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 (PLA) as follows: COV ϭ V/W Ϫ G SPRA Ϫ GPPLA, where W, GS, and GP denote linear parameters. In seven dogs under total heart bypass, CO V, PRA, PLA, and V were varied to determine the three parameters in each animal with use of multivariate analysis. The coefficient of determination (r 2 ϭ 0.92-0.99) indicated the flatness of the venous return surface. The averaged surface was CO V ϭ V/0.129 Ϫ 19.61PRA Ϫ 3.49PLA. 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 ϭ 0.90x ϩ 5.6, r 2 ϭ 0.95, standard error of the estimate (SEE) ϭ 8.7 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 ], PRA (y ϭ 0.96x, r 2 ϭ 0.98, SEE ϭ 0.2 mmHg), and P LA (y ϭ 0.89x ϩ 0.5, r 2 ϭ 0.98, SEE ϭ 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. venous return; cardiac output; hemodynamics THE FRAMEWORK FOR CIRCULATORY EQUILIBRIUM was pioneered by Guyton and associates in the 1950s (14 -17). They characterized the venous return properties of the systemic vein by the venous return curve and the apparent pumping ability of the cardiothoracic compartment by the cardiac output (CO) curve (Fig. 1A). The intersection of the two curves determines equilibrium CO and right atrial pressure (P RA ) (14). This concept clearly defined the circulatory equilibrium under rather simple pathophysiological conditions, such as hemorrhage and exercise, and deepened our understanding of control mechanisms of CO. However, because the original framework lumped various subsystem components, such as the right ventricle, pulmonary vascular system, and left ventricle, into a single cardiothoracic compartment, the lack of consideration of the venous return properties of the pulmonary circulation and the pumping ability of the individual ventricles makes it difficult to define the circulatory equilibrium under more complex conditions such as unilateral ventricular failures, which are often seen in clinical settings (2). In other words, redistribution of blood between the systemic and pulmonary circulations cannot be defined by their original framework.To deal with the blood redistribution, Guyton et al. (15) modified the original framework and developed a two-compartment model. However, the analysis of hem...

. High plasma norepinephrine attenuates the dynamic heart rate response to vagal stimulation. Am J Physiol Heart Circ Physiol 284: H2412-H2418, 2003. First published February 21, 2003 10.1152/ajpheart.00660.2002To 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 g ⅐ kg Ϫ1 ⅐ h Ϫ1 iv) attenuated the dynamic gain from 6.2 Ϯ 0.8 to 3.9 Ϯ 1.2 beats ⅐ min Ϫ1 ⅐ Hz Ϫ1 (n ϭ 7, P Ͻ 0.05) without affecting the corner frequency or pure delay. Simultaneous intravenous administration of phentolamine (1 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ) and NE (100 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) abolished the inhibitory effect of NE on the dynamic gain (6.3 Ϯ 0.8 vs. 6.4 Ϯ 1.3 beats ⅐ min Ϫ1 ⅐ Hz Ϫ1 , not significant, n ϭ 7). The inhibitory effect of NE at infusion rates of 10, 50, and 100 g ⅐ kg Ϫ1 ⅐ h Ϫ1on dynamic vagal control of HR was dose-dependent (n ϭ 5).In conclusion, high plasma NE attenuated the dynamic HR response to vagal stimulation, probably via activation of ␣-adrenergic receptors on the preganglionic and/or postganglionic cardiac vagal nerve terminals. systems analysis; transfer function; ␣-adrenergic receptors; heart rate variability; rabbit HEART RATE (HR) is mainly regulated by the sympathetic and parasympathetic nervous systems. Sympathetic activation and/or vagal withdrawal increases HR, whereas sympathetic withdrawal and/or vagal activation decreases HR. Accordingly, information on the mean level of HR alone does not allow a separate estimate of efferent activities of the two divisions of the autonomic nervous system. In contrast, information on the dynamic HR response has been considered useful in assessing vagal efferent nerve activity separately from sympathetic efferent nerve activity, because dynamic HR regulation is much faster via the vagal system than via the sympathetic system (3, 12). Accordingly, the high-frequency (HF) component (Ͼ0.15 Hz in humans) of HR variability (HRV) might reflect the cardiac vagal efferent nerve activity (2, 23). However, this notion is simplistic, in that it disregards interactions between the sympathetic and vagal systems.Complex sympathovagal interactions are known to occur in regulation of HR. An increase in the background sympathetic tone augmented the HR response to vagal nerve activity (16,17). Levy (17) termed this phenomenon an accentuated antagonism of the vagal control of HR. Accumulation of cAMP in the sinus nodal cells via activation of the postjunctional ␤-adrenergic receptors contributed to the accentuated antagonism (20). On the other hand, activation of the prejunctional ␣-adrenergic receptors influenc...

bution of viable myocardium in the ischemic myocardium has not been quantified and fully elucidated. To address this issue, we evaluated transmural myocardial strain profile (TMSP) in dogs with myocardial infarction using a newly developed tissue strain imaging. TMSP was obtained from the posterior wall at the epicardial left ventricular short-axis view in 13 anesthetized open-chest dogs. After control measurements, the left circumflex coronary artery was occluded for 90 min to induce subendocardial infarction (SMI). Subsequently, latex microbeads (90 m) were injected in the same artery to create transmural infarction (TMI). In each stage, measurements were done before and after dobutamine challenge (10 g ⅐ kg Ϫ1 ⅐ min Ϫ1 for 10 min) to estimate transmural myocardial viability. Strain in the subendocardium in the control stage increased by dobutamine (from 53.6 Ϯ 17.1 to 73.3 Ϯ 21.8%, P Ͻ 0.001), whereas that in SMI and TMI stages was almost zero at baseline and did not increase significantly by dobutamine [from 0.8 Ϯ 8.8 to 1.3 Ϯ 7.0%, P ϭ not significant (NS) for SMI, from Ϫ3.9 Ϯ 5.6 to Ϫ1.9 Ϯ 6.0%, P ϭ NS for TMI]. Strain in the subepicardium increased by dobutamine in the control stage (from 23.9 Ϯ 6.1 to 26.3 Ϯ 6.4%, P Ͻ 0.05) and in the SMI stage (from 12.4 Ϯ 7.3 to 27.1 Ϯ 8.8%, P Ͻ 0.005), whereas that in the TMI stage did not change (from Ϫ1.0 Ϯ 7.8 to Ϫ0.7 Ϯ 8.3%, P ϭ NS). In SMI, the subendocardial contraction was lost, but the subepicardium showed a significant increase in contraction with dobutamine. However, in TMI, even the subepicardial increase was not seen. Assessment of transmural strain profile using tissue strain imaging was a new and useful method to estimate transmural distribution of the viable myocardium in myocardial infarction. myocardial infarction; strain; viability; echocardiography IT IS WELL KNOWN that myocardial contraction has transmural heterogeneity. Several experimental studies confirmed that the subendocardium contributes greater to overall myocardial thickening than the subepicardium (6, 25). On the other hand, when a reduction of coronary blood flow occurs, a severe reduction of perfusion and kinesis occurs in the subendocardium, but only a trivial reduction can be detected in the subepicardium (5, 31). After a long period of ischemia, myocardial necrosis progresses from the endocardium to the epicardium (8, 13).Myocardial strain reflects regional myocardial function. With the recent advancement of tissue Doppler echocardiography, myocardial strain can be obtained noninvasively (3, 33) and has been reported to be useful to quantify regional myocardial systolic function in ischemic heart disease (9, 11, 24, 29, 36). The recently developed myocardial strain imaging system provides us myocardial strain in each wall layer and shows its distribution in a form of transmural myocardial strain profile (TMSP; see Ref. 1). Thus combination of TMSP and dobutamine stress echocardiography (DSE), which has been used for the assessment of myocardial viability (18), is expected to demonstr...

nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and ␤-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) with or without a magnesium infusion (1 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). The dose response to small doses of isoproterenol (0.025-0.2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and ␤-adrenergic desensitization. calcium overload; free radical; dog, left ventricular; tau SYMPATHETIC ACTIVATION IS a crucial compensatory mechanism in heart failure, and serum catecholamine levels are an indicator of the clinical severity (8). However, excess catecholamine may actually induce cardiac cell injury, leading to cardiac dysfunction (34). This is one of the rationales for the clinical beneficial effects of ␤-adrenergic receptor blockade on the prognosis and cardiac function in chronic heart failure (7, 13, 27, 32). Excess isoproterenol (ISO), a selective ␤-adrenergic receptor agonist, induces myocardial necrosis and apoptosis, interstitial fibrosis, and left ventricular (LV) hypertrophy and dysfunction (14, 36). The mechanism of cardiac dysfunction induced by excess ISO may be attributed to calcium overload (19) and free radical generation (37). Moreover, excess ISO induces ␤-adrenergic desensitization (18), one of the hallmarks of heart failure, which potentially exacerbates cardiac dysfunction.Magnesium is known as a cardioprotective factor in the treatment of hypertension, ischemic heart disease, and chronic heart failure (2, 21, 38, 43). In experiments on cardiac ischemia-reperfusion, magnesium has been reported to reduce myocardial calcium overload (44), free radical generation (11), and myocardial infarct size (26). High magnesium levels have been reported to suppress ␤-adrenergic desensitization (9). However, the beneficial effects of magnesium in acute heart failure remain to be elucidated.The goal of the present study was to investigate whether magnesium prev...

Functional laterality of cardiac sympathetic nerve stimulation in chronotropic and inotropic effects is well known. Whether left (LSNA) and right (RSNA) cardiac sympathetic nerve activities show laterality during dynamic baroreflex activation remains to be determined. In nine anesthetized, vagotomized, and aortic-denervated rabbits, we randomly perturbed intracarotid sinus pressure (CSP) in both carotid sinus regions while simultaneously recording LSNA and RSNA. The baroreflex neural arc transfer function from CSP to LSNA and from CSP to RSNA revealed derivative characteristics, i.e., the magnitude of LSNA and RSNA responses became greater as the input frequency of CSP perturbation increased. The average slope of increasing gain in the frequencies between 0.03 and 0.3 Hz showed no difference between LSNA and RSNA responses (9.7 +/- 2.9 vs. 9.7 +/- 3.1 dB/decade, means +/- SD). The amplitude ratio and phase difference between LSNA and RSNA approximated unity and zero radians, respectively, in the frequencies from 0.01 to 1 Hz. In addition, the LSNA-RSNA relationship during stepwise CSP perturbation from 40 to 160 mmHg showed a straight line (r(2) ranged from 0.969 to 0.999). These findings indicate no laterality in the dynamic as well as static baroreflex regulation of LSNA and RSNA as far as grouped axonal activity is concerned.