|Year : 2019 | Volume
| Issue : 2 | Page : 86-92
Differential effects of sympatholytic agents on the power spectrum of rats during the cooling-induced hemodynamic perturbations
Yung-Nien Yang1, Hsien-Lung Tsai2, Yu-Chieh Lin3, Yia-Ping Liu4, Che-Se Tung3
1 Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan
2 Department of Emergency, Cheng Hsin General Hospital, Taipei, Taiwan
3 Department of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan
4 Department of Physiology, National Defense Medical Center; Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan
|Date of Submission||27-Dec-2018|
|Date of Decision||25-Mar-2019|
|Date of Acceptance||26-Mar-2019|
|Date of Web Publication||25-Apr-2019|
Prof. Che-Se Tung
Division of Medical Research and Education, Cheng Hsin General Hospital, No. 45, Cheng Hsin St., Beitou, Taipei 11280
Source of Support: None, Conflict of Interest: None
Cold stress-elicited hemodynamic perturbations (CEHP) its underlying mechanisms still not clear. We examined the difference of two effector arms of sympathetic outflows, the sympathoadrenal system, and postganglionic sympathetic neurons, their role in CEHP genesis by using two sympatholytic agents, fusaric acid (FA, dopamine-β-hydroxylase inhibitor) and guanethidine (GUA, norepinephrine-depleting drug). Adult male Sprague-Dawley rats were divided into three groups (n = 6, each), an intraperitoneal injection of control vehicle saline or FA or GUA and then all rats were subjected to a 10-min CS trial. Systolic blood pressure (SBP), heart rate (HR), dicrotic notch (Dn), power spectrum of blood pressure variability and HR variability (BPV, HRV), and coherence spectrum at very-low, low, and high frequency regions (VLF: 0.02–0.2 Hz, LF: 0.2–0.6 Hz, and HF: 0.6–3.0 Hz) were monitored using telemetry throughout the experiment course. We observed both FA and GUA attenuated SBP and HR and the spectral powers of BPV at VLF, LF, and HF in both baseline (PreCS) and cold stimuli (CS) conditions, but apparently, FA exerted stronger effects than GUA did. Both FA and GUA generally attenuated the responses of CS-induced pressor and tachycardia and the CS-increased VLFBPV, LFBPV, and HFBPV, but different effects between FA and GUA, when compared with control vehicle under CS. FA reduced the CS-reduced VLFHRV and the CS-increased LFBPV and HFBPV more than GUA did. We further observed in both PreCS and CS, GUA but not FA increased HFHRV; FA reduced but apparently, GUA increased the occurrence of Dn. Finally, we observed FA weakened, but GUA strengthened the coherence between BPV and HRV at both LF and HF regions. Taken together, the different effects between FA and GUA on CEHP indicate a role of the sympathoadrenal mechanism in response to CS.
Keywords: Blood pressure variability, cold stress-evoked hemodynamic perturbations, dopamine-β-hydroxylase inhibitor, heart rate variability, norepinephrine-depleting drug
|How to cite this article:|
Yang YN, Tsai HL, Lin YC, Liu YP, Tung CS. Differential effects of sympatholytic agents on the power spectrum of rats during the cooling-induced hemodynamic perturbations. Chin J Physiol 2019;62:86-92
|How to cite this URL:|
Yang YN, Tsai HL, Lin YC, Liu YP, Tung CS. Differential effects of sympatholytic agents on the power spectrum of rats during the cooling-induced hemodynamic perturbations. Chin J Physiol [serial online] 2019 [cited 2020 Aug 10];62:86-92. Available from: http://www.cjphysiology.org/text.asp?2019/62/2/86/257184
Yung-Nien Yang & Hsien-Lung Tsai - Equal contribution
| Introduction|| |
Acute cold stimuli (CS) elicits hemodynamic perturbations (CEHP) as oscillations of the sympathetic outflow activity throughout the cooling progression, such effect has been thought to play a role in against tissue damage. In general, CEHP is characterized by cold-induced pressor (CIP), tachycardia (CIT), greater adrenergic neurotransmissions, and increased norepinephrine (NE) and epinephrine (E) in plasma which are commonly used in the diagnosis of autonomic control in cardiovascular regulation so-called the cold pressor test.
Although the underlying mechanisms are still unclear, intact baroreflex mechanisms and compensatory humoral factors are known to direct the vasoconstrictor responses of CEHP. Spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV) using frequency domain approaches has been widely applied to investigate the baroreflex control of cardiovascular homeostasis – a dynamic interplay between ongoing blood pressure (BP) perturbation and compensatory cardiovascular response., The standard indices commonly used are the following: (a) the high frequency (HF) BPV (HFBPV) indicates the oscillation in cardiac output secondary to mechanic respiratory sinus arrhythmia, whereas HF of HRV (HFHRV) indicates oscillation in respiration and efferent vagal modulation of heart rate (HR); (b) the low frequency (LF) of BPV (LFBPV) indicates oscillation in efferent sympathetic modulation of vascular resistance, whereas LF of HRV (LFHRV) indicates oscillation in sympathetic modulation of HR, and (c) the very-low frequency (VLF) of BPV (VLFBPV) or HRV (VLFHRV), a heterogeneously frequency band; however, its physiological background is mostly unrevealed but has been variously ascribed to the thermoregulatory vasomotor modulation, activity of hormonal systems, and autonomic nervous system itself.,,, Recently, our serial studies to investigate the causes of CEHP have found the power spectral density of VLFBPV reflects the myogenic vascular responsiveness to CS. Our findings support that sympathetic activation causes CEHP, which, in turn, may increase vasculomyogenic oscillations (VLFBPV) to prevent tissue damage.
Dopamine-β-hydroxylase as an essential enzyme for NE synthesis which is known critical for setting NE levels in synaptic neurotransmission. On the other hand, the NE transporter is responsible for the neuronal reuptake of NE and is located presynaptically on noradrenergic nerve terminals, where reuptake of NE contributes to the termination of noradrenergic transmission. The present study aimed to address the importance of sympathetic outflow activity to react to CS. We explored the difference of two effector arms of sympathetic outflows, the sympathoadrenal system and postganglionic sympathetic neurons, their role in CEHP genesis by using fusaric acid (FA), a potent and specific inhibitor of dopamine-β-hydroxylase, and guanethidine (GUA),,,, a NE-depleting drug for chemical sympathectomy but spares the effect on adrenal medulla.
| Materials and Methods|| |
Adult male Sprague-Dawley rats weighing between 300 and 350 g were received at Laboratory Animal Center of the National Defense Medical Center (NDMC, Taiwan) 1 week before the experiments. The studies were performed according to a protocol approved by the Institutional Animal Care and Use Committee of NDMC. All efforts were made to reduce the number of experimental animals and their suffering in experiments. The rats in the same experimental group were housed together in an ambient thermoneutral environment (23°C) and humidity-controlled holding facility with a 12-h light/dark cycle (lights on from 07:00 to 19:00) maintained by manual light control switches as required by the experiment, and they received food and water ad libitum.
The time sequence of dosing drugs is shown in [Figure 1]. Rats were randomly distributed into three groups with each group of six rats. The control group rats (Control Vehicle) were given the vehicle (0.9% NaCl solution) 0.5 ml through an intraperitoneal injection for baseline comparisons, and the other two groups of rats were given sympatholytic agents (a) the dopamine-β-hydroxylase (DBH) inhibitor by FA (70 mg/kg) via an intraperitoneal injection up to 60 min before the CS trial or (b) by an intraperitoneal injection of GUA (30 mg/kg) seven times a week for 1 week including an additional dose 60 min before the CS trial in the testing day. All chemicals were purchased from Sigma-Aldrich Corp (St. Louis, MO, USA).
|Figure 1: General protocol for (A) the implantation of telemetry device in rat 14 days before the testing day and (B) the sequence of testing day procedures in the following order, PreCS, CS, and PostCS, for a rat in a Plexiglas cage. The control group rats (Control Vehicle) were given the vehicle (0.9% NaCl solution) 0.5 ml via an intraperitoneal injection for baseline comparisons, and the other two groups of rats were given sympatholytic agents (a) the DBH inhibitor by fusaric acid (70 mg/kg) via an intraperitoneal injection up to 60 min before the CS trial or (b) by an intraperitoneal injection of guanethidine (30 mg/kg) seven times a week for 1 week including an additional dose 60 min before the CS trial in the testing day|
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All rats were brought to an adjacent room and given the same acute cooling procedure after they have adjusted the experimental environments. There was a maximum of eight rats tested and four rats being tested at the same time every day. Total experiments were performed between 08:30 and 11:30.
Following a complete stabilization of systolic blood pressure (SBP) and HR at room temperature, each rat was quickly placed in a Plexiglas cage to immerse its glabrous palms and soles for 10 min in ice water as the CS trial. After this cooling procedure, the rat was removed from the cage, dried with a cloth, and placed in a similar cage for 20 min to facilitate recovery. Beat-to-beat SBP signals were recorded continuously through a telemetric monitoring equipment (TL11M2-M2-C50-PXT, Data Sciences International, St. Paul, Minnesota, USA), including 10 min before CS (PreCS), 10 min during CS, and 20–30 min after CS (PostCS). Successive signals during a period of approximately 5 min (3–8 min) for each experimental condition were taken for spectral analysis. The dicrotic notch (Dn) and counts were handled manually.
Surgical intervention and spectrum signal acquisition and processing
The surgery and spectral and cross-spectral analysis methods have been reported previously in detail., Briefly, the acquired SBP signals were preprocessed by applying a band-pass filter (0.1–18 Hz, zero phase fourth order) to remove the DC components. After identifying all the SBP peak maxima between 2 zero-cross points, the extracted beat-by-beat SBP and inter-beat interval (IBI) time series were detrended, interpolated, and resampled at 0.05 s to generate a new time series of evenly spaced SBP samples, allowing a direct spectral analysis of each distribution using the Fast Fourier transform algorithm. The HRV calculation was based on Chart software developed by PowerLab (ADInstruments, Colorado Springs, Colorado, USA). For a 5-min period, we calculated power, including total power (0.00–3.0 Hz, TP), VLF power (0.02–0.2 Hz, VLF), LF power (0.20–0.60 Hz, LF), and HF power (0.60–3.0 Hz, HF). The modulus of the spectral density for each frequency had units of BPV (mmHg2) and HRV (ms2). The squared coherence function was computed as the square of the cross-spectrum normalized by the product of the spectra of the BPV and HRV signals. When the peak coherence value (K2IBI/SBP) exceeded 0.58 within a frequency range, the two signals were considered to covary significantly at that frequency.
The statistical analyses of the present study were conducted using SPSS software version 18.0 for Windows (SPSS Inc., Chicago, USA). The normality of the variance was first confirmed using the Kolmogorov–Smirnov test. Data were then analyzed using multi-factor analysis of variance with a within-subject factor, TRIAL (three conditions: PreCS, CS, and PostCS), and a between-subject factor, GROUP (thre interventions: NS, FA, and GUA). If necessary, post hoc comparisons were carried out using the Tukey or Student's t-tests where appropriate. The results are expressed as mean ± standard error of the mean. Results were considered statistically significant at value of P < 0.05.
| Results|| |
Averaged data are shown in [Figure 2], [Figure 3], [Figure 4] and [Table S1]. Statistical information of df and F of data analysis are shown in [Table S2].
|Figure 2: The effects on (a) systolic blood pressure and heart rate and (b) the appearance of dicrotic notch of rats throughout the experiment course in the three experimental groups. Data are presented as mean value per group ± standard error of the mean. Significant differences between PreCS and CS (*P < 0.05, †P < 0.01, ‡P < 0.001), between PostCS and CS (§ P < 0.05, ||P < 0.01, ¶P < 0.001), and between groups (#P < 0.05, **P < 0.01) were assessed by the multi-factor analysis of variance and post hoc comparisons|
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|Figure 3: Changes in the mean spectral powers in regions of (a) very-low frequency, (b) low frequency, and (c) high frequency for blood pressure variability of the right column and heart rate variability of the left column of rats in the three experimental groups throughout the experiment course. Data are presented as mean value per group ± standard error of the mean. Statistical significance is shown as in Figure 2|
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|Figure 4: The relationship between heart rate and systolic blood pressure oscillations as assessed by peak coherence K2IBI/SBP value between blood pressure variability and heart rate variability in the very-low frequency, low frequency, and high frequency regions of rats in the three experimental groups throughout the experiment course. Data are presented as mean value per group ± standard error of the mean|
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The responses of systolic blood pressure, heart rate, and appearance of dicrotic notch of the different interventions rats throughout the experiment course
As shown in [Figure 2]a, inhibition of DBH by FA attenuates SBP compared to that of the control vehicle throughout the experiment course (PreCS: P < 0.001; CS: P < 0.001; PostCS: P < 0.001), whereas FA attenuates the higher HR of control vehicle in both PreCS and CS (PreCS: P < 0.001; CS: P < 0.01). On the other hand, when compared with the control vehicle, DBH inhibition by FA still shows the cooling-induced pressor response (CIP, CS versus PreCS: P < 0.01) and cooling-induced tachycardia response (CIT, CS versus PreCS: P < 0.001; CS versus PostCS: P < 0.001). Chemical sympathectomy by GUA, however, attenuates both SBP and HR compared to those of the control vehicle only in CS (SBP: P < 0.01; HR: P < 0.001). In contrast, when compared with the control vehicle, GUA vanishes CIP but still presents CIT (CS versus PreCS: P < 0.001; CS versus PostCS: P < 0.001) in CS.
As shown in [Figure 2]b, FA generally vanishes the presence of Dn (with Dn) compared to the control vehicle, whereas GUA shows the Dn present obviously throughout the experiment course (P < 0.001).
The responses of frequency powers of the different interventions of rats throughout the experiment
When compared with the control vehicle in PreCS, FA and GUA both attenuate VLFBPV (all P < 0.05) [[Figure 3]a: Upper right] and LFBPV (FA: P < 0.05; GUA: P = 0.056) [[Figure 2]b: Middle right], whereas only FA attenuates both VLFHRV (P < 0.001) [[Figure 2]b: Upper left] and LFHRV (P < 0.05) [[Figure 3]b: Middle left]. On the other hand, when compared with the control vehicle in CS, both FA and GUA also attenuate VLFBPV (FA: P < 0.01; GUA: P < 0.05) [[Figure 3]a: Upper right], LFBPV (FA: P < 0.001; GUA: P < 0.01) [[Figure 3]b: Middle right], and HFBPV (FA: P < 0.01; GUA: P = 0.05) [[Figure 3]c: Lower right], whereas FA attenuates VLFHRV (P < 0.01) and GUA increases HFHRV (P < 0.001) [[Figure 3]c: Lower left].
Furthermore, when compared with the period of CS with its own PreCS, both FA and GUA increase VLFBPV (FA: PreCS and PostCS versus CS, all P < 0.05; GUA: PreCS versus CS, P < 0.05) [[Figure 2]a: Upper right] and LFBPV (FA and GUA: PreCS versus CS, all P < 0.05) [[Figure 3]b: Middle right], whereas GUA increases HFBPV (PreCS and PostCS versus CS, all P < 0.05) [[Figure 2]c: Lower right] and HFHRV as well (PreCS and PostCS versus CS, all P < 0.05) [[Figure 3]c: Lower left].
The responses of coherence function of the different interventions of rats throughout the experiment
The coherence relationships assessed by the peak coherence values (K2IBI/SBP) between BPV and HRV for the three major frequency regions are summarized in [Figure 4]. When compared with the control vehicle throughout the experiment course, FA generally showed low K2IBI/SBP in the LF region (FA vs. Control Vehicle: PreCS: 0.38 ± 0.02 vs. 0.55 ± 0.03; CS: 0.48 ± 0.03 vs. 0.57 ± 0.03; PostCS: 0.28 ± 0.02 vs. 0.53 ± 0.03) and also low K2IBI/SBP in the HF region (FA vs. Control Vehicle: PreCS: 0.39 ± 0.01 vs. 0.75 ± 0.03; CS: 0.38 ± 0.03 vs. 0.74 ± 0.03; PostCS: 0.46 ± 0.03 vs. 0.69 ± 0.03). In contrast, GUA generally still showed high K2IBI/SBP in the LF region (GUA vs. Control Vehicle: PreCS: 0.64 ± 0.03 vs. 0.55 ± 0.03; CS: 0.61 ± 0.04 vs. 0.57 ± 0.03; PostCS: 0.60 ± 0.02 vs. 0.53 ± 0.03) and high K2IBI/SBP in the HF region as well (GUA vs. Control Vehicle: PreCS: 0.62 ± 0.01 vs. 0.75 ± 0.03; CS: 0.64 ± 0.02 vs. 0.74 ± 0.03; PostCS: 0.61 ± 0.02 vs. 0.69 ± 0.03). However, we did not find a consistent coherence relationship between the BPV and HRV in the VLF region (K2IBI/SBP < 0.58) for the rats treated with either control vehicle or sympatholytic interventions.
| Discussion|| |
In this study, we sought to investigate the role of two effector arms of sympathetic outflows on CEHP. We focus on the discussion of spectral powers, HF, LF, and VLF, in respective HRV and BPV changes because of their specific indication in cardiorespiratory activity, sympathetic outflows, and myogenic vascular oscillations. Overall, results indicate both FA and GUA attenuate SBP and HR and the spectral powers of BPV and HRV in both baseline (PreCS) and cold stimuli (CS) conditions.
We observed different changes in spectral powers of HRV between GUA and FA, GUA did not affect VLFHRV and LFHRV but a tendency increase HFHRV in PreCS and increase HFHRV in CS. FA, in contrast, attenuated both VLFHRV and LFHRV but did not affect HFHRV in PreCS. FA also attenuated VLFHRV but did not affect LFHRV in CS. Furthermore, we observed the coherence value between BPV and HRV at both LF and HF regions were low in FA but still high in GUA.
In PreCS, we found that both SBP and HR were decreased by FA. On the other hand, the spectral powers for indication of sympathetic efferent oscillations, LFBPV and LFHRV, and myocardium oscillations, VLFHRV, were generally decreased by FA but not much affected by GUA. We speculate these distinct effects on spectral pattern between FA and GUA could be due to the sparing effects of GUA on adrenal medulla. In the case of GUA, the release of epinephrine from adrenal medulla activates the renin-angiotensin-aldosterone system and produces a positive chronotropic effect through β-adrenergic receptors. Furthermore, the decrease of SBP by FA appears related to the relative vascular tone. FA abolishes spontaneous sympathetic outflows to the resistance vessels causing the vasodilatation effect.
In CS, however, our previous study found that throughout the progression of CEHP, plasma NE and epinephrine concentrations both increased. NE increases HR and blood pressure while epinephrine increases respiration rate and blood flow. Besides, we found the presence of CIP and CIT has concomitant with a significant increase in spectral powers of the sympathetic discharges (LFBPV) and myogenic vascular oscillations (VLFBPV), in which the enhanced shear stress to the LFBPV activation causes the increase of VLFBPV., In this study, we further found the spectral powers of BPV were attenuated markedly after pretreatment with FA or GUA. We, thus, suggest that during the period of CIP, vasoconstriction is mediated by NE and epinephrine released from sympathetic terminals and adrenal medulla to affect the related adrenergic receptors, particularly the postsynaptic α2-adrenoreceptors. We theorize that in CS, the period of cooling-induced vasodilation is primarily because of the cooling-induced vasoconstriction which is attenuated by the nitric oxide released from the vascular endothelial cells after cooling-induced shear stress.
In the present study, we used FA and GUA for discriminable two different sympathetic effector arms role in the CEHP genesis. In respect of BPV, we found both FA and GUA have a similar potency to attenuate the spectral powers of VLFBPV, LFBPV, and HFBPV in CS. The results are consistent with our previous notion that activation of the efferent sympathetic rhythmicity stands the primary cause of the increase of the vascular myogenic oscillations in CS. Although at first glance both FA and GUA exert similar effects, a detailed comparison, however, revealed that FA is high than GUA to attenuate CIP as well as the CS-increased LFBPV in CS. We also observed FA high than GUA attenuates the spontaneous LFBPV in PreCS and high than GUA attenuates the CS-increased HFBPV in CS. We discuss the possible mechanisms below.
Substantial evidence suggests that epinephrine acts directly on the airways and lungs to open them up and accelerate breathing. Epinephrine has been known to be one of the blood-borne factors that mediate hyperpnoea by an action on CO2 chemosensitivity. As per the concept of HFBPV imitated BP changes induced by respiration,, we thus speculate the observed changes after entirely sympathetic removal by FA is because phrenic nerve activity slows down then diminishes respiratory oscillation causing the decreases of HFBPV. This speculation supports the notion that HFBPV depends on oscillatory cardiac output and generally counteracted by the sympathetic tone. Nevertheless, we observed although both FA and GUA exert an effect to attenuate the spontaneous LFBPV and CS-increased LFBPV effects, GUA, however, lesser than FA of such attenuation effects in both PreCS and CS. As per the concept of LFBPV imitated sympathetic activation induced by CS, we thus speculate the observed changes of LFBPV by GUA is because the phenomenon of electrical/chemical dissociation existed for GUA, i.e., efferent sympathetic neurons (sympathetic outflows) are intact, action potential still appears, but failed neurotransmissions in responses to CS, a phenomenon analogous to an engine idling.,,
In respect of HRV, as mentioned above, we observed FA completely diminished the CS-reduced VLFHRV and the spontaneous LFHRV in PreCS. GUA, by contrast, did not affect either VLFHRV or LFHRV but increases HFHRV in both PreCS and CS. The difference between these two sympatholytic interventions could be explained by the sparing effects of GUA on adrenal medulla.,,, The epinephrine released into plasma might activate to counterbalance the chronotropic and inotropic effects of FA as falling of sympathocardiac oscillations (LFHRV) and myocardium oscillations (VLFHRV). The increase of HFHRV of GUA could because of the effects of epinephrine stimulate ventilation.,
In respect of the coherence strength, we observed FA has low K2IBI/SBP value in both LF and HF regions throughout the experiment course. As per the concept of the cross-spectrum analysis, we speculate the observed effects of the LF region is because that FA interrupts the NE neurotransmission in postganglionic sympathetic neurons that detached the sympathetic-mediated baroreflex mechanism. On the other hand, the decreases of K2IBI/SBP of the HF region by FA suggest that the oscillations in HRV and BPV are unrelated to their respiratory movement, i.e., a detached cardiorespiratory coupling.
Finally, we observed that throughout the experiment course, FA reduced but apparently, GUA increased the magnitude of the appearance of Dn. As per the concept of a higher Dn indicates the increased vascular resistance to modifying reflected pressure waves in conduit artery and additional information about the myogenic vascular responses to the hemodynamic perturbations,, we speculate the observed increases of Dn by GUA is again, because of the sparing effects of the released epinephrine which increases vascular resistance. On the other hand, the disappearance of Dn by FA is because of entirely sympathetic removal which causes flaccid vascular tonicity.
| Conclusions|| |
Our overall data provide evidence underlying the difference between sympatholytic mechanisms of FA and GUA, i.e., FA abolishes either the tonic sympathetic rhythmicity or the cooling-evoked sympathetic activation for the vascular resistance, but GUA spares effect on adrenal medulla to release epinephrine. Consequently, the circulatory epinephrine could make the differences between FA and GUA in changes of autonomic cardiovascular responses to cold stress.
Financial support and sponsorship
This work was supported by grants from the Ministry of Science and Technology (MOST 102 and 103-2320-B-350-001) and the Cheng Hsin General Hospital-National Defense Medical Center cooperative research project (CH-NDMC-107-1), Taipei, Taiwan, R.O.C.
Conflicts of interest
There are no conflicts of interest.
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