Slowly Rising Pressure

Anyone who grows up in Mississippi gains respect for the effects of slowly moving fluid. The fertile soil of the Mississippi Delta, from Memphis down through Clarksdale and Yazoo City to Vicksburg, accumulated over millenia of flooding and deposition of silt carried by the river from northern tributaries. As a boy, Ott Guyton certainly heard about the Great Flood of 1927 and read with interest about the expansion of levees and scientific study of hydraulics by the U.S. Army Corps of Engineers.[1] Floods in Mississippi typically don’t burst upon the scene in an onrushing torrent. Instead the water rises inch by inch often under clear skies in bright sunlight with inescapable devastating effect.

Fluid Poultry_and_livestock_sit_on_levee_out_of_floodwaters_-_NARA_-_285965 2
Flood scene – at least the chickens survive

Yet people in Mississippi also understand that water nourishes the land. They learn to make the best of their relationship with creeks and rivers. The interactions of fluid and solid – soil, water, and mud – become familiar.

Ott and his boyhood friends once dammed a small stream in a ravine on the Faulkner property to make a swimming hole. After they built their solid dam, they had to wait for 2 or 3 heavy spring storms to fill the pool. The swelling current of the rain-filled stream was just the one factor toward the goal, the other factor was time, and overall the childhood project served as a perfectly intuitive example of integral calculus.

In his laboratory at the University of Mississippi Medical School, Ott (now Arthur) at the beginning of the 1960s achieved his first widely recognized success in physiology by measuring negative interstitial pressure, a fundamental property of fluid in body tissues. “Negative pressure” meant simply that the pressure in interstitial fluid (between the body’s cells) was less than atmospheric pressure. Theory predicted just such a low pressure, but experiments had always given results above atmospheric pressure. Arthur’s article in Circulation Research discussed the experimental challenge –

Interstitial pressure has usually been measured by inserting a very small needle into a tissue and then determining the minimum pressure required to make fluid flow from the needle into the tissue. Unfortunately, even when extremely small needles are used for this purpose, such as 25 to 30 gauge, the external diameter of the needle is still some 300 to 500 times as large as the widths of the tissue spaces. The insertion of such needles into the tissues must distort the spaces greatly and could easily give a false measure of the interstitial pressure.[2]

Arthur took a different approach. He devised a perforated hollow plastic ball, somewhat like a ping-pong ball, though only half the size, with 200 holes drilled all over its surface.[3] He implanted the ball under the skin of the animal and let it fill with tissue fluid over 2 to 3 weeks, then simply inserted a regular hypodermic needle through one of the holes in the ball to measure the fluid pressure with a standard electrical manometer. It was less than atmospheric, and it matched the prediction based on the difference between the osmotic pressure of blood plasma and tissue lymph. That made big news at the annual FASEB meeting in Atlantic City in 1962.[4]

 

Fluid Daddy early photo in lab 2
Arthur Guyton early in his physiology career

He turned his attention to the question of what regulates cardiac output, the volume of blood pumped by the heart every minute. The simplest proposal to answer this question would be that the strength of contraction of the heart should determine cardiac output. That answer, however, failed to predict experimental results in several different situations. Several researchers began to favor the idea of a complex interplay with the autonomic nervous system, but again experimental confirmation proved difficult to obtain. Through a long series of experiments in Arthur’s laboratory, a completely different answer emerged. The heart pumps all the blood that comes to it. Venous return is the name given to the slow movement of blood back toward the heart from body tissues. Slowly moving fluid, familiar to a young man from Mississippi.

Arthur found a way to measure experimentally the force governing venous return, by suddenly (and temporarily) stopping a dog’s heart, then measuring the transiently stable pressure in the largest veins that carried blood toward the heart. He called it the mean circulatory filling pressure.

The result became clear. The forceful impulsion of blood out of the heart into the aorta and then into other major arteries is not regulated; all the blood coming to the heart is pumped out. Instead, venous return, the blood moving slowly from tissues back to the heart, is the regulated flow. This regulation actually occurs in the tissues by the opening and closing of myriads of tiny arterioles based on the oxygen needs of each tissue – a phenomenon called autoregulation.

As fundamental as the concepts of tissue pressure and autoregulation seem, Arthur Guyton is best remembered today for his discovery that long-term regulation of blood pressure occurs in the kidney, not in the heart as one might expect, nor in the nervous system, despite dramatic short-term effects sometimes encountered when heart or nerve function is altered. His ability to discern slowly evolving effects and to think mathematically proved crucial.

I was in college at Ole Miss when my father, his colleagues, post-docs, and graduate students at the Medical Center in Jackson developed their theory of kidney control of blood pressure. During a holiday visit at home, knowing my interest in electronics, he said I should come down to his laboratory to see the analog computer that provided the critical insight.

What on earth is an analog computer? It’s a computer built from electronic amplifiers, capacitors, resistors, and other components that gives results in terms of electrical voltages and currents rather than binary numbers. The component parts of a complicated regulatory system are represented on a physical circuit board by actual electronic components, and their interactions are simulated by real copper wire connections that carry electrical information from one segment of the system to another.

By that time I already had some experience with an IBM 1620 digital computer. Would the future lie with analog or digital computers? My father agreed that digital computers were progressing rapidly and would come to dominate. However, he thought that analog computers, which must be physically assembled into a regulatory system, provided a learning experience that would be missed when everything turned digital. An example of this is his concept of “infinite gain.” It refers to the gain, or amplification ratio, required by the operational amplifier in the kidney component of the blood pressure regulatory system in order to match laboratory results in dog experiments. Outside of that context “infinite gain” is not so easy to grasp.

The notion that the long-term control of blood pressure occurred in the kidney met with fierce resistance. Too many laboratories had invested sweat, money, and decades of research into other hypotheses. Their efforts would not be thrown away easily. Challenges came from those who believed the answer must be hidden in sympathetic nervous system responses, and from those who proposed the “mosaic theory,” which described blood pressure control as a little bit of everything.

The title of Arthur’s 1972 paper boldly proclaimed the new theory: “Arterial pressure regulation: overriding dominance of the kidneys in long-term regulation and in hypertension.” It met more resistance than acceptance.

A remarkable meeting on hypertension organized by John Laragh of Cornell University in 1980 brought together 102 invited participants from throughout the world for 3 days of sessions at the Metropolitan Club in New York City. Among them were Arthur and two younger colleagues from Mississippi, as well as a former trainee who had recently become Chair of Physiology at the University of Wisconsin.

An early session in the meeting was headlined by Arthur’s presentation. He presented his theory with a surprisingly uncompromising tone. Here is the key figure from his paper in the proceedings, followed by the accompanying text:Fluid pressure-natriuresis figure 2

There are 2 basic laws of pressure control that can be derived from Figs. 4 and 5 and from the infinite-gain principle of pressure control by the kidney-sodium-volume-pressure system:

LAW NO. 1:  It is impossible to develop hypertension unless the equilibrium point is shifted to a high pressure level. Thus, in Fig. 5, let us assume that a person has hypertension with a mean arterial pressure of 175 mmHg. it would be impossible for this person to maintain this hypertensive state unless the equilibrium point for balance between sodium intake and output were also at 175 mmHg….

LAW NO. 2:  If the equilibrium point for balance between intake and output of sodium increases to a hypertensive level, then the person will develop hypertension up to the pressure level of the equilibrium point. Figure 5 also substantiates this law…. If the renal function crosses the intake level of sodium at any one of the points B through F, then it is clear that the equilibrium point for balance between intake and output of sodium has now been increased to 175 mmHg. The infinite-gain principle for pressure control requires that sodium be retained until the arterial pressure rises to 175 mmHg. Only then will sodium retention cease. (One might wonder what would have happened if the arterial pressure failed to rise to the 175-mmHg level? The answer to this is that sodium would continue to be retained forever, and the clinical picture would be that of typical progressive decompensated heart failure. But if the heart is strong enough, the excess volume will eventually raise the pressure to the level of the equilibrium point.)[5]

Did that make sense? Let me give an interpretive version. The circulatory system includes the heart as well as blood vessels supplying the kidneys, lungs, intestines, and various other tissues. Salt (sodium) and water come into the circulatory system through the intestine; salt and water exit the circulatory system mainly through the kidneys and leave the body in urine. Because the heart as the pump for circulation of blood is generating blood pressure, the simplest theory might assign a primary role to the heart for controlling blood pressure. But that is not true.

As soon as the circulatory system was modeled on the analog computer in Jackson, Mississippi, the truth became clear. Humans take in a fairly constant amount of sodium each day. If the blood pressure is not high enough to cause the kidneys to excrete each day’s allotment of sodium into the urine, then the extra sodium, not excreted by the kidneys, will build up day after day in the body. Water accumulates along with sodium. Thus the total fluid volume will increase. This makes the heart pump harder. Blood pressure will rise as the heart pumps harder. How high will it rise? The answer is precisely high enough that the kidneys begin to excrete each day’s allotment of sodium in the urine. Only then can the circulatory system reach the balance point.

Why did Arthur present his theory in terms of Law No. 1 and Law No. 2? Scientific discoveries are rarely framed in such a dogmatic manner. The philosophic principle of induction, upon which science is largely based, provides only probabilities, not certainties.

The answer is that Arthur’s two Laws of Hypertension came from mathematics – that is, the analysis of a mathematical model that he initially assembled with operational amplifiers and other electronic components on a circuit board. Digital computer analysis gave the same answer as the analog model. A mathematical model can be reproduced by any kind of calculating apparatus. Conclusions from mathematics do not come from induction and probabilities, but from deduction and logic.

I once failed in a grant application because of mathematics. The review team for our project grant came to Baylor College of Medicine in Houston for a site visit. My part of the project depended on geometric analysis of electron micrographs. Thinking myself clever, I took the math one simple step beyond what was written in standard texts. My chief reviewer referred to the standard analysis and stated that my extra step was wrong. I defended my point as clearly as possible in my allotted 2 minutes, but the reviewer wouldn’t budge. My part in the project application was denied. I was absolutely right about the math. Ten minutes of explanation one-on-one could have convinced anybody, but the agenda and setting afforded no opportunity. I still breathe harder, wince, and get a whiff of nausea when I think about it.

Yet I’m glad for the experience, because it helps me to understand how my father must have felt when he tried to explain the (much more important) control of blood pressure by the kidney to distinguished scientists from all over the world. Below I’ve reproduced part of the discussion following his presentation at the New York meeting.[6]

(You will need to know the meaning of “pressure-natriuresis.” It’s the centerpiece of Arthur’s new theory about hypertension. Natriuresis means sodium excretion by the kidneys, and pressure-natriuresis refers to the recognition that higher blood pressure will increase sodium excretion. “Interment” in the discussion does not describe physiology, but has its usual meaning of “burial.”)

Dr. Zanchetti (Milan, Italy) (Chairman):  . . . Is there someone here willing to define the theory of pressure-natriuresis?

Dr. Doyle (Heidelberg, Australia): I feel that we are very privileged in being here at the final interment of this hypothesis. I think that the data Dr. Guyton showed us in relation to the SHR [spontaneously hypertensive rat] where we have an animal that has high blood pressure and is perfectly capable of controlling his sodium without any hint at all of the relationship between pressure and natriuresis really illustrates exactly how unpivotal the role of the kidney is. What we are really saying, of course, is these animals are hypertensive while they retain a perfectly normal capacity to excrete sodium irrespective of blood pressure. Now I suspect that in all cases, other than perhaps the situation in which two-thirds of both kidneys have been removed, that is in fact the normal situation.

Dr. Guyton (Jackson, Miss.): I am surprised that you would say that this is the interment of the hypothesis because, if you had looked at the renal function curves carefully, you would have seen that in the SHR, it is only at the higher pressure that the kidneys will excrete sodium – that at the lower pressures they won’t excrete, they turn off, and the blood volume then increases. Thus, in fact, they require the higher pressure to excrete sodium normally.

Dr. Boyd (Hobart, Australia): Like Dr. Korner, I am very puzzled by the long time-course of Dr. Guyton’s so-called autoregulation, and I agree that we should be very careful about calling it that. An alternative explanation of the gradually increasing resistance after volume loading is that the increased blood pressure which results from the elevated cardiac output, through Dr. Folkow’s related mechanisms, bring about structural changes in the arterials. Could I, therefore, ask Dr. Folkow whether he has ever seen structural arteriolar changes over such a time-course in hypertension, particularly those due to a volume load.

Dr. Folkow (Göteborg, Sweden): Concerning the exchange between Drs. Doyle and Guyton, I think it is fair to say that both have a point. In adult SHR with established hypertension, the renal excretion curve is in fact displaced in parallel toward a higher pressure level, but in young SHR with less hypertension, it is essentially equal to that in normotensive controls. Actually, in the course of SHR hypertension, the renal curve gradually shifts to the right simply because there occurs the same structural increase of the preglomerular resistance as afflicts all other systemic precapillary resistance vessels, being an adaptive response to the increased load.[7]

The final segment of Frontiers in Hypertension Research, which described the New York meeting, is marked “Epilogue: After Dinner Science and Friendship.” The word “friendship” rarely appears in scientific texts, but it rings true. In any scientific field, researchers have a common purpose in the discovery of truth about the natural world. They form a community of people who debate their proposals vigorously – the validity of results depends on overcoming criticism – but who remain able to share the delight of discovery and to connect with each other as friends and colleagues in a common cause.

Despite polio, Arthur Guyton traveled both the U.S. and the world frequently. On domestic trips he rarely carried much more than underwear and toothbrush in a briefcase with metal hooks attaching it to the handle of his right crutch, the side of his stronger arm.

On overseas trips Ruth accompanied him. She was his strength for long trips. As he said, “She could lift me out of the wheelchair quite easily.” Luggage with rollers did not exist then. Ruth carried both of their suitcases when necessary. Besides that, he recognized that Ruth “has that ability to charm virtually everyone with whom she comes in contact.”[8] As a couple they maintained a warm friendship with the Folkows and made several trips to Göteborg (Gothenburg).

Three of the participants in the hypertension meeting in New York came from the Soviet Union. Arthur received an invitation to travel behind the Iron Curtain to discuss his views on the role of the kidney. Of course, Ruth traveled with him.

When they returned to Mississippi, he declared that her star had shone brighter. She had received official recognition as a Heroine Mother. She laughed about it, but I think she enjoyed the label. If you wonder, look back at the last blog.

In those travels my mother developed an appreciation for her husband’s work that spouses sometimes can miss. He depended on her for very basic needs, and that dependence brought them closer together.

In the early 1600s an Englishman named William Harvey first demonstrated the circulation of blood, proved that the heart is a pump, and measured blood pressure in a horse. Arthur Guyton’s role in forging a new understanding of circulatory physiology in the 20th century is perhaps best signaled by an honor bestowed by the Royal Society of Physicians. That distinguished group chose Arthur to deliver the William Harvey Lecture in London on the 400th birthday of the scientific pioneer.

 

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Featured image:  Arthur Guyton in his office at the University of Mississippi Medical Center, photo by John E. Hall with permission. Flood scene, U.S. National Archives and Records Administration, CC0 Public domain, Wikimedia commons. Arthur Guyton as a young researcher, after polio, noting atrophy of his left shoulder.

[1] Today the federal Waterways Experiment Station in Vicksburg employs over 600 engineers.

[2] Guyton AC. Circulation Research 1963;12:399-413.

[3] Perhaps the inspiration came from ping-pong. Despite his polio, Arthur played a tough game. He retained quick reflexes and hand-eye coordination that allowed him to beat his teenage children most of the time – a reflection of his former skill at tennis. He put mystifying spins on the ball, but had trouble reaching balls hit wide to the corners.

[4] Federation of American Societies of Experimental Biology

[5] Guyton AC, Hall JE, Lohmeier TE, Manning RD Jr, Jackson TE. Position paper: The concept of whole body autoregulation and the dominant role of the kidneys for long-term blood pressure regulation. In JA Laragh, F Bühler, DW Seldin, Frontiers in Hypertension Research. Springer Verlag, New York, 1981, pp 131-140.

[6] Discussants were Alberto Zanchetti, A. E. Doyle, Arthur Guyton, Graham Boyd, and Bjorn Folkow.

[7] Frontiers in Hypertension Research, pp 131-140. 

[8] Brinson, C. Arthur C. Guyton – His Life, His Family, His Achievements. Oakdale Press, Jackson, MS, 1989, p. 52.

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