Acupoint dependence of depressor and bradycardic responses elicited by manual acupuncture stimulation in humans.

The cardiovascular effects of the autonomic nervous system (ANS) are modulated by inputs from peripheral sensors and other brain regions. However, it currently remains unknown whether the manual acupuncture (MA) stimulation of different acupuncture points evokes different responses by the heart and vasculature, a phenomenon known as "site specificity". Sixty healthy subjects were randomly divided into a control group and MA stimulation groups at the lower leg, ear, abdomen, and forearm. MA was performed at 1 Hz for 2 min. A depressor response was observed only in the lower leg stimulation group, in which mean blood pressure significantly decreased from 83.4 ± 10.1 to 80.9 ± 11.7 mmHg (p < 0.003). A bradycardic response was elicited in all MA stimulation groups. There was no significant differences in the magnitude of the bradycardic response between groups. MA-induced cardiovascular responses, which may be mediated by the modulation of ANS, differ depending on acupuncture points.

Tonic aortic depressor nerve stimulation does not impede baroreflex dynamic characteristics concomitantly mediated by the stimulated nerve.

Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 ± 70.9 vs. 247.3 ± 47.2 arbitrary units, P < 0.01) and mean AP (98.4 ± 7.8 vs. 89.2 ± 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 ± 1.0 vs. 14.7 ± 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

Electroacupuncture most effectively elicits depressor and bradycardic responses at 1 Hz in humans.

PURPOSE: Acupuncture stimulation is known to act on the autonomic nervous system and elicits depressor and bradycardic effects. However, previous studies on humans did not conduct quantitative analyses on optimal acupuncture conditions such as the stimulation frequency and duration to achieve maximum depressor and bradycardic effects. The aim of the present study was to investigate the effects of varying stimulation frequencies of electroacupuncture on time-dependent changes in blood pressure and heart rate in humans. METHODS: Twelve healthy volunteers participated in the study. An acupuncture needle was inserted at the Ximen acupoint (PC4 according to WHO nomenclature), located at the anterior aspect of the forearm. An electrical stimulation was delivered through the acupuncture needle at an intensity of 1 V, pulse width of 5 ms, and stimulation frequencies of 0.5, 1, 5, and 10 Hz in a random order. The duration of electroacupuncture was 6 min, during which blood pressure and heart rate responses were monitored. RESULTS: Group-averaged data indicated that 1-Hz electroacupuncture decreased blood pressure and heart rate. Blood pressure was significantly decreased from the prestimulation baseline value of 86.6 ± 2.9 to 81.4 ± 2.3 mmHg during 4-6 min of 1-Hz electroacupuncture (mean ± SE, P < 0.01). Heart rate was also significantly decreased (from 66.2 ± 2.0 to 62.7 ± 1.7 beats/min, P < 0.01). CONCLUSIONS: These results provide fundamental evidence that bradycardiac and depressor responses are effectively produced by electrical acupuncture in humans.

Effects of L-type Ca2+ channel blocker nifedipine on dynamic arterial blood pressure control.

Dynamic characteristics of arterial pressure (AP) regulation are important components in our understanding of rapid AP restoration by the arterial baroreflex system. The present study examined the effects of an L-type Ca(2+) channel blocker nifedipine on baroreflex-mediated dynamic AP regulation. In anesthetized and vagotomized rats, carotid sinus pressure was externally perturbed using a Gaussian white noise signal, and the neural arc transfer function from pressure input to efferent sympathetic nerve activity (SNA) and the peripheral arc transfer function from SNA to AP were identified. The peripheral arc transfer function approximated a second-order low-pass filter with pure dead time. Intravenous administration of nifedipine significantly decreased the steady-state gain and increased the damping ratio of the peripheral arc without affecting the dynamic characteristics of the neural arc. When the step response of AP was calculated based on the peripheral arc transfer function alone, nifedipine prolonged 80% rise time by 26%. When the closed-loop AP response was simulated based on both the neural arc and peripheral arc transfer functions and the dynamic gain of the baroreflex total loop was assumed to be 2.0, nifedipine prolonged 80% recovery time by 107%. In conclusion, L-type Ca(2+) channel blockade may compromise the baroreflex-mediated AP control not only in the magnitude but also in the speed of AP restoration.

Involvement of the mechanoreceptors in the sensory mechanisms of manual and electrical acupuncture.

The modalities of acupuncture can be broadly classified into manual acupuncture (MA) and electroacupuncture (EA). Although MA has been reported to cause winding of tissue around the needle and subsequent activation of the sensory mechanoreceptors and nociceptors, the sensory mechanisms of acupuncture stimulation are not fully understood. To test the hypothesis that the involvement of the mechanoreceptors in the sensory mechanism is different in MA and EA, we examined the effects of a stretch-activated channel blocker gadolinium on the hemodynamic responses to hind limb MA and EA in anesthetized rats (n = 9). Gadolinium significantly attenuated the MA-induced bradycardic response (-22 ± 5 vs. -10 ± 3 bpm, P<0.05) and tended to attenuate the MA-induced depressor response (-30 ± 5 vs. -18 ± 4 mmHg, P = 0.06). On the other hand, gadolinium significantly attenuated both the EA-induced bradycardic (-22 ± 5 vs. -9 ± 4 bpm, P<0.01) and depressor responses (-32 ± 6 vs. -15 ± 5 mmHg, P<0.01). These results indicate that the mechanoreceptors are involved in the sensory mechanisms for both MA and EA.

Servo-controlled hind-limb electrical stimulation for short-term arterial pressure control.

BACKGROUND: Autonomic neural intervention is a promising tool for modulating the circulatory system thereby treating some cardiovascular diseases. METHODS AND RESULTS: In 8 pentobarbital-anesthetized cats, it was examined whether the arterial pressure (AP) could be controlled by acupuncture-like hind-limb electrical stimulation (HES). With a 0.5-ms pulse width, HES monotonically reduced AP as the stimulus current increased from 1 to 5 mA, suggesting that the stimulus current could be a primary control variable. In contrast, the depressor effect of HES showed a nadir approximately 10 Hz in the frequency range between 1 and 100 Hz. Dynamic characteristics of the AP response to HES approximated a second-order low-pass filter with dead time (gain: -10.2 +/- 1.6 mmHg/mA, natural frequency: 0.040 +/- 0.004 Hz, damping ratio 1.80 +/- 0.24, dead time: 1.38 +/- 0.13 s, mean +/- SE). Based on these dynamic characteristics, a servo-controlled HES system was developed. When a target AP value was set at 20 mmHg below the baseline AP, the time required for the AP response to reach 90% of the target level was 38 +/- 10 s. The steady-state error between the measured and target AP values was 1.3 +/- 0.1 mmHg. CONCLUSIONS: Autonomic neural intervention by acupuncture-like HES might provide an additional modality to quantitatively control the circulatory system.

Electroacupuncture changes the relationship between cardiac and renal sympathetic nerve activities in anesthetized cats.

Electroacupuncture (EA) is known to affect hemodynamics through modulation of efferent sympathetic nerve activity (SNA), however, possible regional differences in the SNA response to EA remains to be examined. Based on the discordance between arterial blood pressure and heart rate changes during EA, we hypothesized that regional differences would occur among SNAs during EA. To test this hypothesis, we compared changes in cardiac and renal SNAs in response to 1-min EA (10 Hz or 2 Hz) of a hind limb in adult cats anesthetized with pentobarbital sodium. Renal SNA remained decreased for 1 min during EA (P<0.01 for both 10 Hz and 2 Hz). In contrast, cardiac SNA tented to decrease only in the beginning of EA. It increased during the end of EA (P<0.05 for 2 Hz) and further increased after the end of EA (P<0.01 both for 10 Hz and 2 Hz). There was a quasi-linear relationship between renal and cardiac SNAs with a slope of 0.69 (i.e., renal SNA was more suppressed than cardiac SNA) during the last 10 s of EA. The discrepancy between the renal and cardiac SNAs persisted after sinoaortic denervation and vagotomy. In conclusion, EA evokes differential patterns of SNA responses and changes the relationship between cardiac and renal SNAs.

Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release.

AIMS: To evaluate vagal stimulation-mediated myocardial protection against ischemia and reperfusion in in vivo ischemic myocardium. MAIN METHODS: We measured myocardial interstitial myoglobin levels in the ischemic region using a cardiac microdialysis technique in anesthetized and vagotomized cats. We occluded the left anterior descending coronary artery (LAD) for 60 min and reperfused it for 60 min (VX group, n = 6). The effects of bilateral vagal stimulation (10 V, 5 Hz, 1-ms pulse duration), initiated immediately after LAD occlusion, were examined (VS group, n = 6). To examine the involvement of phosphatidylinositol 3-kinase (PI3K), vagal stimulation was performed after pretreatment with a PI3K inhibitor wortmannin (0.6 mg/kg, i.v.) (VS-W group, n = 6). To examine the contribution of bradycardia, vagal stimulation was performed with fixed-rate ventricular pacing (VS-P group, n = 6). KEY FINDINGS: The average myoglobin level during the ischemic period was 1170+/-141 in VX (in ng/ml, mean+/-SE), which was significantly attenuated in VS (466+/-87, P<0.05) and VS-W (613+/-124, P<0.05) but not in VS-P (953+/-203). Reperfusion increased the myoglobin level to 2500+/-544 in VX, whereas it was suppressed in VS (824+/-213, P<0.05) and VS-W (948+/-315, P<0.05) but not in VS-P (1710+/-253). SIGNIFICANCE: Vagal stimulation, initiated immediately after LAD occlusion, attenuated the myocardial injury. Moreover, bradycardia, independent of PI3K pathway, plays a significant role in vagally induced cardioprotection during acute myocardial ischemia.

Modification of autonomic balance by electrical acupuncture does not affect baroreflex dynamic characteristics.

BACKGROUND: We have demonstrated that modification of autonomic balance by electrical vagal stimulation delays progression of cardiac dysfunction and cardiac remodeling, and prolongs survival in rats with severe heart failure. We have also shown that we were able to modify autonomic balance by electrical acupuncture at the acupoint of Zusanli, potentially applicable for the treatment of heart failure. We examined the effect of the acupuncture on the dynamic characteristics of the baroreflex system to exclude the possible deleterious effect on orthostatic tolerance. METHOD: In anesthetized 8 and 6 rabbits, we examined static and dynamic characteristics of baroreflex, respectively, with and without electrical acupuncture (1 Hz, 5 mA, and 5msec). Dynamic characteristics were examined by imposing pseudorandom binary changes in isolated carotid sinus pressure. RESULTS: With the stimulation condition to decrease arterial blood pressure and sympathetic nerve activity (resulted form decreased response range of neural arc), either of the dynamic characteristics of neural arc or those of peripheral arc did not change by electrical acupuncture at Zusanli. CONCLUSION: We conclude that application of electrical acupuncture at Zusanli can suppress sympathetic nerve activity but does not affect the dynamic characteristics of the arterial baroreflex system, indicating no deleterious effect on orthostatic tolerance.

Electrical acupuncture modifies autonomic balance by resetting the neural arc of arterial baroreflex system.

Contribution of abnormal cardiovascular regulation to the maintenance and progression of heart failure has been repeatedly demonstrated. Besides the current therapeutic modalities, development of an additional therapeutic strategy is needed. We have been developing a bionic system, an artificial device designed for integration into native physiological systems. By communicating with the physiological regulatory system, we tried to not only restore lost function but also correct abnormal function. We have already shown that modification of autonomic balance by direct electrical vagal stimulation has inhibited cardiac remodeling, and improved survival in rats. Because the benefit of the correction of autonomic balance would be greatly enhanced if available by a less invasive method, we examined the possibility of modifying the autonomic balance by electrical acupuncture. The results indicated that electrical acupuncture resets the neural arc of the arterial baroreflex (SNA response range decreases from 144.0+/-35.0 to 112.6+/-9.2, p<0.005) and is able to attenuate sympathetic nerve activity.

Short-term electroacupuncture at Zusanli resets the arterial baroreflex neural arc toward lower sympathetic nerve activity.

Although electroacupuncture reduces sympathetic nerve activity (SNA) and arterial pressure (AP), the effects of electroacupuncture on the arterial baroreflex remain to be systematically analyzed. We investigated the effects of electroacupuncture of Zusanli on the arterial baroreflex using an equilibrium diagram comprised of neural and peripheral arcs. In anesthetized, vagotomized, and aortic-denervated rabbits, we isolated carotid sinuses and changed intra-carotid sinus pressure (CSP) from 40 to 160 mmHg in increments of 20 mmHg/min while recording cardiac SNA and AP. Electroacupuncture of Zusanli was applied with a pulse duration of 5 ms and a frequency of 1 Hz. An electric current 10 times the minimal threshold current required for visible muscle twitches was used and was determined to be 4.8 +/- 0.3 mA. Electroacupuncture for 8 min decreased SNA and AP (n = 6). It shifted the neural arc (i.e., CSP-SNA relationship) to lower SNA but did not affect the peripheral arc (i.e., SNA-AP relationship) (n = 8). SNA and AP at the closed-loop operating point, determined by the intersection of the neural and peripheral arcs, decreased from 100 +/- 4 to 80 +/- 9 arbitrary units and from 108 +/- 9 to 99 +/- 8 mmHg (each P < 0.005), respectively. Peroneal denervation eliminated the shift of neural arc by electroacupuncture (n = 6). Decreasing the pulse duration to <2.5 ms eliminated the effects of SNA and AP reduction. In conclusion, short-term electroacupuncture resets the neural arc to lower SNA, which moves the operating point toward lower AP and SNA under baroreflex closed-loop conditions.

Bionic epidural stimulation restores arterial pressure regulation during orthostasis.

A bionic baroreflex system (BBS) is a computer-assisted intelligent feedback system to control arterial pressure (AP) for the treatment of baroreflex failure. To apply this system clinically, an appropriate efferent neural (sympathetic vasomotor) interface has to be explored. We examined whether the spinal cord is a candidate site for such interface. In six anesthetized and baroreflex-deafferentiated cats, a multielectrode catheter was inserted into the epidural space to deliver epidural spinal cord stimulation (ESCS). Stepwise changes in ESCS rate revealed a linear correlation between ESCS rate and AP for ESCS rates of 2 pulses/s and above (r2, 0.876-0.979; slope, 14.3 +/- 5.8 mmHg.pulses(-1).s; pressure axis intercept, 35.7 +/- 25.9 mmHg). Random changes in ESCS rate with a white noise sequence revealed dynamic transfer function of peripheral effectors. The transfer function resembled a second-order, low-pass filter with a lag time (gain, 16.7 +/- 8.3 mmHg.pulses(-1).s; natural frequency, 0.022 +/- 0.007 Hz; damping coefficient, 2.40 +/- 1.07; lag time, 1.06 +/- 0.41 s). On the basis of the transfer function, we designed an artificial vasomotor center to attenuate hypotension. We evaluated the performance of the BBS against hypotension induced by 60 degrees head-up tilt. In the cats with baroreflex failure, head-up tilt dropped AP by 37 +/- 5 mmHg in 5 s and 59 +/- 11 mmHg in 30 s. BBS with optimized feedback parameters attenuated hypotension to 21 +/- 2 mmHg in 5 s (P < 0.05) and 8 +/- 4 mmHg in 30 s (P < 0.05). These results indicate that ESCS-mediated BBS prevents orthostatic hypotension. Because epidural stimulation is a clinically feasible procedure, this BBS can be applied clinically to combat hypotension associated with various pathophysiologies.

Input-size dependence of the baroreflex neural arc transfer characteristics.

Static characteristics of the baroreflex neural arc from pressure input to sympathetic nerve activity (SNA) show sigmoidal nonlinearity, whereas its dynamic characteristics approximate a derivative filter where the magnitude of SNA response becomes greater as the input frequency increases. To reconcile the static nonlinear and dynamic linear components, we examined the effects of input amplitude on the apparent linear transfer function of the neural arc. In nine anesthetized rabbits, we perturbed isolated carotid sinus pressure by using binary white noise while varying the input amplitude among 5, 10, 20, and 40 mmHg. With increasing input amplitude, the transfer gain at 0.01 Hz decreased from 1.21 +/- 0.27 to 0.49 +/- 0.28 arbitrary units/mmHg (P < 0.01). Moreover, the slope of the transfer gain between 0.03 and 0.3 Hz decreased from 14.3 +/- 3.7 to 6.5 +/- 2.5 dB/decade (P < 0.01). We conclude that the model consisting of a sigmoidal component following rather than preceding a derivative component explains the observed results and thus can be used as a first approximation of the overall neural arc transfer characteristics.