascular Dynamics ational Cardiovascular Center Research Institute Abstract- A transer unction rom baroreceptor pressure input to sympathetic nerve activity (A) shows high-pass characteristics in the requency range rom. to z in anesthetized rabbits. The high-pass characteristics o the neural arc contribute to a quick and stable arterial pressure (AP) regulation. owever, i the high-pass characteristics hold up to the requency o heart rate (3-5 z), a pulsatile pressure component in AP would yield an extremely large amplitude o pulsatility in A. uch a large amplitude in A would hit the nonlinearities in barorelex pathways, thereby disable the barorelex regulation o AP. We hypothesized thereore that the transer gain at the requency o heart rate would be much smaller than that predicted rom the high-pass characteristics o the neural arc. In anesthetized rabbits (n=6), we perturbed carotid sinus pressure (CP) according to a binary white noise with a switching interval o 5 ms. The transer unction rom CP to cardiac A was then estimated in the range rom. to z. The neural arc transer unction showed high-pass characteristics in the requencies below.7 z, while losing the transer gain above the requency at - db/decade. A simulation study indicated that the attenuation o the pulsatile pressure component in the neural arc was eective to retain the relex regulation o AP. Keywords- transer unction, simulation revealed that the neural arc approximates the irst-order high-pass ilter in the requency range between. and z. In contrast, the peripheral arc approximates the secondorder low-pass ilter in this requency range. A numerical simulation indicated that the ast neural arc compensated or the slow peripheral arc to achieve a quick and stable AP regulation. This simulation result was obtained based on nonpulsatile AP []. owever, i we made AP pulsatile (4- z sinusoid with peak-to-peak amplitude o mmg), the pulsatile pressure yield an extremely large amplitude o pusatility in A due to the high-pass characteristics o the neural arc. This phenomenon does not aect the resulting AP regulation as long as the barorelex system linearly operates. owever, there exist nonlinearities such as threshold and saturation in the native barorelex system. Thus, i the pulsatile signal is in act ampliied by the highpass characteristics o the neural arc, the large amplitude o A would hit the nonlinearities in the barorelex pathways, thereby disable the barorelex regulation o AP. We hypothesized thereore that the transer gain o the neural arc would wane somewhere below the requency o heart rate. To test the hypothesis, we estimated the neural arc transer unction rom CP to A in anesthetized rabbits extending the upper requency limit o the analysis to z. I. ITRODUCTIO Estimation o transer unctions among cardiovascular variables is useul in providing insight into the mechanisms o cardiovascular regulation [-6]. In a previous study, we decomposed the carotid sinus barorelex system into the neural arc rom carotid sinus pressure (CP) to sympathetic nerve activity (A) and the peripheral arc rom A to arterial pressure (AP) []. A transer unction analysis This study was supported by Grants-in-Aid or cientiic Research (B , B 55766, C 6776) and or Encouragement o Young cientists (377378, ) rom the Japan ociety or the Promotion o cience, by Research Grants or Cardiovascular Diseases (C-3) and a ealth ciences Research Grant or Advanced Medical Technology rom the Ministry o ealth and Welare o Japan, Research and Development Grant or Applying Advanced Computational cience and Technology rom Japan cience and Technology Corporation, Program or Promotion o Fundamental tudies in ealth cience o the Organization or Pharmaceutical aety and Research, Ground-Based Research Grant or the pace Utilization rom ational pace Development Agency o Japan and Japan pace Forum. II. METOD ix Japanese white rabbits weighing.6 to 3.4 kg were anesthetized by intravenous injection ( ml/kg) o a mixture o urethane (5 mg/ml) and α-chloralose (4 mg/ml), and mechanically ventilated with oxygen enriched room air. To eliminate the eects o barorelexes rom the cardiopulmonary region and aortic arch, the vagal nerves and aortic depressor nerves were sectioned bilaterally through a midline cervical incision. The carotid sinuses were isolated bilaterally rom the rest o the systemic circulation. The right cardiac sympathetic nerve originating rom the stellate ganglia was sectioned through a midline thoracotomy, and a pair o stainless steel wire electorodes (Biolex wire A633, Cooner Wire) were attached to the nerve to record eerent A. The preampliied nerve signal was band-pass iltered at 5- z, and was then ullwave rectiied and low-pass iltered with a cuto requency o 3 z. To estimate the transer unction rom CP to

2 Report Documentation Page Report Date 5 Oct Report Type /A Dates Covered (rom... to) - Title and ubtitle Attenuation o A Pulsatile Pressure Component in the eural ARC o the Arterial Barorelex Contract umber Grant umber Program Element umber Author(s) Project umber Task umber Work Unit umber Perorming Organization ame(s) and Address(es) Department o Cardiovascular Dynamics ational Cardiovascular Center Research Institute Japan ponsoring/monitoring Agency ame(s) and Address(es) U Army Research, Development & tandardization Group (UK) PC 8 Box 5 FPO AE Perorming Organization Report umber ponsor/monitor s Acronym(s) ponsor/monitor s Report umber(s) Distribution/Availability tatement Approved or public release, distribution unlimited upplementary otes Papers rom 3rd Annual International Conerence o the IEEE Engineering in Medicine and Biology ociety, October 5-6, held in Istanbul, Turkey. ee also ADM35 or entire conerence on cd-rom. Abstract ubject Terms Report Classiication unclassiied Classiication o Abstract unclassiied Classiication o this page unclassiied Limitation o Abstract UU umber o Pages 4

3 A, we perturbed CP according to a binary white noise signal with a switching interval o 5 ms or min, using a servo-controlled piston pump (model ET-6A, Labworks). The mean CP was adjusted to the equilibrium pressure between CP and AP. The peak-to-peak amplitude o CP perturbation was set at 4 mmg. CP, A, and AP data were recorded at a sampling rate o z and stored on a hard disk o a dedicated laboratory computer system. In order to estimate the neural arc transer unction, we treated CP as the input and A as the output o the system. We segmented the input-output data pairs into ten sets o 5% overlapping bins o 4 data points each. For each segment, a linear trend was subtracted, and a anning window was applied. We then obtained requency spectra o the input and output by a ast Fourier transorm. We ensemble averaged the input power, CP CP (ƒ), output power, A A (ƒ), and crosspower between the input and output, A CP (ƒ) over the ten segments. ƒ represents requency. Finally, we calculated the neural arc transer unction using the ollowing equation [7]. ( ) = A CP CP CP ( ) ( ) To quantiy the linear dependence between the input and output, we calculated a magnitude-squared coherence unction using the ollowing equation [7]. Coh( ) = Coh.. π CP CP A CP ( ) ( ) A A ( ).. requency (z) Fig.. Transer unction rom carotid sinus pressure to sympathetic nerve activity. The solid and dashed lines indicate mean and mean+.d. values. IV. REULT Figure shows a transer unction rom CP to A averaged rom all animals. The gain plot (top), phase plot (middle), and coherence unction (bottom) are shown. The gain value increased as the requency increased rom. to.7 z. Above.8 z, however, the gain value decreased as the requency increased. The gain value at 5 z was similar to that at. z, indicating that the pulsatile pressure component would not be enhanced in the neural arc o the arterial barorelex. The phase value approximated π radians in the lowest requencies, relecting the negative eedback nature o the neural arc. The coherence values showed moderate linearity between CP and A in the requency range between. and z. The coherence values were smaller in the requencies below. z and above z. The coherence values approached zero in the requencies above 5 z. V. DICUIO Although the high-pass characteristics o the neural arc have been identiied in our previous study [], the transer unction o the neural arc around the requency o heart rate (3-5 in rabbits) remained unknown. To our best knowledge, this is the irst to reveal the neural arc transer unction beyond z (Figure ). The neural arc lost its transer gain above.8 z in agreement with our hypothesis. In order to elucidate the physiological meaning o the decreasing gain above.8 z seen in Figure, we constructed two types o simulators or the arterial barorelex. One simulator (IM) has a neural arc with highpass characteristics alone (Fig. A). The mathematical description o the neural arc or IM is as ollows. ( ) = + j exp( pjl) C where ƒ C and L indicate the corner requency (in z) o the high-pass ilter and lag time (in s), respectively. ƒ indicates the requency (in z). j is the imaginary unit. We set ƒ C at. z and L at.5 s. The other simulator (IM) has a neural arc that mimicked the native neural arc transer unction (Fig. 3A). The mathematical description o the neural arc or IM is as ollows. + j C ( ) = exp( pjl) + j C

4 where ƒ C indicates the corner requency o the high-pass ilter, and ƒ C indicates the higher requency limit above which the transer gain decreases. We set ƒ C and ƒ C at. and.8 z, respectively. For both IM and IM, the peripheral arc transer unction was modeled using a second-order low-pass ilter with a lag time as ollows []. P ( ) = +? j exp( pjl) where ƒ and ζ indicate the natural requency and damping rate, respectively. We set ƒ and ζ at.7 z and.37, respectively. The lag time, L, was set at s or the peripheral arc. First, we simulated the closed-loop AP response against 4-mmg stepwise pressure decrease using IM and IM without including any nonlinearities. The pulsatile pressure was simulated by a 4-z sinusoidal pressure variation with the peak-to-peak amplitude o mmg. As shown in Figures B and 3B, the exogenous perturbation was attenuated to - mmg, on average, both in IM and IM. The time or the AP response to reach steady state was slightly shorter in IM than in IM, indicating that the high-pass characteristics beyond z was eective to improve the quickness o the AP response against exogenous perturbation. owever, at the requency o 4 z, the input amplitude was enhanced as much as 4-olds that at. z in IM. Thus, the peripheral arc in IM was exposed to A changes comparable to the peak-to-peak input amplitude o 8 mmg ( mmg 4). The native A. -π.. requency (z) B C AP (mmg) AP (mmg) time (sec) Fig.. A: The neural arc transer unction model with high-pass characteristics alone. B: A simulation result o arterial pressure (AP) response against stepwise pressure decrease obtained rom a linear model. C: A simulation result o AP response against stepwise pressure decrease obtained rom a model including nonlineaities with threshold and saturation. peripheral arc unlikely has the operating range wide enough to process this large signal. ext, we put a nonlinear component with threshold and saturation in the course rom the neural arc to the periphral arc components as a typical example. Because the magnitude o the AP response to static changes in A would be at most mmg centering around the operating pressure, we set the threshold and saturation by A values corresponding to the peak-to-peak input amplitude o mmg. This nonlinearity did not yield any deteriorating eects on the AP regulation in both IM and IM when nonpusatile AP was used or the simulation. owever, when pulsatile AP was used or the simulation, the relex regulation o AP against exogenous pressure perturbation was blunted in IM by the inclusion o the nonlinearity (Figure C). In contrast, the relex regulation o AP against exogenous pressure perturbation was well preserved in IM even in the presence o the nonlinearity (Figure 3C). These simulation results indicate that the attenuation o the pulsatile component is eective to avoid the ailure o AP regulation by the arterial barorelex. There are several limitations to the present study. First, we did not measure the nonlinearity o the peripheral arc between A and AP. owever, the lowest and highest pressure values attained by barorelex activation and deactivation were about 5 mmg and 5 mmg, respectively, in our experimental settings. Because we set the threshold and saturation o the nonlinearity based on A values corresponding to -mmg below and - mmg above the operating point, respectively, the linear range o our simulation would cover physiological linear range o the peripheral arc. Although our simulation settings less likely caused the nonlinear AP response than the native peripheral arc, the pulsatile pressure with peak-to-peak A. -π.. requency (z) B C AP (mmg) AP (mmg) time (sec) Fig. 3. A: The neural arc transer unction model mimicking changes in transer gain o the native neural arc. B: A simulation result o arterial pressure (AP) response against stepwise pressure decrease obtained rom a linear model. C: A simulation result o AP response against stepwise pressure decrease obtained rom a model including nonlinearities with threshold and saturation.

5 amplitude o mmg still blunted the relex regulation o AP in IM. Thus, we believe that the attenuation o the pulsatile pressure component plays an important role to retain the relex regulation o AP in the native barorelex system as well. econd, there exists a species dierence in the requency o heart rate. Because the neural arc transer unction at the requency o heart rate in other species remains unknown, the simulation results in the present study should be careully interpreted. [7] P. Z. Marmarelis and V. Z. Marmaleris. The white noise method in system identiication. In: Analysis o Physiological ystems. ew York: Plenum, 978, p. 3-. VI. COCLUIO The neural arc o the barorelex attenuates the pulsatile pressure component to retain the ability o relex regulation o AP in rabbits. I the attenuation does not exist, the enhanced pulsatile pressure component would saturate the peripheral arc signal transduction, hampering the relex regulation o AP against exogenous pressure perturbation. REFERECE [] Y. Ikeda, T. Kawada, M. ugimachi, O. Kawaguchi, T. hishido et al. eural arc o barorelex optimizes dynamic pressure regulation in achieving both stability and quickness. Am. J. Physiol. eart Circ. Physiol. 7: 88-89, 996. [] T. Kawada, M. ugimachi, T. ato,. Miyano, T. hishido et al. Closed-loop identiication o carotid sinus barorelex open-loop transer characteristics in rabbits. Am. J. Physiol. eart Circ. Physiol. 73: 4-3, 997. [3]. Miyano, T. Kawada, T. hishido, T. ato, M. ugimachi et al. Inhibition o O synthesis minimally aects the dynamic barorelex regulation o sympathetic nerve activity. Am. J. Physiol. eart Circ. Physiol. 7: , 997. [4]. Miyano, T. Kawada, M. ugimachi, T. hishido, T. ato et al. Inhibition o O synthesis does not potentiate dynamic cardiovascular response to sympathetic nerve activity. Am. J. Physiol. eart Circ. Physiol. 73: 38-43, 997. [5] T. Kawada, T. ato, T. hishido, M. Inagaki, T. Tatewaki et al. ummation o dynamic transer characteristics o let and right carotid sinus barorelexes in rabbits. Am. J. Physiol. eart Circ. Physiol. 77: , 999. [6] T. Kawada, T. hishido, M. Inagaki, T. Tatewaki, C. Zheng et al. Dierential dynamic barorelex regulation o cardiac and renal sympathetic nerve activities. Am. J. Physiol. eart Circ. Physiol. 8: 58-59,.