Sympathetic afferent stimulation inhibits central vagal activation induced by intravenous medetomidine in rats.

AIM: To examine whether sympathetic afferent stimulation (SAS) inhibits central vagal activation induced by α2 -adrenergic stimulation. METHODS: In anaesthetized Wistar-Kyoto rats, a cardiac microdialysis technique was applied to the left ventricle, and the effect of α2 -adrenergic stimulation by medetomidine on myocardial interstitial acetylcholine (ACh) levels was examined in the absence (n = 6) or the presence (n = 6) of SAS delivered from the left stellate ganglion. The effect of electrical vagal efferent stimulation on myocardial interstitial ACh release was also examined in the absence or the presence of SAS (n = 6). RESULTS: Intravenous medetomidine (0.1 mg kg(-1) ) significantly increased myocardial interstitial ACh levels in the absence of SAS (from 1.95 ± 0.79 to 3.36 ± 1.61 nM, P < 0.05), but not in the presence of SAS (from 1.67 ± 0.67 to 2.01 ± 0.78 nM). In contrast, electrical vagal nerve stimulation increased myocardial interstitial ACh level to the same degree regardless of SAS (from 1.66 ± 0.16 to 3.93 ± 0.72 nM without SAS vs. 4.05 ± 0.89 nM with SAS). CONCLUSION: Sympathetic afferent stimulation inhibited medetomidine-induced ACh release, but not electrical stimulation-induced ACh release, suggesting that SAS inhibited medetomidine-induced vagal activation via central mechanisms. While central vagal activation by α2 -adrenergic agonists could be an alternative to electrical vagal activation, blocking sympathetic afferent input may be important to increase the efficacy of α2 -adrenergic agonists in enhancing vagal nerve activity.

High-frequency dominant depression of peripheral vagal control of heart rate in rats with chronic heart failure.

AIM: To examine whether dynamic characteristics of the peripheral vagal control of heart rate (HR) are altered in chronic heart failure (CHF). METHODS: The right vagal nerve was electrically stimulated according to a binary white noise signal, and the transfer function from vagal nerve stimulation (VNS) to HR was estimated in the frequency range from 0.01 to 1 Hz in five control rats and five CHF rats under anaesthetized conditions. The rate of VNS was changed among 10, 20 and 40 Hz. RESULTS: A multiple linear regression analysis indicated that the increase in the VNS rate augmented the ratio of the high-frequency (HF) gain to the steady-state gain in the control group but not in the CHF group. As a result, the dynamic gain of the transfer function in the frequencies near 1 Hz decreased more in the CHF group than in the control group. CONCLUSION: Changes in the dynamic characteristics of the peripheral vagal control of HR may contribute to the manifestation of decreased HF components of HR variability observed in CHF.

Central vagal activation by alpha(2) -adrenergic stimulation is impaired in spontaneously hypertensive rats.

AIM: To elucidate the abnormality of vagal control in spontaneously hypertensive rats (SHR) by measuring left ventricular myocardial interstitial acetylcholine (ACh) release in response to α(2) -adrenergic stimulation as an index of in vivo vagal nerve activity. METHODS: A cardiac microdialysis technique was applied to the rat left ventricle in vivo, and the effect of α(2) -adrenergic stimulation by medetomidine or electrical vagal nerve stimulation on myocardial interstitial ACh levels was examined in normotensive Wistar-Kyoto rats (WKY) and SHR under anaesthetized conditions. RESULTS: Intravenous medetomidine (0.1 mg kg(-1) ) significantly increased the ACh levels in WKY (from 2.4 ± 0.6 to 4.2 ± 1.3 nmol L(-1) , P < 0.05, n = 7) but not in SHR (from 2.5 ± 0.7 to 2.7 ± 0.7 nmol L(-1) , n = 7). In contrast, electrical vagal nerve stimulation increased the ACh levels in both WKY (from 1.0 ± 0.4 to 2.9 ± 0.9 nmol L(-1) , P < 0.001, n = 6) and SHR (from 0.9 ± 0.2 to 2.2 ± 0.4 nmol L(-1) , P < 0.001, n = 6). Intravenous administration of medetomidine (0.1 mg kg(-1) ) did not affect the vagal nerve stimulation-induced ACh release in either WKY or SHR. CONCLUSION: Medetomidine-induced central vagal activation was impaired in SHR, whereas peripheral vagal control of ACh release was preserved. In addition to abnormal sympathetic control, vagal control by the central nervous system may be impaired in SHR.

Characterization of ouabain-induced noradrenaline and acetylcholine release from in situ cardiac autonomic nerve endings.

AIM: Although ouabain modulates autonomic nerve ending function, it is uncertain whether ouabain-induced releasing mechanism differs between in vivo sympathetic and parasympathetic nerve endings. Using cardiac dialysis, we examined how ouabain induces neurotransmitter release from autonomic nerve ending. METHODS: Dialysis probe was implanted in left ventricle, and dialysate noradrenaline (NA) or acetylcholine (ACh) levels in the anaesthetized cats were measured as indices of neurotransmitter release from post-ganglionic autonomic nerve endings. RESULTS: Locally applied ouabain (100 microm) increased in dialysate NA or ACh levels. The ouabain-induced increases in NA levels remained unaffected by cardiac sympathetic denervation and tetrodotoxin (Na+ channel blocker, TTX), but the ouabain-induced increases in ACh levels were attenuated by TTX. The ouabain-induced increases in NA levels were suppressed by pretreatment with desipramine (NA transport blocker) and augmented by reserpine (vesicle NA transport blocker). In contrast, the ouabain-induced increases in ACh levels remained unaffected by pretreatment with hemicholinium-3 (choline transport blocker) but suppressed by vesamicol (vesicle ACh transport blocker). The ouabain-induced increases in NA levels were suppressed by pretreatment with omega-conotoxin GVIA (N-type Ca2+ channel blocker), verapamil (L-type Ca2+ channel blocker) and TMB-8 (intracellular Ca2+ antagonist). The ouabain-induced increases in ACh levels were suppressed by pretreatment with omega-conotoxin MVIIC (P/Q-type Ca2+ channel blocker), and TMB-8. CONCLUSIONS: Ouabain-induced NA release is attributable to the mechanisms of regional exocytosis and/or carrier-mediated outward transport of NA, from stored NA vesicle and/or axoplasma, respectively, while the ouabain-induced ACh release is attributable to the mechanism of exocytosis, which is triggered by regional depolarization. At both sympathetic and parasympathetic nerve endings, the regional exocytosis is because of opening of calcium channels and intracellular calcium mobilization.

Myocardial interstitial choline and glutamate levels during acute myocardial ischaemia and local ouabain administration.

AIM: Noradrenaline (NA) uptake transporters are known to reverse their action during acute myocardial ischaemia and to contribute to ischaemia-induced myocardial interstitial NA release. By contrast, functional roles of choline and glutamate transporters during acute myocardial ischaemia remain to be investigated. Because both transporters are driven by the normal Na+ gradient across the plasma membrane in a similar manner to NA transporters, the loss of Na+ gradient would affect the transporter function, which would in turn alter myocardial interstitial choline and glutamate levels. The aim of the present study was to examine the effects of acute myocardial ischaemia and the inhibition of Na+,K+-ATPase on myocardial interstitial glutamate and choline levels. METHODS: In anaesthetized cats, we measured myocardial interstitial glutamate and choline levels while inducing acute myocardial ischaemia or inhibiting Na+,K+-ATPase by local administration of ouabain. RESULTS: The choline level was not changed significantly by ischaemia (from 0.93 +/- 0.06 to 0.82 +/- 0.13 microm, mean +/- SE, n = 6) and was decreased slightly by ouabain (from 1.30 +/- 0.06 to 1.05 +/- 0.07 microm, P < 0.05, n = 6). The glutamate level was significantly increased from 9.5 +/- 1.9 to 34.7 +/- 6.1 microm by ischaemia (P < 0.01, n = 6) and from 8.9 +/- 1.0 to 15.9 +/- 2.3 microm by ouabain (P < 0.05, n = 6). Inhibition of glutamate transport by trans-L-pyrrolidine-2,4-dicarboxylate (t-PDC) suppressed ischaemia- and ouabain-induced glutamate release. CONCLUSION: Myocardial interstitial choline level was not increased by acute myocardial ischaemia or by Na+,K+-ATPase inhibition. By contrast, myocardial interstitial glutamate level was increased by both interventions. The glutamate transporter contributed to glutamate release via retrograde transport.

Transfer function analysis of carotid sinus baroreceptor transduction.

The carotid sinus baroreflex is one of the most important negative feedback systems that regulate arterial pressure. The neural arc transfer function from carotid sinus pressure (CSP) input to efferent sympathetic nerve activity shows a gain increase of approximately 10 dB when input frequency increases from 0.01 to 0.5 Hz. The transfer gain of the neural arc decreases in the frequency range above 0.8 Hz. The aim of the present study was to elucidate the extent of contribution of the carotid sinus baroreceptor transduction to the determination of the neural arc dynamic characteristics. In 7 anesthetized rabbits, we isolated the right carotid sinus and controlled CSP while recording afferent nerve activity (ANA) from the carotid sinus nerve. CSP was randomly assigned to either 80 or 120 mmHg with a switching interval of 50 ms according to a binary white noise signal for 15 min. The transfer function from CSP to ANA was estimated in the frequency range from 0.01 to 3 Hz. The transfer function showed a gain increase of approximately 4.6 dB when input frequency increased from 0.01 to 0.3 Hz. The transfer gain remained relatively constant up to 3 Hz. These results suggest that the carotid sinus baroreceptor transduction partly contributes to the gain increase of the baroreflex neural arc in the frequency range from 0.01 to 0.5 Hz but not the gain decrease above 0.8 Hz.

Intravascular parasympathetic cardiac nerve stimulation prevents ventricular arrhythmias during acute myocardial ischemia.

UNLABELLED: Although previous animal studies clearly demonstrated antiarrhythmic effects of vagal stimulation during acute myocardial ischemia, highly invasive nature of vagal stimulation limited its clinical use. Recently, intravascular parasympathetic cardiac nerve stimulation (IPS) has emerged as a novel approach to the cardiac autonomic nervous system. We hypothesized that IPS might prevent ventricular arrhythmias during acute myocardial ischemia. METHODS: The IPS (36 V, 10 Hz) was performed in superior vena cava using an expandable electrode-basket catheter. In 18 open-chest dogs, left anterior descending coronary artery ligation was performed without IPS (control group, n= 6), with IPS (IPS group, n= 6) and with IPS and right atrial pacing at 180/min (IPS+P group, n=6). The ECGs were monitored for 60 min. The incidence and severity of ventricular arrhythmias were analyzed. RESULTS: The IPS significantly decreased the frequency of premature ventricular contractions (control group: 9.1 ± 4.6/min, IPS group: 0.2 ± 0.4 /min, IPS+P group: 10.6 ± 4.2 / min; p<0.05). The frequency of ventricular tachycardia was lower in IPS group (0 ± 0 /min) than in control group (0.15 ± 0.18 /min, p<0.05) and than in IPS+P group (0.17 ± 0.12 /min, p<0.05). The incidence of ventricular fibrillation was lower in IPS group (0%) than in control group (33.3%) and than in IPS+P group (33.3%). CONCLUSIONS: The IPS suppressed ventricular arrhythmias during acute ischemia mainly through its bradycardiac effect.

Insignificant effects of plasma catecholamines on dynamic heart rate regulation by the cardiac sympathetic nerve.

Although plasma catecholamines such as norepinephrine (NE) and epinephrine (Epi) increase during severe exercise, the effects of high levels of plasma catecholamines on dynamic heart rate (HR) regulation by the cardiac sympathetic nerve remains unknown. The aim of the present study was to examine the effects of plasma catecholamines on the transfer function from sympathetic nerve stimulation to HR. In anesthetized rabbits, we randomly stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring HR. The effects of intravenous NE administration at 1 and 10 mugmiddotkg-1middoth-1 were examined in 6 rabbits. The effects of intravenous Epi administration at 1 and 10 mugmiddotkg-1middoth-1 were examined in different 6 rabbits. Although plasma NE increased 10 times as high as the baseline level during the NE administration at mugmiddotkg-1middoth-1 , dynamic gain of the transfer function was not changed significantly (7.1plusmn1.2, 6.9plusmn1.1, and 7.7plusmn1.1 beatsmiddotmin-1middotHz-1). Similarly, although plasma Epi increased 10 times as high as the baseline level during the Epi administration at 10 mugmiddotkg-1middoth-1, dynamic gain of the transfer function was not changed significantly (7.5plusmn0.8, 7.9plusmn0.8, and 7.6plusmn1.2 beatsmiddotmin-1middotHz-1). In conclusion, plasma catecholamines of physiologically-relevant high concentrations did not interfere with the dynamic HR regulation by the cardiac sympathetic nerve.

Bezold-Jarisch reflex blunts arterial baroreflex via the shift of neural arc toward lower sympathetic nerve activity.

Although the Bezold-Jarisch (BJ) reflex is potentially evoked during acute myocardial ischemia or infarction, its effects on the static characteristics of the arterial baroreflex remain to be analyzed in terms of an equilibrium diagram between the neural and peripheral arcs. The neural arc represents the static input-output relationship between baroreceptor pressure input and efferent sympathetic nerve activity (SNA), whereas the peripheral arc represents that between SNA and arterial pressure (AP). In 8 anesthetized rabbits, we increased carotid sinus pressure stepwise from 40 to 160 mmHg in increments of 20 mmHg at one-minute intervals while measuring renal SNA and AP under control conditions and during the activation of the BJ reflex by intravenous administration of phenylbiguanide (PBG, 100 microg.kg(-1).min(-1)). The neural arc approximated a sigmoid curve whereas the peripheral arc approximated a straight line. PBG decreased AP at the operating point from -91.3 +/- 2.4 to -71.7 +/- 3.1 mmHg (P < 0.01), and attenuated the total loop gain at the operating point from -1.31 +/- 0.44 to -0.51 +/- 0.14 (P < 0.05). The equilibrium diagram indicated that PBG caused a parallel shift of the neural arc toward lower SNA such that the maximum SNA was reduced to approximately 60% of control. PBG decreased neural and peripheral arc gains at the operating point to approximately 43% and 77%, respectively. In conclusion, the BJ reflex blunts arterial baroreflex via the shift of the neural arc toward lower SNA.

High resolution optical mapping of cardiac action potentials in freely beating rabbit hearts.

UNLABELLED: Optical mapping of action potentials (APs) has become important tools for the cardiac electrophysiology. However, cardiac contraction unavoidably produces motion artifacts (MA) in optical signal. We developed a method to suppress motion artifacts without arresting the hearts. METHODS: Using a dual-wavelength optical mapping system, APs were recorded on the surface of an isolated rabbit heart. Transmembrane APs were simultaneously recorded using glass microelectrodes. We eliminated MA in a frontal plane by a motion tracking technique. Subsequently, a dual-wavelength ratiometric method was used to remove MA in a vertical direction to a frontal plane. RESULTS: MA were effectively removed from optical signals. Action potential duration measured from optical signals corresponded with those measured from microelectrodes (r2=0.9677). Our method enables us to map action potentials in freely beating hearts.

A comprehensive physiological model of circulation enables automatic piloting of hemodynamics in patients with acute heart failure.

A comprehensive physiological model of the whole circulation is mandatory to quantitatively diagnose pathophysiology and to guide an appropriate treatment. Such a model would enable automatic piloting of hemodynamics in patients with acute heart failure. By extending Guyton's model, so as to deal with heart failure predominantly affecting left heart and to quantify left atrial pressure, we constructed such a model consisting of a venous return (VR) surface and a cardiac output (CO) curve. VR surface, the integrated property of systemic and pulmonary vascular beds, relates VR and left and right atrial pressures (P(LA), P(RA)) linearly as VR = V/W - G(R)P(RA) - G(L)P(LA), given total blood volume (V). CO curve, the pumping ability of hearts, relates CO and either P(LA) or P(RA) approximately by logarithmic functions, respectively, as CO = S(L) [ln (P(LA)- B(L)) + C(L)] = S(R) [ln (P(RA) - B(R)) + C(R)]. The slopes (S(R) and S(L)) of CO curve mainly describes the pump performance. W, G(R), G(L), B(R), B(L), C(R) and C(L) are parameters. We validate the model with animal experiments. Parameters W, G's, B's and C's were relatively constant in 19 dogs. In other 8 dogs, with or without acute left heart failure, we determined V and S's from a single set of CO, P(RA), P(LA) and standard parameter values. We then predicted hemodynamics (CO, P(RA), P(LA)) for altered V from -8 to +8 ml/kg. We identified standard values of parameters as W (0.13 min), G(R) (19.6 ml/min/kg/mmHg), G(L) (3.5 ml/min/kg/mmHg). B(L) (2.1 mmHg), C(L) (1.9), B(R) (2.0 mmHg) and C(R) (0.80). Using these, we could accurately predict CO (y = 0.93x + 6.5, r2 = 0.96, Figure 2), P(RA) (y = 0.87x + 0.4, r2 = 0.91) and P(LA) (y = 0.90x + 0.48, r2 = 0.93). Our comprehensive physiological model of circulation is useful in accurately predicting hemodynamics from the measurement of a single set of CO, P(RA) and (P(LA) following blood volume changes. Therefore, this model enables continuous monitoring of blood volume and pump performance for automatic hemodynamic piloting.

A sieve electrode as a potential autonomic neural interface for bionic medicine.

We examined the applicability of a sieve electrode to the autonomic nervous system as a potential neural interface for bionic medicine. We developed, using a Si-semiconductor process, a sieve electrode having a square diaphragm (1 mm in one side, 12 microm in thickness) with 30-81 penetrating square holes (50-100 microm in one side). In the first protocol, we implanted the sieve electrode to the vagal nerve in rats. One hundred and twenty days after the implantation, cuff electrodes were attached to the vagal nerve proximal and distal to the sieve electrode under halothane anesthesia. The evoked action potential was recorded from the sieve electrode by nerve stimulation via the cuff electrodes. The evoked action potential was also recorded from the cuff electrodes by nerve stimulation via the sieve electrode. In the second protocol, we implanted the sieve electrode to the renal sympathetic nerve in rabbits. Forty days after the implantation, the spontaneous action potential or sympathetic nerve activity was recorded under pentobarbital anesthesia. In conclusion, we were able to record the evoked and spontaneous action potentials using the sieve electrode. The sieve electrode will provide a useful neural interface for recording and stimulating the autonomic nervous system.

Effects of partial left ventriculectomy on left ventricular pump function studied by theoretical analyses.

Although partial left ventriculectomy (PLV) was devised to reduce myocardial wall stress in patients with severe heart failure, whether the operation acutely improves cardiac pump function has not been determined either clinically or experimentally. Because precise control of preload, afterload, and heart rate is virtually impossible in animal experiments as well as clinically before and after surgery, we took advantage of the theoretical analysis to study quantitatively the changes in pump function by PLV. We reconstructed the endsystolic and end-diastolic pressure-volume relationships based on two different geometric conditions (i.e., before and after volume reduction) but from the same myocardial stress-strain relationship. The effect of volume reduction surgery on left ventricular pump function depended on preoperative conditions. We found that the improvement in pump function was achieved only if elastance (Ees) was low and if the end-systolic strain-axis scaling parameter (k) value was low. The presence of hypertrophy amplified the improved function, but again with low Ees and low end-systolic k. We conclude that the favorable hemodynamics are expected only in limited cases during the acute phase. Candidates for favorable preoperative factors include low end-systolic Ees, an end-systolic pressure-volume relationship being less convexed toward the volume axis (low k), and large left ventricular mass.

Improved left ventricular contraction and energetics in a patient with Chagas' disease undergoing partial left ventriculectomy.

A 43-year-old patient with heart failure, precluded from heart transplantation or dynamic cardiomyoplasty because of Chagas' disease cardiomyopathy, mitral regurgitation, and ventricular mural thrombi, underwent mitral valvuloplasty and partial left ventriculectomy (PLV) between the papillary muscles. Intraoperative pressure-volume relationship analyses suggested improvement in left ventricular contraction, energetics, isovolumic relaxation, and mitral valve competency. These improvements allowed prompt, short-term recovery despite unchanged myocardial pathology, which suggests that a surgical approach can alter anatomic-geometric factors and achieve clinical improvement in a dilated failing ventricle.

Perioperative hemodynamics in patients undergoing partial left ventriculectomy.

OBJECTIVES: Effects of partial left ventriculectomy (PLV) were studied by analyzing perioperative hemodynamics with measurements of left ventricular (LV) pressure-volume (PV) relationships and thermodilution catheter measurements in the pulmonary artery. METHODS: Between July and October 1996, 43 consecutive patients underwent PLV with and without mitral valvuloplasty with a thermodilution catheter and PV loop analysis immediately before and after surgery. Patients were 52+/-13 years and 67+/-13 kg, with reduced functional capacity (New York Heart Association 3.3+/-0.3) due to cardiomyopathy (24), ischemic disease (13), valvular disease (3), and Chagas' disease (3). RESULTS: PLV required cardiopulmonary bypass for 44+/-24 minutes, with the heart arrested in 10 patients for 26+/-22 minutes for coronary artery bypass grafting (8), aortic valve replacement (2), and autotransplantation (2). Two patients failed to come off bypass, six died in the hospital and 35 (35 [81.4%] of 43) were discharged. Changes in PV loops included decreased end-diastolic and end-systolic volume, resulting in no change in stroke volume. Pulmonary artery wedge pressure decreased despite elevated end-diastolic pressure. Ejection fraction, end-systolic elastance (E-max), afterload recruitable stroke work, and volume intercepts all improved and resulted in similar stroke work with less energy expenditure (less PV area), thus improving myocardial energetic efficiency. CONCLUSION: Results suggest that PLV improves systolic function but decreases diastolic compliance, which results in reduced net ventricular function immediately after surgery. Thus, immediate hemodynamic improvements appeared to derive from reduced severity in mitral regurgitation and perioperative load manipulation. Improved myocardial energetics may ameliorate LV function and improve the course of underlying myocardial disease.

Heart rate-independent vagal effect on end-systolic elastance of the canine left ventricle under various levels of sympathetic tone.

BACKGROUND: Although we have shown that in rabbits the direct (heart rate [HR]-independent) vagal effect on left ventricular end-systolic elastance (E(es)) was negligible under minimal sympathetic tone, how underlying sympathetic tone modulates the inotropic response to vagal stimulation remains unknown. METHODS AND RESULTS: We used an isolated canine heart preparation with functioning autonomic nerves. We examined the direct vagal inotropic effect by measuring E(es) under fixed-rate atrial pacing with or without concomitant sympathetic nerve stimulation. Right and left vagal stimulation at 20 Hz decreased HR by 27+/-3% and 14+/-2%, respectively, and decreased E(es) by 11+/-2% and 6+/-2%, respectively. When we fixed HR by atrial pacing, right and left vagal stimulation at 20 Hz did not decrease E(es) (0.01+/-0.3% and 0.3+/-0.4%; NS). Concomitant left sympathetic nerve stimulation at 4 Hz enhanced direct vagal negative inotropism to -19+/-3% and -34+/-5% for 20-Hz right and left vagal stimulation (interaction, P<0.01). CONCLUSIONS: Direct vagal negative inotropism was unobservable with minimal sympathetic tone in dogs but was enhanced with concomitant sympathetic stimulation.

Laterality in direct and indirect inotropic effects of sympathetic stimulation in isolated canine heart.

Although sympathetic nerve stimulation is known to increase ventricular contractility, concomitant increases in heart rate (HR) make it difficult to separate its direct inotropic effect from indirect inotropic effect through a force-frequency mechanism. We stimulated the stellate ganglia in 8 isolated canine hearts with functional sympathetic nerves. Right sympathetic stimulation at 10 Hz increased ventricular end-systolic elastance (E(es)) by 95.7 +/- 7.5% (p < 0.001) and HR by 32.5 +/- 4.2% (p < 0.05). In contrast, left sympathetic stimulation at 10 Hz increased E(es) by 70.7 +/- 6.5% (p < 0.001) without significant changes in HR. Preventing the chronotropic response by fixed-rate pacing attenuated the E(es) response to right sympathetic stimulation at 5 Hz (52.0 +/- 5.1 vs. 22.8 +/- 2.8%, p < 0.001), but not to left sympathetic stimulation at 5 Hz (54.5 +/- 3.4 vs. 53.3 +/- 2.2%, NS). In the isolated canine heart, the right sympathetic nerve affected E(es) by both the direct inotropic effect and the indirect HR-dependent inotropic effect. In contrast, the left sympathetic nerve regulated E(es) primarily by its direct inotropic effect.

A new model-based method of reconstructing central aortic pressure from peripheral arterial pressure.

We have shown in our previous study that the transfer function between central aortic pressure and tonometric radial arterial pressure can be modeled as a pure elastic lossless tube terminated with a modified Windkessel. We hypothesized, using the model-derived radial arterial flow, that central pressure could be reconstructed by adding the time-shifted forward and backward pressure components (Stergiopulos et al.: Am J Physiol 274: H1386---H1392, 1998). In eight patients (age 16--75), central micromanometric and radial arterial tonometric pressure were measured simultaneously. We imposed measured tonometric pressure to the terminal modified Windkessel to estimate radial arterial flow, with which tonometric pressure was separated into forward and backward components. These components were then appropriately time shifted, and summed to central pressure. We used average parameter values for the terminal impedance, but individualized the transmission delay. The poor correlation (r(2)) between tonometric and central pressure (0.264--0.765) was improved by both central pressure reconstruction methods (generalized transfer function: 0.887--0.974, model-based method: 0.849--0.979). The sensitivity analysis indicated that the key model parameter in reconstructing central pressure was the transmission delay. We conclude that our model-based method was capable of reconstructing central pressure as precisely as the generalized transfer function method, and also capable of individualizing the transfer function by changing the transmission delay.

In vivo assessment of acetylcholine-releasing function at cardiac vagal nerve terminals.

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.

Low compliance rather than high reflection of arterial system decreases stroke volume in arteriosclerosis: a simulation.

Although various investigators have suggested that the left ventricles of aged subjects suffer from high-frequency reflection, arterial reflection is larger in the low-frequency range because of a larger impedance mismatch. It has not been quantified whether high-frequency reflection rather than low-frequency reflection has larger deleterious effects on stroke volume. We used a computer simulation method to evaluate how increases in high- and low-frequency arterial reflections associated with age-related arterial sclerosis affect left ventricular (LV) pump function. Low-frequency reflections derive principally from the total arterial compliance, and high-frequency reflections result from impedance fluctuations in the high-frequency range. We numerically coupled a time-varying elastance LV model with a variety of arterial impedances to quantitatively evaluate the effects of low- and high-frequency reflections on LV pump performance. When we simultaneously increased low- and high-frequency reflections to levels of sclerotic impedance (type A in Murgo et al., Circulation 62: 105-116, 1980), stroke volume decreased by 4.4%. Further increases of the reflections up to 8 times of the type A impedance lowered stroke volume by 15.9%. This trend was clearly seen with selective increases in low-frequency reflections (3.5 and 20.2% decrease in stroke volume, respectively), but not with those in high-frequency reflections (1.0% decrease and 0.9% increase in stroke volume, respectively). Thus we conclude that the detrimental effect of increases in arterial reflections associated with arterial sclerosis on stroke volume is mild and mainly attributable to decreased compliance rather than to increased high-frequency reflections.