Advan. Physiol. Edu. 29: 132-135, 2005;
doi:10.1152/advan.00010.2005
1043-4046/05 $8.00
ADV PHYSIOL EDUC 29:132-135, 2005
© 2005 American Physiological Society
ILLUMINATIONS
"FUTILE CYCLING" IN PHYSIOLOGIC CONTROL SYSTEMS: A PRICE PAID FOR FINE CONTROL
Krishnamurthy Aishwarya,
Krishna Rachana and
E. Sankaranarayanan Prakash
Department of Physiology
Jawaharlal Institute of Postgraduate Medical Education and Research
Pondicherry 605006, India.
E-mail: dresprakash{at}yahoo.com
"Substrate cycling" is a term widely used by biochemists to refer to the simultaneous occurrence of opposing reactions although at different rates. It is described as allowing fine tuning of metabolism (1). A classic example is the simultaneous occurrence of reactions catalyzed by phosphofructokinase-1 and fructose 1,6-bisphosphatase (1).
From the illustration in Table 1, it is apparent that if there were no substrate cycling in the baseline state, a great change (380% increase in this instance) in the activity of phosphofructokinase-1 is required to elicit a 380% increment in glycolytic rate. However, when substrate cycling occurs, a mere 20% increase in the activity of phosphofructokinase-1 and a 20% decrease in the activity of fructose 1,6-bisphosphatase results in the same 380% increase in glycolytic rate.
We questioned whether there is a similar paradigm in physiological control systems. We drew an analogy between substrate cycling in metabolic pathways and tonic activity (=cycling) in opposing neural systems and applied it to the case of heart rate (HR) regulation by the two limbs of the autonomic nervous system. Given here is a summary of the analogy as we presented it in a 15-min lecture to 57 first-year medical students who had completed course work in metabolic pathways, regulation of metabolism, and cardiovascular regulatory mechanisms. The idea was to stimulate them to look for such analogies in their learning endeavors.
After finishing with the above-mentioned description of the use of the term "substrate cycling" in biochemical parlance, we gave a brief description of regulation of HR. The description was as follows. Like the rates of metabolic pathways are determined by activities of enzymes with opposing actions, HR is also reciprocally regulated by the two limbs of the autonomic nervous system. At any instant, HR depends on sympathovagal balance; i.e., the balance between the opposing influences of acceleratory sympathetic and inhibitory vagal inputs to the sinoatrial (SA) node. Both neural systems exhibit activity in the baseline state (i.e., at rest) (5). This is what we mean by cycling. The evidence for this is that administration of atropine, which leaves sympathetic tone unopposed, results in an increase in HR to about 150 beats/min (5). Also, when a beta-blocker is administered, HR decreases from 70 to 
60 beats/min, depending on baseline sympathetic tone (7).
To understand this analogy, let us assume that for the HR control system we describe here, intrinsic HR (HR after complete double autonomic blockade with an optimal dose of atropine and atenolol) is 100 beats/min, minimum HR with unrestrained vagal tone is 40 beats/min, and maximal HR with unrestrained maximal sympathetic tone is 200 beats/min. The operating range of this system is thus 40 –200 beats/min. The baseline state is taken to correspond to a HR of 70 beats/min, less than the intrinsic HR by virtue of a dominating vagal tone. Our use of the terms vagal activity and sympathetic activity throughout this article refers to the cardioinhibitory and cardioaccelaratory effects of activity in the respective nerves rather than nerve traffic per se.
Consider the cases mentioned in Table 2. In both situations, two neural controllers are available. However, when there is no sympathetic activity in the baseline state, a decrease in HR from 70 down to 48 beats/min (for example, as occurs during sleep) can be achieved only with a 75% increase in activity in the vagal system. However, when cycling occurs in the baseline state, only a 25% decrease in sympathetic activity and 25% increase in vagal outflow are adequate to achieve the same. Clearly, cycling proves advantageous. Let us now examine whether there is a similar advantage when HR increments are required. If HR needs to be increased from 70 to 115 beats/min, this is achieved by inhibiting vagal activity and increasing sympathetic activity. However, when there is no sympathetic activity in the baseline state, the sensitivity of the target (SA node) to sympathetic stimulation will presumably be greater, and larger increments in HR could occur. This would be even more wasteful of energy.
In summary, the physiologic advantage of the situation in which cycling occurs is that fine HR modulation around the baseline value could be achieved faster and more reliably by small, simultaneous and reciprocal changes in activity in two systems rather than sequential changes in one. The other assumptions we have made are that sympathetic and vagal systems for HR modulation are equipotent. We have assigned an arbitrary value of +30 beats/min and –30 beats/min for 1 unit of activity in the sympathetic and vagal systems, respectively. In our illustration, we have assumed that in the conditions with or without cycling in the baseline state, both controllers will be equally utilized from the baseline state onwards to achieve increments in HR. For the entire illustration, we constructed values assuming that the HR control system behaves linearly throughout.
In reality, the dynamics of HR regulation are complex and additional mechanisms besides cycling, for example, differences in conduction speeds, and time constants between vagal and sympathetic systems are involved (3). However, the sole purpose of this analogy is to exemplify the adaptive value of cycling in the baseline state. Given the fact that effects of activity in sympathetic and parasympathetic systems take a definite time to develop, the presence of cycling in the baseline state allows for quicker modulation of HR since the effects of simultaneous and reciprocal changes in sympathetic and vagal activity would undergo spatial summation, meaning the summation of two or more inputs (here, sympathetic and vagal) acting concurrently on an integrator (here, the SA node). Considering the fact that HR changes are the fastest buffer of blood pressure oscillations (8), this facility is of great importance for short-term control of arterial blood pressure. In fact, a decline in autonomic modulation of HR is also a feature of hypertension and heart failure (8).
Another example of apparently futile cycling is the case of regulation of peripheral vascular resistance. Resistance vessels in the microcirculation are under the influence of two systems with opposite effects on vascular resistance. One is the "vasoconstrictor system," which includes the sympathetic vasoconstrictor system and endothelial vasoconstrictor molecules. The second is the "vasodilator system," which includes endothelial vasodilator molecules, local vasodilator metabolites, and a sympathetic vasodilator system. Sympathectomy has been shown to increase blood flow to resting skeletal muscle (4). Also, there is a basal level of endothelial vasodilator molecules and local vasodilator metabolites in the blood stream (2, 5). Thus, it is clear that in the baseline state, in which blood pressure and vascular resistance are normal, there is "activity" in both vasodilator and vasoconstrictor systems. The occurrence of cycling makes possible great changes in tissue blood flow. For example, as much as a 30-fold increase in blood flow could be achieved in exercising skeletal muscle by reducing the efficacy of activity in the vasoconstrictor system and by the direct action of vasodilator molecules and metabolites on resistance vessels (2, 4). It must be carefully noted that although sympathetic nerve activity has been described to increase even in exercising skeletal muscle, the vasoconstrictor effects of increased sympathetic activity are greatly mitigated by actions of local vasodilator metabolites (2). The same analogy could be extended to explain rapid and fine regulation of the diameter of the pupil by simultaneous and reciprocal changes in activity in the sympathetic and parasympathetic nerves controlling the smooth muscle of the iris.
Besides influencing the rate at which a controlled parameter could be changed, cycling may have other important consequences for control. Activity in a system in the baseline state may be essential for maintaining optimal sensitivity of the target cells to a change in the activity of the controller. For example, it is well known that when skeletal muscle is denervated, it gradually becomes hypersensitive to acetylcholine (6). Similarly, when the upper extremity is sympathectomized by removing the stellate ganglion, episodic vasospasm occurs due to hypersensitivity to circulating norepinephrine (6). This strongly suggests that if there were no cardiac sympathetic tone in the baseline state, responses of the SA node to sympathetic stimulation may be unpredictable and exaggerated, rendering fine control impossible. It is the possibility that makes it difficult to predict what would happen to sympathetic activity and HR in the situation without cycling when HR needs to be increased from 70 to 115 beats/min (Table 2).
Student feedback on various aspects of the session was obtained and is presented in Table 3. In general, the analogy was very well received. Written comments were also invited. There were several insightful comments, and some of them are mentioned in Table 4. In view of some of their comments, the values in Table 2 were slightly modified from an original version to what is presented here. We hope that this analogy would make an exciting and useful addition to routine lectures in cardiovascular physiology. To avoid assumptions we have made here about regulation of HR, one could take an entirely hypothetical situation (example, two presynaptic inputs with contrasting influences on a postsynaptic neuron) and still render the same analogy. We believed that students would enjoy a discussion of regulation of HR rather than something entirely hypothetical. That is why we gave this example. We conclude that "cycling" is essentially an adaptive feature in control systems, whatever the level of organization. If we also consider that energy expended is proportional to the sum of activity in the two opposing control arms, it could be noted from the illustration in Table 2 that cycling entails greater expenditure of energy. However, this is a small price paid for the finer control that it endows. As one of our students put it, "It (the analogy) was very good. It helps us understand the seemingly useless things around us as having immense advantage. Otherwise, such a system would not have survived and evolved."
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Acknowledgments
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We thank our students for their insightful comments on the classroom presentation of this analogy.
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References
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Copyright © 2005 by the American Physiological Society.
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