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Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance ( R p ), arterial compliance ( C p ), characteristic impedance of the proximal arteries ( Z c ), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated R p , increased C p , and prolonged transmission time without affecting Z c . It reduced R p more pronouncedly in MCT-PAH rats, whereas it increased C p and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state. NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.

Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under β-blockade. In anesthetized rats ( n = 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V 0-10 ), between 0 and 20 Hz (V 0-20 ), and between 0 and 40 Hz (V 0-40 ). The transfer function from VNS to HR was estimated. Under β-blockade (propranolol, 2 mg/kg iv), IVA (2 mg/kg iv) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V 0-10 (0.53 ± 0.10 vs. 1.74 ± 0.40 beats/min/Hz, P < 0.01) and V 0-20 (0.79 ± 0.14 vs. 2.06 ± 0.47 beats/min/Hz, P < 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel ( I K,ACh ) pathway after IVA, because the HR control via the I K,ACh pathway is faster and acts in the frequency range higher than the cAMP-mediated pathway. NEW & NOTEWORTHY Since ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide-gated channels, interactions among the sympathetic effect, vagal effect, and IVA can occur in the control of heart rate (HR). To remove the sympathetic effect, we estimated the transfer function from vagal nerve stimulation to HR under β-blockade in anesthetized rats. IVA augmented the high-frequency dynamic gain during low- and moderate-intensity vagal nerve stimulation. Untethering the hyperpolarizing effect of acetylcholine-sensitive potassium channels after IVA may be a possible underlying mechanism.

Ivabradine is a selective bradycardic agent that reduces the heart rate (HR) by inhibiting the hyperpolarization-activated cyclic nucleotide-gated channels. Although its cardiovascular effect is thought to be minimal except for inducing bradycardia, ivabradine could interact with cardiovascular regulation by the autonomic nervous system. We tested whether ivabradine modifies dynamic characteristics of peripheral vagal HR control. In anesthetized Wistar-Kyoto rats ( n = 7), the right vagal nerve was sectioned and stimulated for 10 min according to a binary white noise sequence with a switching interval of 500 ms. The efferent vagal nerve stimulation (VNS) trials were performed using three different rates (10, 20, and 40 Hz), and were designated as V 0-10 , V 0-20 , and V 0-40 , respectively. The transfer function from the VNS to the HR was estimated before and after the intravenous administration of ivabradine (2 mg/kg). Ivabradine increased the asymptotic dynamic gain in V 0-20 [from 3.88 (1.78-5.79) to 6.62 (3.12-8.31) beats·min -1 ·Hz -1 , P < 0.01, median (range)] but not in V 0-10 or V 0-40 . Ivabradine increased the corner frequency in V 0-10 [from 0.032 (0.026-0.041) to 0.064 (0.029-0.090) Hz, P < 0.01] and V 0-20 [from 0.040 (0.037-0.056) to 0.068 (0.051-0.100) Hz, P < 0.01] but not in V 0-40 . In conclusion, ivabradine augmented the dynamic HR response to moderate VNS. At high VNS, however, ivabradine did not significantly augment the dynamic HR response, possibly because ivabradine reduced the baseline HR and limited the range for the bradycardic response to high VNS. NEW & NOTEWORTHY Ivabradine is considered to be a pure bradycardic agent that has little effect on cardiovascular function except inducing bradycardia. The present study demonstrated that ivabradine interacts with the dynamic vagal heart rate control in a manner that augments the heart rate response to moderate-intensity efferent vagal nerve stimulation.

Patients with diabetes mellitus (DM) often show arterial pressure (AP) lability associated with cardiovascular autonomic neuropathy. Because the arterial baroreflex tightly regulates AP via sympathetic nerve activity (SNA), we investigated the systematic baroreflex function, considering the control theory in DM by open-loop analysis. We used Zucker diabetic fatty (ZDF) rats as a type 2 DM model. Under general anesthesia, we isolated the carotid sinuses from the systemic circulation, changed intracarotid sinus pressure (CSP), and recorded SNA and AP responses. We compared CSP-AP (total loop), CSP-SNA (afferent arc), and SNA-AP (efferent arc) relationships between ZDF lean ( n = 8) and ZDF fatty rats ( n = 6). Although the total loop gain of baroreflex (ΔAP/ΔCSP) at the operating point did not differ between the two groups, the average gain in the lower CSP range was markedly reduced in ZDF fatty rats (0.03 ± 0.01 vs. 0.87 ± 0.10 mmHg/mmHg, P < 0.001). The afferent arc showed the same trend as the total loop, with a response threshold of 139.8 ± 1.0 mmHg in ZDF fatty rats. There were no significant differences in the gain of efferent arc between the two groups. Simulation experiments indicated a markedly higher AP fall and lower total loop gain of baroreflex in ZDF fatty rats than in ZDF lean rats against hypotensive stress because the efferent arc intersected with the afferent arc in the SNA unresponsive range. Thus, we concluded that impaired baroreflex sympathetic regulation in the lower AP range attenuates the pressure response against hypotensive stress and may partially contribute to AP lability in DM. NEW & NOTEWORTHY In this study, we investigated the open-loop baroreflex function, considering the control theory in type 2 diabetes mellitus model rats to address the systematic mechanism of arterial pressure (AP) lability in diabetes mellitus. The unresponsiveness of baroreflex sympathetic regulation in the lower AP range was observed in type 2 diabetic rats. It may attenuate the baroreflex pressure-stabilizing function and induce greater AP fall against hypotensive stress.

Pulmonary artery (PA) impedance provides detailed information on right ventricular (RV) afterload in pulmonary hypertension (PH). This study aimed to examine PA impedance in a rat model of monocrotaline-induced PH (MCT-PH) and to develop an experimental system for in vivo loading of pathological PA impedance on the RV of normal rats. PA impedance was quantified in normal (n= 10) and MCT-PH rats (n= 10) using a three-element Windkessel (3-WK) model. Compared with normal rats, MCT-PH rats had higher characteristic impedance (ZC) and peripheral pulmonary resistance (RP) (ZC: 0.121 ± 0.039 vs. 0.053 ± 0.017 mmHg·min·ml(-1), P< 0.001; RP: 0.581 ± 0.334 vs. 0.252 ± 0.105 mmHg·min·ml(-1), P= 0.013) and lower pulmonary artery compliance (CP) (0.242 ± 0.131 vs. 0.700 ± 0.186 ml/mmHg, P< 0.001). In another group of 10 normal rats, a computer-controlled servo pump was connected to the left PA for loading PA impedance with parameters in pathological ranges designed by the 3-WK model. Activation of the servo pump decreased the error of measured vs. target PA impedance (modulus: from 0.047 ± 0.020 without pump activation to 0.019 ± 0.007 with pump activation,P< 0.001; phase: 0.085 ± 0.028 to 0.043 ± 0.012 radians,P< 0.001). In conclusion, MCT-PH increases ZC and RP and decreases CP Our servo pump system, which is capable of imposing arbitrary PA impedance with pathological parameters, may offer a unique opportunity to delineate the pathological significance of PA impedance in PH., (Copyright © 2016 the American Physiological Society.)

Decreased carotid arterial compliance has been reported in obese subjects and animals. Carotid baroreceptors are located at the bifurcation of the common carotid artery, and respond to distension of the arterial wall, suggesting that higher pressure is required to obtain the same distension in obese subjects and animals. A hyperosmotic NaCl solution induces circulatory volume expansion and arterial pressure (AP) increase, which reflexively augment renal excretion. Thus, we hypothesized that sodium regulation via the baroreflex might be impaired in response to chronic hyperosmotic NaCl infusion in rats fed a high-fat diet. To examine this hypothesis, we used rats fed a high-fat (Fat) or normal (NFD) diet, and measured mean AP, water and sodium balance, and renal function in response to chronic infusion of hyperosmotic NaCl solution via a venous catheter. Furthermore, we examined arterial baroreflex characteristics with static open-loop analysis and distensibility of the common carotid artery. Significant positive water and sodium balance was observed on the 1st day of 9% NaCl infusion; however, this disappeared by the 2nd day in Fat rats. Mean AP was significantly higher during 9% NaCl infusion in Fat rats compared with NFD rats. In the open-loop analysis of carotid sinus baroreflex, a rightward shift of the neural arc was observed in Fat rats compared with NFD rats. Furthermore, distensibility of the common carotid artery was significantly reduced in Fat rats. These results indicate that a reduced baroreceptor distensibility-induced rightward shift of the neural arc might contribute to impairment of sodium regulation in Fat rats., (Copyright © 2015 the American Physiological Society.)

Since humans are under ceaseless orthostatic stress, the mechanisms to maintain arterial pressure (AP) against gravitational fluid shift are important. As one mechanism, it was reported that upright tilt reset baroreflex control of renal sympathetic nerve activity (SNA) to a higher SNA in anesthetized rabbits. In the present study, we tested the hypothesis that upright tilt causes a parallel resetting of baroreflex control of renal and cardiac SNAs in anesthetized rabbits. In anesthetized rabbits (n = 8, vagotomized and aortic denervated) with 0 degrees supine and 60 degrees upright tilt postures, renal and cardiac SNAs were simultaneously recorded while isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg. Upright tilt shifted the reverse-sigmoidal curve of the CSP-SNA relationship to higher SNA similarly in renal and cardiac SNAs. Although upright tilt increased the maximal gain, the response range and the minimum value of SNA, the curves were almost superimposable in these SNAs regardless of postures. Scatter plotting of cardiac SNA over renal SNA during the stepwise changes in CSP was close to the line of identity in 0 degrees supine and 60 degrees upright tilt postures. In addition, upright tilt also shifted the reverse-sigmoidal curve of the CSP-heart rate relationship to a higher heart rate, with increases in the maximal gain and the response range. In conclusion, upright posture caused a resetting of arterial baroreflex control of SNA similarly in renal and cardiac SNAs in anesthetized rabbits.

Many earlier human studies have reported that increasing the tilt angle of head-up tilt (HUT) results in greater muscle sympathetic nerve activity (MSNA) response, indicating the amplitude dependence of sympathetic activation in response to orthostatic stress. However, little is known about whether and how the inclining speed of HUT influences the MSNA response to HUT, independent of the magnitude of HUT. Twelve healthy subjects participated in passive 30 degrees HUT tests at inclining speeds of 1 degrees (control), 0.1 degrees (slow), and 0.0167 degrees (very slow) per second. We recorded MSNA (tibial nerve) by microneurography and assessed nonstationary time-dependent changes of R-R interval variability using a complex demodulation technique. MSNA averaged over every 10 degrees tilt angle increased during inclination from 0 degrees to 30 degrees , with smaller increases in the slow and very slow tests than in the control test. Although a 3-min MSNA overshoot after reaching 30 degrees HUT was observed in the control test, no overshoot was detected in the slow and very slow tests. In contrast with MSNA, increases in heart rate during the inclination and after reaching 30 degrees were similar in these tests, probably because when compared with the control test, greater increases in plasma epinephrine counteracted smaller autonomic responses in the very slow test. These results indicate that slower HUT results in lower activation of MSNA, suggesting that HUT-induced sympathetic activation depends partially on the speed of inclination during HUT in humans.

To better understand the pathophysiological role of angiotensin II (ANG II) in the dynamic autonomic regulation of heart rate (HR), we examined the effects of intravenous administration of ANG II (10 microg.kg(-1).h(-1)) on the transfer function from vagal or sympathetic nerve stimulation to HR in anesthetized rabbits with sinoaortic denervation and vagotomy. In the vagal stimulation group (n = 7), we stimulated the right vagal nerve for 10 min using binary white noise (0-10 Hz). The transfer function from vagal stimulation to HR approximated a first-order low-pass filter with pure delay. ANG II attenuated the dynamic gain from 7.6 +/- 0.9 to 5.8 +/- 0.9 beats.min(-1).Hz(-1) (means +/- SD; P < 0.01) without affecting the corner frequency or pure delay. In the sympathetic stimulation group (n = 7), we stimulated the right postganglionic cardiac sympathetic nerve for 20 min using binary white noise (0-5 Hz). The transfer function from sympathetic stimulation to HR approximated a second-order low-pass filter with pure delay. ANG II slightly attenuated the dynamic gain from 10.8 +/- 2.6 to 10.2 +/- 3.1 beats.min(-1).Hz(-1) (P = 0.049) without affecting the natural frequency, damping ratio, or pure delay. The disproportional suppression of the dynamic vagal and sympathetic regulation of HR would result in a relative sympathetic predominance in the presence of ANG II. The reduced high-frequency component of HR variability in patients with cardiovascular diseases, such as myocardial infarction and heart failure, may be explained in part by the peripheral effects of ANG II on the dynamic autonomic regulation of HR.

Presynaptic alpha2-adrenergic receptors are known to exert feedback inhibition on norepinephrine release from the sympathetic nerve terminals. To elucidate the dynamic characteristics of the inhibition, we stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring heart rate (HR) in anesthetized rabbits (n = 6). We estimated the transfer function from cardiac sympathetic nerve stimulation to HR and the corresponding step response of HR, with and without the blockade of presynaptic inhibition by yohimbine (1 mg/kg followed by 0.1 mg.kg(-1).h(-1) iv). We also examined the effect of the alpha2-adrenergic receptor agonist clonidine (0.3 and 1.5 mg.kg(-1).h(-1) iv) in different rabbits (n = 5). Yohimbine increased the maximum step response (from 7.2 +/- 0.8 to 12.2 +/- 1.7 beats/min, means +/- SE, P < 0.05) without significantly affecting the initial slope (0.93 +/- 0.23 vs. 0.94 +/- 0.22 beats.min(-1).s(-1)). Higher dose but not lower dose clonidine significantly decreased the maximum step response (from 6.3 +/- 0.8 to 6.8 +/- 1.0 and 2.8 +/- 0.5 beats/min, P < 0.05) and also reduced the initial slope (from 0.56 +/- 0.07 to 0.51 +/- 0.04 and 0.22 +/- 0.06 beats.min(-1).s(-1), P < 0.05). Our findings indicate that presynaptic alpha2-adrenergic autoinhibition limits the maximum response without significantly compromising the rapidity of effector response. In contrast, pharmacologic augmentation of the presynaptic inhibition not only attenuates the maximum response but also results in a sluggish effector response.

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.

Vagal nerve stimulation has been suggested to ameliorate left ventricular (LV) remodeling in heart failure. However, it is not known whether and to what degree vagal nerve stimulation affects matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in myocardium, which are known to play crucial roles in LV remodeling. We therefore investigated the effects of electrical stimulation of efferent vagal nerve on myocardial expression and activation of MMPs and TIMPs in a rabbit model of myocardial ischemia-reperfusion (I/R) injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (I/R-VS, n = 8) or without vagal nerve stimulation (I/R, n = 7). Rabbits not subjected to coronary occlusion with (VS, n = 7) or without vagal stimulation (sham, n = 7) were used as controls. Total MMP-9 protein increased significantly after left coronary artery occlusion in I/R-VS and I/R to a similar degree compared with VS and sham values. Endogenous active MMP-9 protein level was significantly lower in I/R-VS compared with I/R. TIMP-1 mRNA expression was significantly increased in I/R-VS compared with the I/R, VS, and sham groups. TIMP-1 protein was significantly increased in I/R-VS and VS compared with the I/R and sham groups. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by coperfusion of atropine. Immunohistochemistry demonstrated a strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial I/R injury, vagal nerve stimulation induced TIMP-1 expression in cardiomyocytes and reduced active MMP-9.

Although ANG II exerts a variety of effects on the cardiovascular system, its effects on the peripheral parasympathetic neurotransmission have only been evaluated by changes in heart rate (an effect on the sinus node). To elucidate the effect of ANG II on the parasympathetic neurotransmission in the left ventricle, we measured myocardial interstitial ACh release in response to vagal stimulation (1 ms, 10 V, 20 Hz) using cardiac microdialysis in anesthetized cats. In a control group (n = 6), vagal stimulation increased the ACh level from 0.85 +/- 0.03 to 10.7 +/- 1.0 (SE) nM. Intravenous administration of ANG II at 10 microg x kg(-1) x h(-1) suppressed the stimulation-induced ACh release to 7.5 +/- 0.6 nM (P < 0.01). In a group with pretreatment of intravenous ANG II receptor subtype 1 (AT(1) receptor) blocker losartan (10 mg/kg, n = 6), ANG II was unable to inhibit the stimulation-induced ACh release (8.6 +/- 1.5 vs. 8.4 +/- 1.7 nM). In contrast, in a group with local administration of losartan (10 mM, n = 6) through the dialysis probe, ANG II inhibited the stimulation-induced ACh release (8.0 +/- 0.8 vs. 5.8 +/- 1.0 nM, P < 0.05). In conclusion, intravenous ANG II significantly inhibited the parasympathetic neurotransmission through AT(1) receptors. The failure of local losartan administration to nullify the inhibitory effect of ANG II on the stimulation-induced ACh release indicates that the site of this inhibitory action is likely at parasympathetic ganglia rather than at postganglionic vagal nerve terminals.

Vagal control of heart rate (HR) is mediated by direct and indirect actions of ACh. Direct action of ACh activates the muscarinic K(+) (K(ACh)) channels, whereas indirect action inhibits adenylyl cyclase. The role of the K(ACh) channels in the overall picture of vagal HR control remains to be elucidated. We examined the role of the K(ACh) channels in the transfer characteristics of the HR response to vagal stimulation. In nine anesthetized sinoaortic-denerved and vagotomized rabbits, the vagal nerve was stimulated with a binary white-noise signal (0-10 Hz) for examination of the dynamic characteristic and in a step-wise manner (5, 10, 15, and 20 Hz/min) for examination of the static characteristic. The dynamic transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with a lag time. Tertiapin, a selective K(ACh) channel blocker (30 nmol/kg iv), significantly decreased the dynamic gain from 5.0 +/- 1.2 to 2.0 +/- 0.6 (mean +/- SD) beats.min(-1).Hz(-1) (P < 0.01) and the corner frequency from 0.25 +/- 0.03 to 0.06 +/- 0.01 Hz (P < 0.01) without changing the lag time (0.37 +/- 0.04 vs. 0.39 +/- 0.05 s). Moreover, tertiapin significantly attenuated the vagal stimulation-induced HR decrease by 46 +/- 21, 58 +/- 18, 65 +/- 15, and 68 +/- 11% at stimulus frequencies of 5, 10, 15, and 20 Hz, respectively. We conclude that K(ACh) channels contribute to a rapid HR change and to a larger decrease in the steady-state HR in response to more potent tonic vagal stimulation.

Although an axoplasmic Ca(2+) increase is associated with an exocytotic acetylcholine (ACh) release from the parasympathetic postganglionic nerve endings, the role of voltage-dependent Ca(2+) channels in ACh release in the mammalian cardiac parasympathetic nerve is not clearly understood. Using a cardiac microdialysis technique, we examined the effects of Ca(2+) channel antagonists on vagal nerve stimulation- and ischemia-induced myocardial interstitial ACh releases in anesthetized cats. The vagal stimulation-induced ACh release [22.4 nM (SD 10.6), n = 7] was significantly attenuated by local administration of an N-type Ca(2+) channel antagonist omega-conotoxin GVIA [11.7 nM (SD 5.8), n = 7, P = 0.0054], or a P/Q-type Ca(2+) channel antagonist omega-conotoxin MVIIC [3.8 nM (SD 2.3), n = 6, P = 0.0002] but not by local administration of an L-type Ca(2+) channel antagonist verapamil [23.5 nM (SD 6.0), n = 5, P = 0.758]. The ischemia-induced myocardial interstitial ACh release [15.0 nM (SD 8.3), n = 8] was not attenuated by local administration of the L-, N-, or P/Q-type Ca(2+) channel antagonists, by inhibition of Na(+)/Ca(2+) exchange, or by blockade of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptor but was significantly suppressed by local administration of gadolinium [2.8 nM (SD 2.6), n = 6, P = 0.0283]. In conclusion, stimulation-induced ACh release from the cardiac postganglionic nerves depends on the N- and P/Q-type Ca(2+) channels (with a dominance of P/Q-type) but probably not on the L-type Ca(2+) channels in cats. In contrast, ischemia-induced ACh release depends on nonselective cation channels or cation-selective stretch activated channels but not on L-, N-, or P/Q type Ca(2+) channels, Na(+)/Ca(2+) exchange, or Ins(1,4,5)P(3) receptor-mediated pathway.

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.

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.

Sympathetic activation during orthostatic stress is accompanied by a marked increase in low-frequency (LF, approximately 0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP (finger photoplethysmography) variability during a 15-min 60 degrees HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability (index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope.

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.

Accurate prediction of cardiac output (CO), left atrial pressure (PLA), and right atrial pressure (PRA) is a prerequisite for management of patients with compromised hemodynamics. In our previous study (Uemura et al. Am J Physiol Heart Circ Physiol 286: H2376-H2385, 2004), we demonstrated a circulatory equilibrium framework, which permits the prediction of CO, PLA, and PRA once the venous return surface and integrated CO curve are known. Inasmuch as we also showed that the surface can be estimated from single-point CO, PLA, and PRA measurements, we hypothesized that a similar single-point estimation of the CO curve would enable us to predict hemodynamics. In seven dogs, we measured the PLA-CO and PRA-CO relations and derived a standardized CO curve using the logarithmic function CO = SL[ln(PLA - 2.03) + 0.80] for the left heart and CO = SR[ln(PRA - 2.13) + 1.90] for the right heart, where SL and SR represent the preload sensitivity of CO, i.e., pumping ability, of the left and right heart, respectively. To estimate the integrated CO curve in each animal, we calculated SL and SR from single-point CO, PLA, and PRA measurements. Estimated and measured CO agreed reasonably well. In another eight dogs, we altered stressed blood volume (-8 to +8 ml/kg of reference volume) under normal and heart failure conditions and predicted the hemodynamics by intersecting the surface and the CO curve thus estimated. We could predict CO [y = 0.93x + 6.5, r2 = 0.96, standard error of estimate (SEE) = 7.5 ml.min(-1).kg(-1)], PLA (y = 0.90x + 0.5, r2= 0.93, SEE = 1.4 mmHg), and PRA (y = 0.87x + 0.4, r2= 0.91, SEE = 0.4 mmHg) reasonably well. In conclusion, single-point estimation of the integrated CO curve enables accurate prediction of hemodynamics in response to extensive changes in stressed blood volume.

Potent cardioinhibitory vagal reflex resulting in bradycardia and hypotension has been observed under particular conditions of transmural inferior ischemia and its reperfusion, such as those observed with acute infarction. However, whether exercise-induced ischemia with ST depressions that is subendocardial and that might be recurrently experienced in daily activities can evoke this reflex remains unknown. In patients with exercise-induced ST depressions due to either inferior [right coronary artery stenosis (RCA), n = 52] or anterior ischemia [left anterior descending artery stenosis (LAD), n = 51], we evaluated post exercise vagal activity (from 0 to 6 min) by the time constant of heart rate (HR) decay and HR variability by 30-s averages of the absolute values of successive RR interval differences (DeltaRR). Exercise parameters were similar between groups. The time constant was slightly but significantly shorter in RCA than LAD patients (79 +/- 24 vs. 93 +/- 29 s, P < 0.01). More significantly, DeltaRR early after exercise (0.5-2.5 min) was approximately twofold greater in RCA than LAD patients (from +76 to +118%, P < 0.001), indicating pronounced vagal activity stimulated by inferior ischemia. Revascularization prolonged the time constant (P < 0.05) and attenuated recovery DeltaRR in RCA patients (P < 0.05, n = 10) but did not change both parameters in LAD patients (n = 12). As well as acute inferior infarction, exercise-induced inferior subendocardial ischemia, which might recurrently occur in daily activities, activates the cardioinhibitory reflex. These new findings must be taken into account in interpreting vagal activity in patients with coronary artery disease.

Using Bluetooth wireless technology, we developed an implantable telemetry system for measurement of the left ventricular pressure-volume relation in conscious, freely moving rats. The telemetry system consisted of a pressure-conductance catheter (1.8-Fr) connected to a small (14-g) fully implantable signal transmitter. To make the system fully telemetric, calibrations such as blood resistivity and parallel conductance were also conducted telemetrically. To estimate blood resistivity, we used four electrodes arranged 0.2 mm apart on the pressure-conductance catheter. To estimate parallel conductance, we used a dual-frequency method. We examined the accuracy of calibrations, stroke volume (SV) measurements, and the reproducibility of the telemetry. The blood resistivity estimated telemetrically agreed with that measured using an ex vivo cuvette method (y=1.09x - 11.9, r2= 0.88, n=10). Parallel conductance estimated by the dual-frequency (2 and 20 kHz) method correlated well with that measured by a conventional saline injection method (y=1.59x - 1.77, r2= 0.87, n=13). The telemetric SV closely correlated with the flowmetric SV during inferior vena cava occlusions (y=0.96x + 7.5, r2=0.96, n=4). In six conscious rats, differences between the repeated telemetries on different days (3 days apart on average) were reasonably small: 13% for end-diastolic volume, 20% for end-systolic volume, 28% for end-diastolic pressure, and 6% for end-systolic pressure. We conclude that the developed telemetry system enables us to estimate the pressure-volume relation with reasonable accuracy and reproducibility in conscious, untethered rats.

Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.

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.

A novel framework of circulatory equilibrium was developed by extending Guyton's original concept. In this framework, venous return (CO(V)) for a given stressed volume (V) was characterized by a flat surface as a function of right atrial pressure (P(RA)) and left atrial pressure (P(LA)) as follows: CO(V) = V/W - G(S)P(RA) - G(P)P(LA), where W, G(S), and G(P) denote linear parameters. In seven dogs under total heart bypass, CO(V), P(RA), P(LA), and V were varied to determine the three parameters in each animal with use of multivariate analysis. The coefficient of determination (r(2) = 0.92-0.99) indicated the flatness of the venous return surface. The averaged surface was CO(V) = V/0.129 - 19.61P(RA) - 3.49P(LA). To examine the invariability of the surface parameters among animals, we predicted the circulatory equilibrium in response to changes in stressed volume in another 12 dogs under normal and heart failure conditions. This was achieved by equating the standard surface with the individually measured cardiac output (CO) curve. In this way, we could predict CO [y = 0.90x + 5.6, r(2) = 0.95, standard error of the estimate (SEE) = 8.7 ml.min(-1).kg(-1)], P(RA) (y = 0.96x, r(2) = 0.98, SEE = 0.2 mmHg), and P(LA) (y = 0.89x + 0.5, r(2) = 0.98, SEE = 0.8 mmHg) reasonably well. We conclude that the venous return surface accurately represents the venous return properties of the systemic and pulmonary circulations. The characteristics of the venous return surface are invariable enough among animals, making it possible to predict circulatory equilibrium, even if those characteristics are unknown in individual animals.

The effects of the muscle mechanoreflex on the arterial baroreflex neural control have not previously been analyzed over the entire operating range of the arterial baroreflex. In anesthetized, vagotomized, and aortic-denervated rabbits (n = 8), we isolated carotid sinuses and changed intracarotid sinus pressure (CSP) from 40 to 160 mmHg in increments of 20 mmHg every minute while recording renal sympathetic nerve activity (SNA) and arterial pressure (AP). Muscle mechanoreflex was induced by passive muscle stretch (5 kg of tension) of the hindlimb. Muscle stretch shifted the CSP-SNA relationship (neural arc) to a higher SNA, whereas it did not affect the SNA-AP relationship (peripheral arc). SNA was almost doubled [from 63 +/- 15 to 118 +/- 14 arbitrary units (au), P < 0.05] at the CSP level of 93 +/- 8 mmHg, and AP was increased approximately 50% by muscle stretch. When the baroreflex negative feedback loop was closed, muscle stretch increased SNA from 63 +/- 15 to 81 +/- 21 au (P < 0.05) and AP from 93 +/- 8 to 109 +/- 12 mmHg (P < 0.05). In conclusion, the muscle mechanoreflex resets the neural arc to a higher SNA, which moves the operating point towards a higher SNA and AP under baroreflex closed-loop conditions. Analysis of the baroreflex equilibrium diagram indicated that changes in the neural arc induced by the muscle mechanoreflex might compensate for pressure falls resulting from exercise-induced vasodilatation.

Although orthostatic hypotension is a common clinical syndrome after spaceflight and its ground-based simulation model, 6 degrees head-down bed rest (HDBR), the pathophysiology remains unclear. The authors' hypothesis that a decrease in sympathetic nerve activity is the major pathophysiology underlying orthostatic hypotension after HDBR was tested in a study involving 14-day HDBR in 22 healthy subjects who showed no orthostatic hypotension during 15-min 60 degrees head-up tilt test (HUT) at baseline. After HDBR, 10 of 22 subjects demonstrated orthostatic hypotension during 60 degrees HUT. In subjects with orthostatic hypotension, total activity of muscle sympathetic nerve activity (MSNA) increased less during the first minute of 60 degrees HUT after HDBR (314% of resting supine activity) than before HDBR (523% of resting supine activity, P < 0.05) despite HDBR-induced reduction in plasma volume (13% of plasma volume before HDBR). The postural increase in total MSNA continued during several more minutes of 60 degrees HUT while arterial pressure was maintained. Thereafter, however, total MSNA was paradoxically suppressed by 104% of the resting supine level at the last minute of HUT (P < 0.05 vs. earlier 60 degrees HUT periods). The suppression of total MSNA was accompanied by a 22 +/- 4-mmHg decrease in mean blood pressure (systolic blood pressure <80 mmHg). In contrast, orthostatic activation of total MSNA was preserved throughout 60 degrees HUT in subjects who did not develop orthostatic hypotension. These data support the hypothesis that a decrease in sympathetic nerve activity is the major pathophysiological factor underlying orthostatic hypotension after HDBR. It appears that the diminished sympathetic activity, in combination with other factors associated with HDBR (e.g., hypovolemia), may predispose some individuals to postural hypotension.

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.

To better understand the pathophysiological significance of high plasma norepinephrine (NE) concentration in regulating heart rate (HR), we examined the interactions between high plasma NE and dynamic vagal control of HR. In anesthetized rabbits with sinoaortic denervation and vagotomy, using a binary white noise sequence (0-10 Hz) for 10 min, we stimulated the right vagus and estimated the transfer function from vagal stimulation to HR response. The transfer function approximated a first-order low-pass filter with pure delay. Infusion of NE (100 microg. kg(-1) x h(-1) iv) attenuated the dynamic gain from 6.2 +/- 0.8 to 3.9 +/- 1.2 beats x min(-1) x Hz(-1) (n = 7, P < 0.05) without affecting the corner frequency or pure delay. Simultaneous intravenous administration of phentolamine (1 mg x kg(-1) x h(-1)) and NE (100 microg x kg(-1) x h(-1)) abolished the inhibitory effect of NE on the dynamic gain (6.3 +/- 0.8 vs. 6.4 +/- 1.3 beats x min(-1) x Hz(-1), not significant, n = 7). The inhibitory effect of NE at infusion rates of 10, 50, and 100 microg x kg(-1) x h(-1) on dynamic vagal control of HR was dose-dependent (n = 5). In conclusion, high plasma NE attenuated the dynamic HR response to vagal stimulation, probably via activation of alpha-adrenergic receptors on the preganglionic and/or postganglionic cardiac vagal nerve terminals.

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.

Despite the importance of vagal control over the ventricle, little is known regarding vagal efferent conduction and nerve terminal function in the postischemic myocardium. To elucidate postischemic changes in the cardiac vagal efferent neuronal function, we measured myocardial interstitial acetylcholine (ACh) levels by using in vivo cardiac microdialysis and examined the ACh responses to electrical stimulation of the vagi or local administration of ouabain in anesthetized cats. Sixty-minute occlusions of the left anterior descending coronary artery (LAD) followed by 60-min reperfusion abolished electrical stimulation-induced ACh release (20.4 +/- 3.9 vs. 0.9 +/- 0.4 nmol/l; means +/- SE, P < 0.01). In different groups of animals, 60-min LAD occlusion followed by 60-min reperfusion decreased but did not completely abolish ouabain-induced release of ACh (9.2 +/- 1.8 vs. 3.9 +/- 0.7 nmol/l; P < 0.05). These results indicate that function of the vagal efferent axon was completely interrupted, whereas the local ACh release was partially suppressed in the postischemic myocardium. The postischemic disruption of vagal efferent neuronal function might exert deleterious effects on cardiac regulation.

A transfer function from baroreceptor pressure input to sympathetic nerve activity (SNA) shows derivative characteristics in the frequency range below 0.8 Hz in rabbits. These derivative characteristics contribute to a quick and stable arterial pressure (AP) regulation. However, if the derivative characteristics hold up to heart rate frequency, the pulsatile pressure input will yield a markedly augmented SNA signal. Such a signal would saturate the baroreflex signal transduction, thereby disabling the baroreflex regulation of AP. We hypothesized that the transfer gain at heart rate frequency would be much smaller than that predicted from extrapolating the derivative characteristics. In anesthetized rabbits (n = 6), we estimated the neural arc transfer function in the frequency range up to 10 Hz. The transfer gain was lost at a rate of -20 dB/decade when the input frequency exceeded 0.8 Hz. A numerical simulation indicated that the high-cut characteristics above 0.8 Hz were effective to attenuate the pulsatile signal and preserve the open-loop gain when the baroreflex dynamic range was finite.

We examined whether the ACh concentration measured by cardiac microdialysis provided information on left ventricular ACh levels under a variety of vagal stimulatory and modulatory conditions in anesthetized cats. Local administration of KCl (n = 5) and ouabain (n = 7) significantly increased the ACh concentration in the dialysate to 4.3 +/- 0.8 and 7.3 +/- 1.3 nmol/l, respectively, from the baseline value of 0.6 +/- 0.5 nmol/l. Intravenous administration of phenylbiguanide (n = 5) and phenylephrine (n = 6) significantly increased the ACh concentration to 5.4 +/- 0.9 and 6.0 +/- 1.5 nmol/l, respectively, suggesting that the Bezold-Jarisch and arterial baroreceptor reflexes affected myocardial ACh levels. Modulation of vagal nerve terminal function by local administration of tetrodotoxin (n = 6), hemicholinium-3 (n = 6), and vesamicol (n = 5) significantly suppressed the electrical stimulation-induced ACh release from 20.4 +/- 3.9 to 0.6 +/- 0.1, 7.2 +/- 1.9, and 2.7 +/- 0.6 nmol/l, respectively. Increasing the heart rate from 120 to 200 beats/min significantly reduced the myocardial ACh levels during electrical vagal stimulation, suggesting a heart rate-dependent washout of ACh. We conclude that ACh concentration measured by cardiac microdialysis provides information regarding ACh release and disposition under a variety of pathophysiological conditions in vivo.

Although power spectra of R-R and P-R intervals in response to random respiration show similar frequency distributions, the way in which dynamic sympathetic regulation contributes to such similarity remains unknown. We estimated the transfer function from sympathetic stimulation to the atrioventricular interval (AV conduction time; T(AV)) with and without constant atrial pacing in seven anesthetized cats. The transfer function from sympathetic stimulation to T(AV), except for absolute gain values, approximated a low-pass filter similar to that from sympathetic stimulation to the A-A interval (heart period; T(AA)). The 90%-rise times did not differ between the T(AA) and T(AV) step responses (32.3 +/- 1.8 vs. 29.6 +/- 3.2 s). Constant pacing augmented the T(AV) step response (-0.58 +/- 0.10 vs. -0.86 +/- 0.12 ms/Hz, P < 0.05) without affecting the 90%-rise time. These findings suggest that the dynamic characteristics of sympathetic control are similar between T(AA) and T(AV) despite the different electrophysiological mechanisms determining T(AA) and T(AV). A numerical simulation indicated that if the dynamic characteristics of the sympathetic control do not match between T(AA) and T(AV), a critical condition for initiation of reentrant tachycardia would be encountered.

Although regional difference in sympathetic efferent nerve activity has been well investigated, whether this regional difference exists in the dynamic baroreflex regulation of sympathetic nerve activity remains uncertain. In anesthetized, vagotomized, and aortic-denervated rabbits, we isolated carotid sinuses and randomly perturbed intracarotid sinus pressure (CSP) while simultaneously recording cardiac (CSNA) and renal sympathetic nerve activities (RSNA). The neural arc transfer function from CSP to CSNA and that from CSP to RSNA revealed high-pass characteristics. The increasing slope of the transfer gain in the frequencies between 0.03 and 0.3 Hz was significantly greater for CSNA than for RSNA (2.96 +/- 0.72 vs. 1.64 +/- 0.73 dB/octave, P < 0.01, n = 9). The difference was hardly explained by the difference in static nonlinear characteristics of CSP-CSNA and CSP-RSNA relationships or by the difference in conduction velocities in the multifiber recording. These results indicate that the central processing in the brain stem differs between CSNA and RSNA. The neural arc of the baroreflex may exert differential effects on the heart and kidney in response to dynamic baroreflex activation.

To elucidate the pathophysiological roles of vagosympathetic interactions in ischemia-induced myocardial norepinephrine (NE) and acetylcholine (ACh) release, we measured myocardial interstitial NE and ACh levels in response to a left anterior descending coronary occlusion in the following groups of anesthetized cats: intact autonomic innervation (INT, n = 7); vagotomy (VX, n = 6); local administration of atropine (Atro, n = 6); transection of the stellate ganglia (TSG, n = 5); local administration of phentolamine (Phen, n = 6); and combined vagotomy and transection of the stellate ganglia (VX+TSG, n = 5). The maximum NE release was enhanced in the VX group (141 +/- 30 nmol/l, means +/- SE, P < 0.05) compared with the INT group (61 +/- 12 nmol/l). Neither the Atro (50 +/- 24 nmol/l) nor VX+TSG groups (84 +/- 25 nmol/l) showed enhanced NE release. The maximum ACh release was unaltered in the TSG and Phen groups compared with the INT group (19 +/- 4, 18 +/- 4, and 13 +/- 3 nmol/l, respectively). These findings indicate that the cardiac vagal afferent but not efferent activity reduced the ischemia-induced myocardial NE release. In contrast, the cardiac sympathetic afferent and efferent activities played little role in the ischemia-induced myocardial ACh release.

To clarify the pathophysiological role of dynamic arterial properties in cardiovascular diseases, we attempted to develop a new control system that imposes desired aortic impedance on in situ rat left ventricle. In 38 anesthetized open-chest rats, ascending aortic pressure and flow waveforms were continuously sampled (1,000 Hz). Desired flow waveforms were calculated from measured aortic pressure waveforms and target impedance. To minimize the difference between measured and desired aortic flow waveforms, the computer generated commands to the servo-pump, connected to a side branch of the aorta. By iterating the process, we could successfully control aortic impedance in such a way as to manipulate compliance and characteristic impedance between 60 and 160% of their respective native values. The error between desired and measured aortic flow waveforms was 70 +/- 34 microl/s (root mean square; 4.4 +/- 1.4% of peak flow), indicating reasonable accuracy in controlling aortic impedance. This system enables us to examine the importance of dynamic arterial properties independently of other hemodynamic and neurohumoral factors in physiological and clinical settings.