Muscle mechanoreflex augments arterial baroreflex-mediated dynamic sympathetic response to carotid sinus pressure

Although the muscle mechanoreflex is one of the pressor reflexes during exercise, its interaction with dynamic characteristics of the arterial baroreflex remains to be quantitatively analyzed. In anesthetized, vagotomized, and aortic-denervated rabbits (n = 7), we randomly perturbed isolated carotid sinus pressure (CSP) using binary white noise while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). We estimated the transfer functions of the baroreflex neural arc (CSP to SNA) and peripheral arc (SNA to AP) under conditions of control and muscle stretch of the hindlimb (5 kg of tension). The muscle stretch increased the dynamic gain of the neural arc while maintaining the derivative characteristics [gain at 0.01 Hz: 1.0 +/- 0.2 vs. 1.4 +/- 0.6 arbitrary units (au)/mmHg, gain at 1 Hz: 1.7 +/- 0.6 vs. 2.7 +/- 1.4 au/mmHg; P < 0.05, control vs. stretch]. In contrast, muscle stretch did not affect the peripheral arc. In the time domain, muscle stretch augmented the steady-state response at 50 s (-1.1 +/- 0.3 vs. -1.7 +/- 0.7 au; P < 0.05, control vs. stretch) and negative peak response (-2.1 +/- 0.5 vs. -3.1 +/- 1.5 au; P < 0.05, control vs. stretch) in the SNA step response. A simulation experiment using the results indicated that the muscle mechanoreflex would accelerate the closed-loop AP regulation via the arterial baroreflex.     

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.     

Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics

Neuronal uptake is the most important mechanism by which norepinephrine (NE) is removed from the synaptic clefts at sympathetic nerve terminals. We examined the effects of neuronal NE uptake blockade on the dynamic sympathetic regulation of the arterial baroreflex because dynamic characteristics are important for understanding the system behavior in response to exogenous disturbance. We perturbed intracarotid sinus pressure (CSP) according to a binary white noise sequence in anesthetized rabbits, while recording cardiac sympathetic nerve activity (SNA), arterial pressure (AP), and heart rate (HR). Intravenous administration of desipramine (1 mg/kg) decreased the normalized gain of the neural arc transfer function from CSP to SNA relative to untreated control (1.03 +/- 0.09 vs. 0.60 +/- 0.08 AU/mmHg, mean +/- SE, P < 0.01) but did not affect that of the peripheral arc transfer function from SNA to AP (1.10 +/- 0.05 vs. 1.08 +/- 0.10 mmHg/AU). The normalized gain of the transfer function from SNA to HR was unaffected (1.01 +/- 0.04 vs. 1.09 +/- 0.12 beats.min(-1).AU(-1)). Desipramine decreased the natural frequency of the transfer function from SNA to AP by 28.7 +/- 7.0% (0.046 +/- 0.007 vs. 0.031 +/- 0.002 Hz, P < 0.05) and that of the transfer function from SNA to HR by 64.4 +/- 2.2% (0.071 +/- 0.003 vs. 0.025 +/- 0.002 Hz, P < 0.01). In conclusion, neuronal NE uptake blockade by intravenous desipramine administration reduced the total buffering capacity of the arterial baroreflex mainly through its action on the neural arc. The differential effects of neuronal NE uptake blockade on the dynamic AP and HR responses to SNA may provide clues for understanding the complex pathophysiology of cardiovascular diseases associated with neuronal NE uptake deficiency.     

Static interaction between muscle mechanoreflex and arterial baroreflex in determining efferent sympathetic nerve activity

Elucidation of the interaction between the muscle mechanoreflex and the arterial baroreflex is essential for better understanding of sympathetic regulation during exercise. We characterized the effects of these two reflexes on sympathetic nerve activity (SNA) in anesthetized rabbits (n = 7). Under open-loop baroreflex conditions, we recorded renal SNA at carotid sinus pressure (CSP) of 40, 80, 120, or 160 mmHg while passively stretching the hindlimb muscle at muscle tension (MT) of 0, 2, 4, or 6 kg. The MT-SNA relationship at CSP of 40 mmHg approximated a straight line. Increase in CSP from 40 to 120 and 160 mmHg shifted the MT-SNA relationship downward and reduced the response range (the difference between maximum and minimum SNA) to 43 +/- 10% and 19 +/- 6%, respectively (P < 0.01). The CSP-SNA relationship at MT of 0 kg approximated a sigmoid curve. Increase in MT from 0 to 2, 4, and 6 kg shifted the CSP-SNA relationship upward and extended the response range to 133 +/- 8%, 156 +/- 14%, and 178 +/- 15%, respectively (P < 0.01). A model of algebraic summation, i.e., parallel shift, with a threshold of SNA functionally reproduced the interaction of the two reflexes (y = 1.00x - 0.01; r(2) = 0.991, root mean square = 2.6% between estimated and measured SNA). In conclusion, the response ranges of SNA to baroreceptor and muscle mechanoreceptor input changed in a manner that could be explained by a parallel shift with threshold.     

A derivative-sigmoidal model reproduces operating point-dependent baroreflex neural arc transfer characteristics

A cascade model comprised of a derivative filter followed by a nonlinear sigmoidal component reproduces the input size dependence of transfer gain in the baroreflex neural arc from baroreceptor pressure input to efferent sympathetic nerve activity (SNA). We examined whether the same model could predict the operating point dependence of the baroreflex neural arc transfer characteristics estimated by a binary white noise input. In eight anesthetized rabbits, we isolated bilateral carotid sinuses from the systemic circulation and controlled intracarotid sinus pressure (CSP). We estimated the linear transfer function from CSP to SNA while varying mean CSP among 70, 100, 130, and 160 mmHg (P(70), P(100), P(130), and P(160), respectively). The transfer gain at 0.01 Hz was significantly smaller at P(70) (0.61 +/- 0.26) and P(160) (0.60 +/- 0.25) than at P(100) (1.32 +/- 0.42) and P(130) (1.36 +/- 0.45) (in arbitrary units/mmHg; means +/- SD; P < 0.05). In contrast, transfer gain values above 0.5 Hz were similar among the protocols. As a result, the slope of increasing gain between 0.1 and 0.5 Hz was significantly steeper at P(70) (17.6 +/- 3.6) and P(160) (14.1 +/- 4.3) than at P(100) (8.1 +/- 4.4) and P(130) (7.4 +/- 6.6) (in dB/decade; means +/- SD; P < 0.05). These results were consistent with those predicted by the derivative-sigmoidal model, where the deviation of mean input pressure from the center of the sigmoidal nonlinearity reduced the transfer gain mainly in the low-frequency range. The derivative-sigmoidal model functionally reproduces the dynamic SNA regulation by the arterial baroreflex over a wide operating range.     

Bezold-Jarisch reflex attenuates dynamic gain of baroreflex neural arc

Although acute myocardial ischemia or infarction may induce the Bezold-Jarisch (BJ) reflex through the activation of serotonin receptors on vagal afferent nerves, the mechanism by which the BJ reflex modulates the dynamic characteristics of arterial pressure (AP) regulation is unknown. The purpose of this study was to examine the effects of the BJ reflex induced by intravenous phenylbiguanide (PBG) on the dynamic characteristics of the arterial baroreflex. In seven anesthetized rabbits, we perturbed intracarotid sinus pressure (CSP) according to a white noise sequence while renal sympathetic nerve activity (RSNA), AP, and heart rate (HR) were recorded. We estimated the transfer function from CSP to RSNA (neural arc) and from RSNA to AP (peripheral arc) before and after 10 min of intravenous administration of PBG (100 microg. kg-1. min-1). The intravenous PBG decreased mean AP from 84.5 +/- 4.0 to 68.2 +/- 4.7 mmHg (P < 0.01), mean RSNA to 76.2 +/- 7.0% (P < 0.05), and mean HR from 301.6 +/- 7.7 to 288.4 +/- 9.0 beats/min (P < 0.01). The intravenous PBG significantly decreased neural arc dynamic gain at 0.01 Hz (1.06 +/- 0.08 vs. 0.59 +/- 0.17, P < 0.05), whereas it did not affect that of the peripheral arc (1.20 +/- 0.12 vs. 1.18 +/- 0.41). In six different rabbits without intravenous PBG, the neural arc transfer function did not change between two experimental runs with intervening interval of 10 min, excluding the possibility that the cumulative effects of anesthetics had altered the neural arc transfer function. In conclusion, excessive activation of the BJ reflex during acute myocardial ischemia may exert an adverse effect on AP regulation, not only by sympathetic suppression, but also by attenuating baroreflex dynamic gain.     

Interaction between vestibulo-cardiovascular reflex and arterial baroreflex during postural change in rats

To examine a cooperative role for the baroreflex and the vestibular system in controlling arterial pressure (AP) during voluntary postural change, AP was measured in freely moving conscious rats, with or without sinoaortic baroreceptor denervation (SAD) and/or peripheral vestibular lesion (VL). Voluntary rear-up induced a slight decrease in AP (-5.6 ± 0.8 mmHg), which was significantly augmented by SAD (-14.7 ± 1.0 mmHg) and further augmented by a combination of VL and SAD (-21 ± 1.0 mmHg). Thus we hypothesized that the vestibular system sensitizes the baroreflex during postural change. To test this hypothesis, open-loop baroreflex analysis was conducted on anesthetized sham-treated and VL rats. The isolated carotid sinus pressure was increased stepwise from 60 to 180 mmHg while rats were placed horizontal prone or in a 60° head-up tilt (HUT) position. HUT shifted the carotid sinus pressure-sympathetic nerve activity (SNA) relationship (neural arc) to a higher SNA, shifted the SNA-AP relationship (peripheral arc) to a lower AP, and, consequently, moved the operating point to a higher SNA while maintaining AP (from 113 ± 5 to 114 ± 5 mmHg). The HUT-induced neural arc shift was completely abolished in VL rats, whereas the peripheral arc shifted to a lower AP and the operating point moved to a lower AP (from 116 ± 3 to 84 ± 5 mmHg). These results indicate that the vestibular system elicits sympathoexcitation, shifting the baroreflex neural arc to a higher SNA and maintaining AP during HUT.     

Baroreflex responsiveness during ventilatory acclimatization in humans

We tested the hypothesis that the decline in muscle sympathetic activity during and after 8 h of poikilocapnic hypoxia (Hx) was associated with a greater sympathetic baroreflex-mediated responsiveness. In 10 healthy men and women (n=2), we measured beat-to-beat blood pressure (Portapres), carotid artery distension (ultrasonography), heart period, and muscle sympathetic nerve activity (SNA; microneurography) during two baroreflex perturbations using the modified Oxford technique before, during, and after 8 h of hypoxia (84% arterial oxygen saturation). The integrated baroreflex response [change of SNA (DeltaSNA)/change of diastolic blood pressure (DeltaDBP)], mechanical (Deltadiastolic diameter/DeltaDBP), and neural (DeltaSNA/Deltadiastolic diameter) components were estimated at each time point. Sympathetic baroreflex responsiveness declined throughout the hypoxic exposure and further declined upon return to normoxia [pre-Hx, -8.3+/-1.2; 1-h Hx, -7.2+/-1.0; 7-h Hx, -4.9+/-1.0; and post-Hx: -4.1+/-0.9 arbitrary integrated units (AIU) x min(-1) x mmHg(-1); P<0.05 vs. previous time point for 1-h, 7-h, and post-Hx values]. This blunting of baroreflex-mediated efferent outflow was not due to a change in the mechanical transduction of arterial pressure into barosensory stretch. Rather, the neural component declined in a similar pattern to that of the integrated reflex response (pre-Hx, -2.70+/-0.53; 1-h Hx, -2.59+/-0.53; 7-h Hx, -1.60+/-0.34; and post-Hx, -1.34+/-0.27 AIU x min(-1) x microm(-1); P < 0.05 vs. pre-Hx for 7-h and post-Hx values). Thus it does not appear as if enhanced baroreflex function is primarily responsible for the reduced muscle SNA observed during intermediate duration hypoxia. However, the central transduction of baroreceptor afferent neural activity into efferent neural activity appears to be reduced during the initial stages of peripheral chemoreceptor acclimatization.     

Dynamic and static baroreflex control of muscle sympathetic nerve activity (SNA) parallels that of renal and cardiac SNA during physiological change in pressure

Despite accumulated knowledge on human baroreflex control of muscle sympathetic nerve activity (SNA), whether baroreflex control of muscle SNA parallels that of other SNAs, in particular renal and cardiac SNAs, remains unclear. Using urethane and alpha-chloralose-anesthetized, vagotomized and aortic-denervated rabbits (n = 10), we recorded muscle SNA from tibial nerve by microneurography, simultaneously with renal and cardiac SNAs by wire electrode. To produce a baroreflex open-loop condition, we isolated the carotid sinuses from systemic circulation and altered the intracarotid sinus pressure (CSP) according to a binary white noise sequence of operating pressure +/- 20 mmHg (for investigating dynamic characteristics of baroreflex) or in stepwise 20-mmHg increments from 40 to 160 mmHg (for investigating static characteristics of baroreflex). Dynamic high-pass characteristics of baroreflex control of muscle SNA, assessed by the increasing slope of transfer gain, showed that more rapid change of arterial pressure resulted in greater response of muscle SNA to pressure change and that these characteristics were similar to cardiac SNA but greater than renal SNA. However, numerical simulation based on the transfer function shows that the differences in dynamic baroreflex control at various organs result in detectable differences among SNAs only when CSP changes at unphysiologically high rates (i.e., 5 mmHg/s). On the other hand, static reverse-sigmoid characteristics of baroreflex control of muscle SNA agreed well with those of renal or cardiac SNAs. In conclusion, dynamic-linear and static-nonlinear baroreflex control of muscle SNA is similar to that of renal and cardiac SNAs under physiological pressure change.     

Baroreflex control of lumbar and renal sympathetic nerve activity in conscious rats

This study compared the baroreflex control of lumbar and renal sympathetic nerve activity (SNA) in conscious rats. Arterial pressure (AP) and lumbar and renal SNA were simultaneously recorded in six freely behaving rats. Pharmacological estimates of lumbar and renal sympathetic baroreflex sensitivity (BRS) were obtained by means of the sequential intravenous administration of sodium nitroprusside and phenylephrine. Sympathetic BRS was significantly (P < 0.05) lower for lumbar [3.0 +/- 0.4 normalized units (NU)/mmHg] than for renal (7.6 +/- 0.6 NU/mmHg) SNA. During a 219-min baseline period, spontaneous lumbar and renal BRS were continuously assessed by computing the gain of the transfer function relating AP and SNA at heart rate frequency over consecutive 61.4-s periods. The transfer gain was considered only when coherence between AP and SNA significantly differed from zero, which was verified in 99 +/- 1 and 96 +/- 3% of cases for lumbar and renal SNA, respectively. When averaged over the entire baseline period, spontaneous BRS was significantly (P < 0.05) lower for lumbar (1.3 +/- 0.2 NU/mmHg) than for renal (2.3 +/- 0.3 NU/mmHg) SNA. For both SNAs, spontaneous BRS showed marked fluctuations (variation coefficients were 26 +/- 2 and 28 +/- 2% for lumbar and renal SNA, respectively). These fluctuations were positively correlated in five of six rats (R = 0.44 +/- 0.06; n = 204 +/- 8; P < 0.0001). We conclude that in conscious rats, the baroreflex control of lumbar and renal SNA shows quantitative differences but is modulated in a mostly coordinated way.     

Dynamic characteristics of baroreflex neural and peripheral arcs are preserved in spontaneously hypertensive rats

Although baroreceptors are known to reset to operate in a higher pressure range in spontaneously hypertensive rats (SHR), the total profile of dynamic arterial pressure (AP) regulation remains to be clarified. We estimated open-loop transfer functions of the carotid sinus baroreflex in SHR and Wistar Kyoto (WKY) rats. Mean input pressures were set at 120 (WKY??? and SHR???) and 160 mmHg (SHR???). The neural arc transfer function from carotid sinus pressure to efferent splanchnic sympathetic nerve activity (SNA) revealed derivative characteristics in both WKY and SHR. The slope of dynamic gain (in decibels per decade) between 0.1 and 1 Hz was not different between WKY??? (10.1 ± 1.0) and SHR??? (10.4 ± 1.1) but was significantly greater in SHR??? (13.2 ± 0.8, P < 0.05 with Bonferroni correction) than in SHR???. The peripheral arc transfer function from SNA to AP showed low-pass characteristics. The slope of dynamic gain (in decibels per decade) did not differ between WKY??? (-34.0 ± 1.2) and SHR??? (-31.4 ± 1.0) or between SHR??? and SHR??? (-32.8 ± 1.3). The total baroreflex showed low-pass characteristics and the dynamic gain at 0.01 Hz did not differ between WKY??? (0.91 ± 0.08) and SHR??? (0.84 ± 0.13) or between SHR??? and SHR??? (0.83 ± 0.11). In both WKY and SHR, the declining slope of dynamic gain was significantly gentler for the total baroreflex than for the peripheral arc, suggesting improved dynamic AP response in the total baroreflex. In conclusion, the dynamic characteristics of AP regulation by the carotid sinus baroreflex were well preserved in SHR despite significantly higher mean AP.     

Closed-loop estimation of the open-loop carotid sinus baroreflex transfer function for the use of animal experiments in space

In order to develop effective counter measures to cardiovascular maladaptation associated with space flight, it is essential to know how dynamic characteristics of blood pressure regulation are altered in space. The open-loop transfer characteristics of the carotid sinus baroreflex can be divided into the neural arc and peripheral arc transfer functions (Ikeda et al. 1996). The neural arc transfer function represents the dynamic input-output characteristics from arterial pressure (AP) to efferent sympathetic nerve activity (SNA), while the peripheral arc transfer function represents those from SNA to AP. Although AP perturbation according to a white noise sequence can be used to estimate the transfer functions under baroreflex closed-loop conditions (Kwanda et al. 1997), arterial catheter implantation necessary to perturb AP limits the applicability of this method to freely moving animal experiments. To overcome this problem, we explored the closed-loop system identification method using electrical stimulation. We used aortic depressor nerve (ADN) stimulation and rapid pacing (RP) of the heart to perturb the arterial baroreflex system.     

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.     

Disuse atrophy increases the muscle mechanoreflex in rats.

We investigated the effect of disuse atrophy on the magnitude of the muscle mechanoreflex. The left leg of eight rats (6-7 wk, male) was put in a plaster cast for 1 wk. The rats were decerebrated at the midcollicular level. We recorded the pressor and cardioaccelerator responses to 30-s stretch of the calcaneal tendon, which selectively stimulated the muscle mechanosensitive receptors in the left atrophied and right control triceps surae muscles. Atrophied muscles showed significantly lower mass control muscles (1.0 +/- 0.1 vs. 1.4 +/- 0.1 g; P < 0.05). At the same stretch tension (229 +/- 20 g), the pressor response to stretch was significantly greater in the atrophied muscles than in the control muscles (13 +/- 3 vs. 4 +/- 2 mmHg, P < 0.05). The cardioaccelerator response was not significantly different (8 +/- 4 vs. 4 +/- 2 beats/min). Comparing responses at the same relative tension (57 +/- 6 vs. 51 +/- 8% of maximal tension), the pressor response was still significantly greater in the atrophied triceps surae than in the control (14 +/- 4 vs. 4 +/- 2 mmHg; P < 0.05). These results suggest that disuse atrophy increases the magnitude of muscle mechanoreflex.     

Effect of hypoxia on arterial baroreflex control of heart rate and muscle sympathetic nerve activity in humans.

We tested the hypothesis that acute hypoxia would alter the sensitivity of arterial baroreflex control of both heart rate and sympathetic vasoconstrictor outflow. In 16 healthy, nonsmoking, normotensive subjects (8 women, 8 men, age 20-33 yr), we assessed baroreflex control of heart rate and muscle sympathetic nerve activity by using the modified Oxford technique during both normoxia and hypoxia (12% O(2)). Compared with normoxia, hypoxia reduced arterial O(2) saturation levels from 96.8 +/- 0.3 to 80.7 +/- 1.4% (P < 0.001), increased heart rate from 59.8 +/- 2.4 to 79.4 +/- 2.9 beats/min (P < 0.001), increased mean arterial pressure from 96.7 +/- 2.5 to 105.0 +/- 3.3 mmHg (P = 0.002), and increased sympathetic activity 126 +/- 58% (P < 0.05). The sensitivity for baroreflex control of both heart rate and sympathetic activity was not altered by hypoxia (heart rate: -1.02 +/- 0.09 vs. -1.02 +/- 0.11 beats. min(-1). mmHg(-1); nerve activity: -5.6 +/- 0.9 vs. -6.2 +/- 0.9 integrated activity. beat(-1). mmHg(-1); both P > 0.05). Acute exposure to hypoxia reset baroreflex control of both heart rate and sympathetic activity to higher pressures without changes in baroreflex sensitivity.     

Impairment of sympathetic baroreceptor reflexes in obese Zucker rats

Adult obese Zucker rats (OZRs) have elevated sympathetic vasomotor tone and arterial pressure (AP) with blunted baroreflex-mediated changes in heart rate (HR) compared with adult lean Zucker rats (LZRs). The present study examined whether compromised cardiac baroreflexes are indicative of attenuated sympathetic responses. In addition, because juvenile OZRs have a normal mean AP, we determined whether baroreflexes are fully functional prior to hypertension. At 13 wk, adult OZRs had an elevated baseline mean AP compared with LZRs (137 +/- 3 vs. 123 +/- 5 mmHg, P < 0.05) under urethane anesthesia. Phenylephrine-induced increases in AP evoked smaller inhibitions of splanchnic sympathetic nerve activity (SNA) and HR in OZRs compared with LZRs. In addition, sympathoexcitatory responses to nitroprusside-induced hypotension were also blunted in OZRs. Sigmoid analysis revealed a decreased gain, a higher mean AP at the midpoint of the curve (AP(50)), and a reduced range of changes in SNA in OZRs. In contrast, at 7 wk of age, although juvenile OZRs weighed more than LZRs (313 +/- 13 vs. 204 +/- 4 g, P < 0.05), mean AP was comparable in both groups (122 +/- 5 vs. 121 +/- 4 mmHg, not significant). In these rats, rapid changes in AP evoked comparable changes in SNA and HR in OZRs and LZRs. Sigmoid analysis revealed that, although the gain of the reflex was blunted in OZRs (P < 0.05), the mean AP(50) and range of changes in SNA were comparable in OZRs and LZRs. Together, these data indicate that in adult OZRs, sympathetic responses to acute changes in AP are smaller than those observed in adult LZRs and that impairment of baroreceptor reflexes in OZR is not limited to the regulation of HR but extends to sympathetic vasomotor control. In addition, most of these deficits in baroreflex control of SNA develop in adulthood long after the onset of obesity and when other deficits in cardiovascular regulation are present.     

Effect of baroreflex loading on the responsiveness of the vestibulosympathetic reflex in humans.

Activation of the vestibular otolith organs with head-down rotation (HDR) increases muscle sympathetic nerve activity (MSNA) in humans. Previously, we demonstrated this vestibulosympathetic reflex (VSR) elicits increases in MSNA during baroreflex unloading (i.e., lower body negative pressure) in humans. Whether such an effect persists during baroreflex loading is unknown. We tested the hypothesis that the ability of the VSR to increase MSNA is preserved during baroreflex unloading and inhibited during baroreflex loading. Ten subjects (26 +/- 1 yr) performed three trials of HDR to activate the VSR. These trials were performed after a period of sustained saline (control), nitroprusside (baroreflex unloading: 0.8-1.0 microg.kg(-1).min(-1)), and phenylephrine (baroreflex loading: 0.6-0.8 microg.kg(-1).min(-1)) infusion. Nitroprusside infusion decreased (Delta7 +/- 1 mmHg, where Delta is change; P < 0.001) and phenylephrine infusion increased mean arterial pressure (Delta8 +/- 1 mmHg; P < 0.001) at rest. HDR performed during the control [Delta3 +/- 2 bursts/min, Delta314 +/- 154 arbitrary units (au) total activity, Delta41 +/- 18% total activity; P < 0.05] and nitroprusside trials [Delta5 +/- 2 bursts/min, Delta713 +/- 241 au total activity, Delta49 +/- 20% total activity; P < 0.05] increased MSNA similarly despite significantly elevated levels at rest (13 +/- 2 to 26 +/- 3 bursts/min) in the latter. In contrast, HDR performed during the phenylephrine trial failed to increase MSNA (Delta0 +/- 1 bursts/min, Delta-15 +/- 33 au total activity, Delta-8 +/- 21% total activity). These results confirm previous findings that the ability of the VSR to increase MSNA is preserved during baroreflex unloading. In contrast, the ability of the VSR to increase MSNA is abolished during baroreflex loading. These results provide further support for the concept that the VSR may act primarily to defend against hypotension in humans.     

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.     

Baroreflex control of muscle sympathetic nerve activity during skin surface cooling.

Skin surface cooling improves orthostatic tolerance through a yet to be identified mechanism. One possibility is that skin surface cooling increases the gain of baroreflex control of efferent responses contributing to the maintenance of blood pressure. To test this hypothesis, muscle sympathetic nerve activity (MSNA), arterial blood pressure, and heart rate were recorded in nine healthy subjects during both normothermic and skin surface cooling conditions, while baroreflex control of MSNA and heart rate were assessed during rapid pharmacologically induced changes in arterial blood pressure. Skin surface cooling decreased mean skin temperature (34.9 +/- 0.2 to 29.8 +/- 0.6 degrees C; P < 0.001) and increased mean arterial blood pressure (85 +/- 2 to 93 +/- 3 mmHg; P < 0.001) without changing MSNA (P = 0.47) or heart rate (P = 0.21). The slope of the relationship between MSNA and diastolic blood pressure during skin surface cooling (-3.54 +/- 0.29 units.beat(-1).mmHg(-1)) was not significantly different from normothermic conditions (-2.94 +/- 0.21 units.beat(-1).mmHg(-1); P = 0.19). The slope depicting baroreflex control of heart rate was also not altered by skin surface cooling. However, skin surface cooling shifted the "operating point" of both baroreflex curves to high arterial blood pressures (i.e., rightward shift). Resetting baroreflex curves to higher pressure might contribute to the elevations in orthostatic tolerance associated with skin surface cooling.     

Interactions of plasma osmolality with arterial and central venous pressures in control of sympathetic activity and heart rate in humans

Plasma osmolality alters control of sympathetic activity and heart rate in animal models; however, it is unknown whether physiological increases in plasma osmolality have such influences in humans and what effect concurrent changes in central venous and/or arterial pressures may have. We tested whether physiological increases in plasma osmolality (similar to those during exercise dehydration) alter control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in humans. We studied 17 healthy young adults (7 women, 10 men) at baseline and during arterial pressure (AP) transients induced by sequential injections of nitroprusside and phenylephrine, under three conditions: control (C), after 1 ml/kg intravenous hypertonic saline (HT1), and after 2 ml/kg hypertonic saline (HT2). We continuously measured HR, AP, central venous pressure (CVP; peripherally inserted central catheter) and MSNA (peroneal microneurography) in all conditions. Plasma osmolality increased from 287 +/- 1 mosmol/kg in C to 290 +/- 1 mosmol/kg in HT1 (P < 0.05) but did not increase further in HT2 (291 +/- 1 mosmol/kg; P > 0.05 vs. C). Mean AP and CVP were similar between C and HT1, but both increased slightly in HT2. HR increased slightly but significantly during both HT1 and HT2 vs. C (P < 0.05). Sensitivity of baroreflex control of MSNA was significantly increased vs. C in HT1 [-7.59 +/- 0.97 (HT1) vs. -5.85 +/- 0.63 (C) arbitrary units (au).beat(-1).mmHg(-1); P < 0.01] but was not different in HT2 (-6.55 +/- 0.94 au.beat(-1).mmHg(-1)). We conclude that physiological changes in plasma osmolality significantly alter control of MSNA and HR in humans, and that this influence can be modified by CVP and AP.