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Neural and Humoral Regulation of Circulatory System

The body is equipped with a number of neural and humoral systems for cardiovascular regulation. To fully understand the cardiovascular system, we must comprehend not only the properties of heart and vessels per se, but also those of the regulatory systems. Such regulatory systems also play crucial roles in various cardiovascular diseases.

To date, due to the complexity of these systems, no one has succeeded in identifying their properties. This complexity includes the negative feedback, transient response, nonlinearity, and multiple input. The Gaussian white noise technique is known to be efficient and unbiased in the analysis of such complex systems. Use of this technique led us to successfully investigate in detail the properties of cardiovascular regulation systems and to treat them from the control engineering viewpoint.

These properties are useful not only as basic data required for logical interfacing with a bionic device (see section A), but also for understanding cardiovascular regulation abnormality in various diseases.

(1) System Analysis of the Baroreflex System: Roles of Central and the Peripheral Arc Dynamic Properties

The baroreflex system, which stabilizes arterial pressure, is one of the most important systems involved in cardiovascular regulation. The transient response of the arterial baroreflex system determines how pressure is stabilized after the body has experienced external perturbation. The baroreflex system must, without delay (quickness) or transient oscillation (stability), counteract the pressure drop caused by standing.

We have separately analyzed the properties of the central (i.e., baroreceptor and baroreflex center) and peripheral (i.e., effecter) arcs of the baroreflex system using Gaussian white noise technique. Our results have shown that the peripheral arc has a low-pass property, indicating that pressure does not change rapidly in response to rapid changes in nerve activity. Without compensation or modification by the central arc, the total baroreflex system also behaves thus; blood pressure changes cannot be counteracted rapidly in response to rapid change in body position. We demonstrated that the high-pass property of the central arc, by preferentially amplifying rapid changes in pressure, compensates for the low-pass property of the peripheral arc. Investigating the effect of central arc gain and time constant, we found that the native central arc has nearly optimal properties to compensate for the peripheral arc in terms of speed and stability. We also found that phenylbiguanide, a stimulant of cardiopulmonary baroreceptors, decreased central arc dynamic gain while angiotension does not affect the dynamic properties of the baroreflex system. In spontaneously hypertensive rat, we confirmed that the dynamic characteristics of baroreflex system were well preserved.


  1. Ikeda Y, Kawada T, Sugimachi M, Kawaguchi O, Shishido T, Sato T, Miyano H, Matsuura W, Alexander J Jr, Sunagawa K: Neural arc of baroreflex optimizes dynamic pressure regulation in achieving both stability and quickness. Am J Physiol 271: H882-H890, 1996.
  2. Kashihara K, Kawada T, Yanagiya Y, Uemura K, Inagaki M, Takaki H, Sugimachi M, Sunagawa K: Bezold-Jarisch reflex attenuates dynamic gain of baroreflex neural arc. Am J Physiol Heart Circ Physiol 285: H833-H840, 2003.
  3. Kashihara K, Takahashi Y, Chatani K, Kawada T, Zheng C, Li M, Sugimachi M, Sunagawa K: Intravenous angiotensin II does not affect dynamic baroreflex characteristics of the neural or peripheral arc. Jpn J Physiol 53: 135-143, 2003.
  4. Kawada T, Miyamoto T, Uemura K, Kashihara K, Kamiya A, Sugimachi M, Sunagawa K. Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics. Am J Physiol Regul Integr Comp Physiol 286: R1110-R1120, 2004.
  5. Kawada T, Shimizu S, Kamiya A, Sata Y, Uemura K, Sugimachi M. Dynamic characteristics of baroreflex neural and periphral arcs are preserved in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 300: R155-65, 2011.

(2) Integrated Model for Baroreflex System

The arterial baroreflex neural arc reveals high-pass characteristics that enhance the rapid pressure changes as mentioned above. On the other hand the operating pressure levels also affect the neural arc responses. The steady-state response are known to show a sigmoidal nonlinearity where the response is largest around normal pressure and is smaller in either high or low pressure range. We examined the two aspects of the baroreflex, i.e., the dynamic and static characteristics, and developed an integrated model explaining the two aspects simultaneously.

When we altered the amplitude of the pressure change that imposed on the arterial baroreflex, the high-pass characteristics became weaker as the input amplitude increased. The results suggest that the rapid variation in the blood pressure is first enhanced by the high-pass characteristics, then the magnitude of the response is transformed with a sigmoidal nonlinearity depending on the pressure level. If the nonlinear sigmoidal transduction is the first process, the degree of the high-pass characteristics should be unchanged. By using the integrated model, a discussion on pathology can be made as to whether the baroreflex system itself is changed or the observed change is just the outcome of observing the same system in different pressure ranges.


  1. Kawada T, Yanagiya Y, Uemura K, Miyamoto T, Zheng C, Li M, Sugimachi M, Sunagawa K: Input-size dependence of the baroreflex neural arc transfer characteristics. Am J Physiol Heart Circ Physiol 284: H404-H415, 2003.
  2. Kawada T, Uemura K, Kashihara K, Kamiya A, Sugimachi M, Sunagawa K. A derivative-sigmoidal model reproduces operating point-dependent baroreflex neural arc transfer characteristics. Am J Physiol Heart Circ Physiol 286: H2272-H2279, 2004.

(3) Equilibrium Diagram Analysis on Baroreflex Operating Point

It is not known what determines the level (operating point) at which the baroreflex system acts to stabilize arterial pressure. We measured the static properties of the central and peripheral arcs, and investigated whether the operating point is determined by their interaction.

We surgically isolated both carotid sinuses in rats to impose a different pressure on the baroreceptor from the arterial pressure. While gradually increasing baroreceptor pressure in a stepwise manner, at each step we measured sympathetic nerve activity and arterial pressure when they reached a steady state. From the results, we determined the intrasinus pressure-nerve activity relationship (static property of central or mechanoneural arc), and the nerve activity-arterial pressure relationship (static property of peripheral or neuromechanical arc).

The control theory suggests that the operating point is at the intersection of these static relationships. The theory is supported by the fact that the operating point pressure thus estimated agreed well with actual measurements in a closed-loop state in rats. With this framework, we can precisely estimate changes in operating point pressure and nerve activity from changes in central or peripheral arc static properties. Conversely, it is also possible to estimate changes in static properties from changes in the operating point. Using this approach, we characterized in detail the central and peripheral static properties during exercise and during electroacupuncture. We also disclosed that in a rat model of heart failure, the percent recovery of arterial pressure was reduced progressively as the size of pressure disturbance increased, suggesting that a reserve for buffering function of arterial pressure is lost despite relatively maintained baseline arterial pressure.


  1. Sato T, Kawada T, Inagaki M, Shishido T, Takaki H, Sugimachi M, Sunagawa K: A new analytical framework for understanding the sympathetic baroreflex control of arterial pressure. Am J Physiol 276: H2251-H2261, 1999.
  2. Yamamoto K, Kawada T, Kamiya A, Takaki H, Miyamoto T, Sugimachi M, Sunagawa K. Muscle mechanoreflex induces the pressor response by resetting the arterial baroreflex neural arc. Am J Physiol Heart Circ Physiol 286: H1382-H1388, 2004.
  3. Michikami D, Kamiya A, Kawada T, Inagaki M, Shishido T, Yamamoto K, Ariumi H, Iwase S, Sugenoya J, Sunagawa K, Sugimachi M. Short-term electroacupuncture at Zusanli resets the arterial baroreflex neural arc toward lower sympathetic nerve activity. Am J Physiol Heart Circ Physiol 291:H318-H326, 2006.
  4. Kawada T, Kamiya A, Li M, Shimizu S, Uemura K, Yamamoto H, Sugimachi M. High levels of circulating angiotensin II shift the open-loop baroreflex control of splanchnic sympathetic nerve activity, heart rate and arterial pressure in anesthetized rats. J Physiol Sci 59: 447-455, 2009.
  5. Kawada T, Li M, Kamiya A, Shimizu S, Uemura K, Yamamoto H, Sugimachi M. Open-loop dynamic and static characteristics of the carotid sinus baroreflex in rats with chronic heart failure after myocardial infarction. J Physiol Sci 60: 283-298, 2010.

(4) Significance of Dual Regulation of Heart Rate by Vagal and Sympathetic Nerves

The significance of dual regulation of heart rate, i.e., by sympathetic and vagal nerves, remains unclear. To clarify it, we investigated the interaction between heart rate regulation by these nerves, using the Gaussian white noise technique. We identified heart rate step response to sympathetic stimulation using data obtained while randomly stimulating sympathetic nerves in anesthetized rabbits. Concurrent tonic vagal stimulation increased the magnitude of step response to sympathetic stimulation. Similarly, concurrent tonic sympathetic stimulation increased the magnitude of step response to vagal stimulation. These findings indicated that sympathetic and vagal nerves mutually facilitate their dynamic regulation, though they mutually inhibit their static regulation. We conjecture that this facilitatory interaction helps extend the physiological dynamic range of heart rate regulation. We also examined the effects of plasma catecholamines on the neural regulation of heart rate. High plasma noradrenaline inhibits the dynamic vagal control of heart rate. In contrast, high plasma noradrenaline or adrenaline does not affect the dynamic sympathetic control of heart rate, suggesting that the heart rate regulation by the sympathetic nerve is much more powerful than that by plasma catecholamines. We investigated the molecular mechanism of heart rate regulation by the vagal nerve. Muscarinic potassium 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.


  1. Kawada T, Sugimachi M, Shishido T, Miyano H, Sato T, Yoshimura R, Miyashita H, Nakahara T, Alexander J Jr, Sunagawa K: Simultaneous identification of static and dynamic vagosympathetic interactions in regulating heart rate. Am J Physiol 276: R782-R789, 1999.
  2. Miyamoto T, Kawada T, Takaki H, Inagaki M, Yanagiya Y, Jin Y, Sugimachi M, Sunagawa K: High plasma norepinephrine attenuates the dynamic heart rate response to vagal stimulation. Am J Physiol Heart Circ Physiol 284: H2412-H2418, 2003.
  3. Miyamoto T, Kawada T, Yanagiya Y, Inagaki M, Takaki H, Sugimachi M, Sunagawa K. Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism. Am J Physiol Heart Circ Physiol 287: H860-H865, 2004.
  4. Kawada T, Miyamoto T, Miyoshi Y, Yamaguchi S, Tanabe Y, Kamiya A, Shishido T, Sugimachi M. Sympathetic Neural Regulation of Heart Rate Is Robust against High Plasma Catecholamines. J Physiol Sci 56: 235-245, 2006.
  5. Mizuno M, Kamiya A, Kawada T, Miyamoto T, Shimizu S, Sugimachi M. Muscarinic potassium channels augment dynamic and static heart rate responses to vagal stimulation. Am J Physiol Heart Circ Physiol 293: H1564-H1570, 2007.
  6. Miyamoto T, Kawada T, Yanagiya Y, Akiyama T, Kamiya A, Mizuno M, Takaki H, Sunagawa K, Sugimachi M. Contrasting effects of presynaptic alpha2-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control. Am J Physiol Heart Circ Physiol 295: H1855-H1866, 2008.
  7. Mizuno M, Kawada T, Kamiya A, Miyamoto T, Shimizu S, Shishido T, Smith SA, Sugimachi M. Dynamic characteristics of heart rate control by the autonomic nervous system in rats. Exp Physiol 95: 919-925, 2010.

(5) Intracellular Signaling of Dual Neural Regulation of Heart Rate

To understand the mechanism of sympatho-vagal interactive regulation of heart rate, we examined interaction through modification of intracellular cyclic AMP concentration. Tonic sympathetic stimulation enhances the bradycardiac response to vagal activation (see above). Sympathetic stimulation is known to exert its effect by increasing cyclic AMP via beta-receptor stimulation and adenyl cyclase activation. We therefore examined whether the vagal bradycardiac response is enhanced by increasing cyclic AMP via other means than sympathetic stimulation.

Experimental results show that the vagal bradycardiac response was enhanced either by isoproterenol administration for beta-receptor stimulation, by forskolin administration for direct activation of adenyl cyclase, or by theophylline administration for inhibition of cyclic AMP degradation, all of which actions are known to increase intracellular cyclic AMP concentration. These pharmacological interventions did not change the vagal bradycardiac response time constant, which result was consistent with those obtained with tonic sympathetic stimulation. These results indicate that interaction through intracellular cyclic AMP concentration changes is partly involved in sympatho-vagal interactive heart rate control in sinoatrial node pacemaker cells.


  1. Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Inagaki M, Alexander J Jr, Sunagawa K: Accumulation of cAMP augments dynamic vagal control of heart rate. Am J Physiol 275: H562-H567, 1998.

(6) Analysis of Cardiac Contractility Regulation by Sympathetic and Vagal Nerves

Though it is well known that sympathetic nerves regulate cardiac contractility, cardiac contractility regulation by vagal nerves remains controversial. Because heart rate changes associated with nerve stimulation may change contractility via rate-induced changes in contractility, the heart rate must be fixed in order to examine the direct action of nerve stimulation. In addition, it is necessary to use canine isolated cross-perfused hearts with functional autonomic nerves, which are suited to precise determination of contractility.

Though a significant decrease in cardiac contractility was observed during vagal stimulation, this decrease disappeared almost completely when heart rate was fixed by pacing. Under enhanced contractility with sympathetic stimulation, however, vagal stimulation attenuated the increase in contractility.


  1. Miyano H, Nakayama Y, Shishido T, Inagaki M, Kawada T, Sato T, Miyashita H, Sugimachi M, Alexander J Jr, Sunagawa K: Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart. Am J Physiol 275: H400-H408, 1998.
  2. Nakayama Y, Miyano H, Shishido T, Inagaki M, Kawada T, Sugimachi M, Sunagawa K. Heart rate-independent vagal effect on end-systolic elastance of the canine left ventricle under various levels of sympathetic tone. Circulation 104: 2277-2279, 2001.
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