1 GASTROENTEROLOGY Copyright )967 by The Williams & Wilkins Co. Vol. 52, No.2, Part 2 Printed in U.S.A. RECENT ADVANCES IN THE GASTROINTESTINAL CIRCULATION AND RELATED AREAS: COMMENTS ON A SYMPOSIUM EUGENE D. JACOBSON, M.D. Department of Physiology, University of Oklahoma Medical Center, Oklahoma City, Oklahoma The last international conference dealing with the gastrointestinal circulation took place 15 years ago. 1 Within the past few years, a number of research accomplishments have occurred which justified holding the present Symposium on the Gastrointestinal Circulation. The neat story about bradykinin and the salivary circulation, which is now textbook truth, has been seriously challenged. Gastric blood flow and secretion have been measured simultaneously in the conscious animal. Contracting smooth muscle of the gut wall influences the resistance to blood flow analogously to what occurs in the heart. Intestinal autoregulatory phenomena have been quantified in the microcirculation. Evidence is available to support an intestinal countercurrent circulatory hypothesis. The role of the splanchnic circulation in shock states has been described, and the implications are striking. In addition, there have been advances in the understanding of the blood vessels and ingenious technical developments in the measurement of regional blood flow. Some of these concepts and methods are applicable to the gastrointestinal circulation. Since the scientists in these areas are not gastrointestinal physiologists, it was logical to bring biophysicists and peripheral vascular physiologists to grips with our neglected circulatory area. Thus, the Symposium on the Gastrointestinal Circulation had its compelling 332 raison d'i2tre. The organization of the meeting followed from the preceding considerations: 1 day devoted to rheology, and methods of measuring blood flow, and 1 day to specific regional circulatory problems. Thirteen pairs of presentations and discussions comprise the body of this special supplement. Economic conside:-ationb dictated that the open discussion of the papers from the floor would not be recorded or published but would, like the Homeric myths, remain in the memory of those who had heard them. Wherever possible, the paired speakers were chosen because their views were not identical. These differences in opinions could stem from a common interest of two investigators in the same field who have interpreted related experimental results differently (as is the case with Drs. Schachter and Lewis). Dissimilar views are also engendered when two investigators in quite different fields share a common interest in a phenomenon like clearances (Drs. Sapirstein and Pitts). In one sense, this leads to disputation, which is, if nothing else, interesting to a group. It also has a dialectical effect: views c hange, experiments are conceived to test hypotheses, and an educational experience is underway. I cannot, in all honesty, declare to the readers of Gastroenterology that this issue consists of light bedtime reading. Great efforts were made by the authors to express clearly the essentials of their fields. However, the role of arterial compliance, the technical limitations of a flowmeter, or splanchnic hemodynamics in endotoxic shock are far r emoved from peptic ulcer, intestinal malabsorption, and the irritable colon. All I can say is that these papers represent a remarkable collection of essays of high quality devoted to the physiology of the gastrointestinal circulation and related subjects. In many cases, this information has not been available to the knowledgeable gastroenterologist (or to others either). It would be a pity indeed if
2 February 1967 JACOBSON 333 this volume of Gastroenterology were to become a reference source for vascular physiologists (as it surely must) but an unread issue for the subscribers of the journal. The issue opens with a charming keynote essay on "life" by a distinguished biologist. Wilfried Mommaerts takes issue with the glamour crowd that has defined life solely in terms of a double helical molecule. He also manages a few jabs in the direction of those whose apparent aim is to replace sentient being with a vegetable existence propped up by artificial pumps and membranes. His classical redefinition of biology will be reassuring, at the least, to a medical reader. The first technical paper is a broad review of the rheology of blood in the microcirculation by an eminent bioengineer, Harold Way land of Caltech. In lucid and logical steps, he defines rheology and the forces which the rheologist studies. Wayland presents the evidence which indicates that plasma behaves as a Newtonian fluid; viz., shear rate is proportional to shear stress, and the origin of the proportionality passes through zero on a linear plot. He discusses the way in which whole blood deviates from this Newtonian behavior and leads us to the hypothesis that there is a dynamic structuring of blood as it flows through the microcirculation. This structuring appears to consist of an interaction between erythrocytes which aggregate and dissociate in a reversible phenomenon. In certain peripheral vascular diseases, extra force is needed to accomplish dissociation, and we can translate this extra cost in terms of the in 'creased resistance to the flow of blood. Textbooks have it that there is a cellfree plasma layer at the intimal lining of micro vessels. Both Wayland and his discussant, Donald McDonald, conclude that the plasmatic zone has been greatly exaggerated in size and importance and that past measurements of the phenomenon have been subject to optic artefacts. The next topic covered is the physical structure of the blood vessel in relation to its role in the body. Michael Taylor approaches the biophysical problem from a unique vantage point. He pretends, for the span of his essay, to be a human engineer assigned the task of designing blood vessel walls which will cost the heart the least energy outlay. He shows how the most efficient means of reducing the steady flow component of the work of the heart in its arterial tree could be to increase the crosssectional area progressively by a certain factor at specified loci. He considers the advantages and disadvantages of using rigid pipes for blood vessels and also the opposite possibility, namely, very distensible walled tubes for this purpose. Naturally, our bioengineer effects a compromise between the extreme tubular materials. Since his arterial system terminates in small bore, thick-walled arterioles, he has to contend with reflected pressure waves which bounce back and increase resistance to flow. By arranging for a multi branching system, the engineer can effectively scatter the waves and induce mutual cancellation. What does he end up with? Naturally it is a system which confirms the wisdom of the body. As Alan Burton notes in his formal discussion of Taylor's paper, the entry of the engineer into biology may not solve the problems of the life sciences, but it should provide engineering with many models and ideas that can be applied to industrial use. For the readers of Gastroenterology who can recall the medical school struggles with the Fick principle, the essay by Leo Sapirstein will be both novel and elucidating. With a clarity one rarely meets in a textbook, this section rolls smoothly through the implications of the Fick principle and its applications to the measurement of cardiac output, estimated hepatic blood flow, and renal and cerebral blood flows. Finally, Sapirstein delves into the Fick principle as he has applied it in the estimation of regional blood flow, using K42 or Rb 86 uptake. These isotopes conform to certain requirements and. hence, can be used to estimate blood f l o ~ to many regions simultaneously; the isotopes are homogenously distributed in arterial blood, and their venous concentra-
3 334 ADVANCES IN GASTROINTESTINAL CIRCULATION Vol. 52, No.2, Part 2 tion is the same fixed fraction of the arterial concentration in most organs. Since the venous-arterial concentration ratio is stable, extrapolation of a series of isotopic measurements in blood back to zero time is justified. In practice, a slug of K42 is injected intravenously, and the animal is sacrificed at a fixed time thereafter. The isotope contents of the various organs are measured and extrapolated back to zero time. From these calculations, the fraction of cardiac output distributed to, let us say, the stomach or gut can be determined. If cardiac output is also measured, the absolute organ blood flow can be assessed as well. Sapirstein's discussant, Robert Pitts, points out some of the possible sources of error with the indicator fractionation technique which can lead to underestimation of regional flow; namely (a) limitation on the intracellular space available for the uptake of isotope; (b) a rapid blood flow not allowing enough time for diffusion of isotope; and (c) barriers to diffusion. Pitts also notes the limitations of this method in situations where the investigator requires frequent or continuous measurement of organ blood flow or where sacrifice of the animal is undesirable. Those with long memories can recall the initial uncritical enthusiasm for, the later disappointment in, and the final abandonment of the thermostrohmuhr as a technique for measuring blood flow in the conscious animal. If we are to avoid repetition of that fate with the electromagnetic flowmeter, we will need an awareness of its limitations and means of circumventing the artdacts. Alvin Sellers and Alan Dobson present a provocative paper intended for those who use the chronically implanted electromagnetic blood flowmeter. The authors pinpoint the sources of error with the instrument and have devised a method of evaluating these artefacts in vivo. These errors fall into two categories, namely, changes in sensitivity and variation in the zero value. The causes of these errors can sometimes be compensated for, e.g., the effect of hematocrit, proper preparation of transducers for implantation, etc. However, the over-all picture painted by Sellers and Dobson is not comforting, and, hopefully, it will engender pressure on the part of investigators to get better and more uniform transducers from the manufacturers. In his critique of the paper by Sellers and Dobson, Alexander Kolin, who has been the Daedalus of the electromagnetic blood flowmeter, raises the essential point about the listed artefacts-are they due to a poor product of industry or are they an inherent flaw in the principle of this instrument? For those of us who lack electronic capability and support but who would like to measure blood flow in conscious animals, an authoritative evaluation of the many commercial transducers now available to determine instrumental quality appears to be imperative. Gas in the intestine would seem to have little to commend it and a scant relation to the theme of our Symposium. An eminent respiratory physiologist, Robert Forster, proves otherwise. In his unique essay, he considers the physiology of gas exchange across membranes and develops a model for using inert gas uptake to measure epithelial blood flow in hollow organs of the gastrointestinal tract. A suitable gas must exchange between the lumen and the blood vessels only at their interface and not be lost into the tissue from the blood at deeper sites. Carbon monoxide, for which hemoglobin has an avid appetite, will not leave the erythrocyte to enter local tissues in the gut. Experimental data with this agent measuring blood flow yield a value of 0.07 ml per min per g of gut. This figure is about 7io of the value measured by Selkurt and Wathen in the companion article; the latter authors employed xenon-133 uptake in the intestine. This suggests that these methods may possibly be measuring different parts of gut wall perfusion. Lest the reader think these techniques are fit only for airy speculation, he will note that Folkow's group is employing a third gas, krypton-85, to gain critical insights into circulatory events in the intestinal epithelium. A thorough analysis of the use of the
4 February 1967 JACOBSON 335 heated thermocouple to estimate tissue perfusion in solid organs is presented by John Grayson, one of the foremost innovators with that technique. He develops the theoretical basis for the method, showing how blood flow and measured thermal conductivity are linearly related. He carefully emphasizes the fact that heat exchange methods do not directly measure total blood flow in a solid organ; the parameter being estimated is the flow of blood in the immediate vicinity of the sensing device. For those interested in measuring liver perfusion, Grayson points out the inherent difficulties in interpretation of findings owing to the complex vascular architecture. The "safer" applications of the technique in the author's hands are indicated. The discussant, Loren Carlson, has also had experience with calorimetric techniques, especially in estimating skin blood flow, and he amplifies the list of possible areas where the heated thermocouple might have application. Someone once noted that history doesn't change; only historians vary. The two classical views of the control of the salivary circulation are those of Bernard, Bayliss, and Dale, on the one hand, who believed in parasympathetic vasodilator nerves, and Barcroft, who proposed that metabolic intermediaries effected a functional hyperemia. The contemporary counterparts of the older physiologists are Melville Schachter, who subscribes to the nervous theory, and Graham Lewis, who with Sidney Hilton has championed the metabolic hypothesis. Essays by Schachter and Lewis clearly set forth these opposing VIews. Schachter and Susanne Beilenson detail the evidence for a cholinergic mediation of vasodilation in salivary glands: parasympathetic stimulation results in a characteristic dilator response in all species tested, and this response is blocked by atropine in doses which also stop the secretory response to nerve stimulation. There is one exceptional case, first observed by Heidenhain-the submaxillary gland of the cat-in which doses of atropine that fully block the secretory response to parasympathetic activation fail to impede the dilator response. The divergent explanations for this interesting dissociation between secretion and blood flow has become a cause celebre in the circulatory physiology of salivary glands. Lewis explains this atropine-resistant dilator response to parasympathetic stimulation in terms of a metabolic intermediary, the kallikrein-bradykinin system of the submaxillary gland. Kallikrein originates in the stimulated gland cells and enters the interstitial space, where it reacts with native protein to release the polypeptide bradykinin, the dilator action of which is atropine-resistant. Schachter challenges this explanation by showing that the circulation of submaxillary glands depleted of kallikrein or prevented from releasing bradykinin still responds normally to parasympathetic stimulation. He feels that the dissociation of responses to atropine is a case of difference in sensitivity to atropine between cholinergic secretory and dilator receptors. In view of the quality of these two strong cases, it seems appropriate to me to withhold my judgment and to allow the reader an intellectual exercise. Swan, Grossman, and I present a paper on the gastric circulation. After reviewing the world's literature on the subject, we felt that certain new methodological approaches were needed-essentially, measurement of gastric mucosal blood flow in the conscious animal during stimulation and inhibition of gastric secretion. We used a chronic pouch preparation for this purpose, employing aminopyrine clearance to determine mucosal blood flow and the electromagnetic flowmeter to measure total arterial inflow to the pouch. We found that changes in gastric secretion were accompanied by directionally corresponding changes in mucosal perfusion; e.g., histamine increased both secretory rate and mucosal blood flow, whereas pitressin inhibited both parameters. We also noted situations in which drugs acted directly upon the mucosal circulation without altering secretory rate. Total arterial inflow was unchanged in a number of circumstances in which mucosal blood flow was
5 336 ADVANCES IN GASTROINTESTINAL CIRCULATION Vol. 52, No.2, Part 2 increased, suggesting a redistribution of perfusion within the wall of the organ. Eugene Grim, who has applied Sapirstein's radioisotopic fractionation technique to measuring gastric blood flow, compares our results with aminopyrine clearance with his use of the isotopic method. In general, he finds that the two approaches yield similar results, except in response to epinephrine, and he suggests possible errors in the aminopyrine method which could account for the discrepancy. A group of cardiovascular physiologists in Gotenborg, Sweden, has accumulated a considerable body of new information about the circulation of the gut. This essay by the leader of that research team, Bjorn Folkow, is "must" reading for those who wish to know about the peripheral vascular physiology of the gut. Folkow defines his area carefully and describes the theory underlying the esoteric techniques that have been evolved in his laboratory. He discusses the evidence for "autoregulatory escape" and the redistribution of blood flow within the wall of the gut. Folkow completes his paper with an explanation of the countercurrent exchange mechanism in the gut which has been proposed by his group, and he speculates on its functional meaning. As often occurs when an interesting hypothesis is laid out, interesting objections arise from unexpected sources. Benjamin Zweifach raises objections to Folkow's countercurrent hypothesis based on microcirculatory architectural considerations. Whether these speculations will lead us to a deeper insight into regional adjustments of the intestinal circulation is conj ectural; what they do indicate at present is a more sophisticated view of the physiological redistribution of blood flow within the gut wall than the classical anatomists' picture of simple arteriovenous shunts. Paul Johnson, an outstanding authority on intestinal autoregulation (the maintenance of steady blood flow through the gut despite fluctuations in arterial blood pressure), spent a sabbatical year at Caltech with Harold Wayland. Some of the results of that collaboration are presented in his paper. After analyzing the prevalent explanations of autoregulation and his previous basis for fa voring a "myogenic" hypothesis, he delves into his recent work on the mesenteric microcirculation. Certain capillaries exhibited a measurable and rhythmical flow pattern which could be varied in response to alterations in intravascular pressure. From this and other related evidence, Johnson evolves a broader theory that he has previously entertained: mesenteric arterioles are flow-sensitive, whereas the precapillary sphincters are controlled by intravascular pressure changes. Flow at the local level of single capillaries does not, then, appear to be determined by metabolic requirements, which seem to operate at the somewhat higher level of the arterioles perfusing many capillaries. This view has borrowed from both metabolic and myogenic explanations of autoregulation. Lerner Hinshaw raises serious objection to the critical experiment Johnson has used in large vessel as well as microcirculatory studies, namely, the elevation of venous outflow resistance to vary intravascular pressure and blood flow in opposite directions. Hinshaw points out that two circulatory areas (the kidney and the liver) generally held to exhibit autoregulation by other criteria show opposite responses when exposed to a raised venous resistance. Is there a structural counterpart in the microcirculation of these organs to the new proposal by Johnson? For many years, the peripheral vascular physiologists under the direction of Francis Haddy have contributed to our knowledge of pressure-flow-resistance relationships in many circulatory areas. Their attention to the hemodynamics of the gut provides new insights into the multifactorial control of regional blood flow. In their present essay, a new factor is stressed which has not received much previous note, namely, the role of intestinal visceral smooth muscle as distinct from the vascular smooth muscle of the enteric circulation. Contractions and relaxation of muscular tissue around blood vessels are known to alter resistance to blood flow in
6 F ebrual'y 1967 JACOBSON 337 the wall of the heart, and a reasonable assumption would be that an analogous situation exists in the contracting or relaxing gut wall. Haddy and his colleagues use this wall factor to explain otherwise puzzling findings. An example is the ileal vascular response to epinephrine where vascular smooth muscle activity constricts, but the effect is offset by visceral smooth muscle relaxation, and there is little net change in over-all resistance to blood flow through the gut. A number of vasoactive substances were studied by Haddy's group, and an analysis of these responses, in the manner noted for epinephrine, is provided. This consideration of intestinal hemodynamic responses to common and naturally occurring vasoactive materials is extended by Harold Green in his discussion paper. The most consistent and intellectually satisfying "'big picture" of the pathogenesis of shock to emerge from the welter of studies in this field has been the concept championed by Jacob Fine. The vigor of his presentation has prompted many other investigations aimed at testing the validity of his view. In a brisk and colorful essay, Fine sets forth his over-all schema: the stress of shock (blood loss, etc.) prompts sympathetic nervous over activity which causes splanchnic ischemia; if prolonged, this inadequate perfusion cripples the ability of the reticuloendothelial system of the liver and spleen to clear circulating endotoxin from the gut; the superimposition of endotoxemia upon the shock state leads to severe damage of the vascular smooth muscle and an irreversibly lethal shock state. This concept has two attractions-it can be tested, and it suggests avenues of treatment in a clinical condition for which prognosis has been bleak. Among the novel therapeutic measures proposed by Fine which may be worthy of trial are celiac blockade to impede splanchnic sympathetic activity, the injection of splenic extracts, and perfusion of the circulation through an extracorporeal spleen to clear circulating endotoxins. A less startling measure which he and others advocate currently is the use of massive doses of an adrenal steroid, dexamethasone. Hiroshi Kuida provides a cool analysis of the concept, pointing to certain limitations evident from the work of other investigators. Sympathetic blockade with phenoxybenzamine is not a panacea in shock, and the germ-free animal is not proof against the lethal effects of hemorrhage. The final pair of papers in this Symposium give further consideration to the splanchnic hemodynamics of shock states. Fuad Bashour presents a series of extensive and detailed studies of the circulatory events in canine endotoxic shock and his interpretation of their meaning. The early response to endotoxin is hepatosplanchnic pooling and a diminished venous return to the heart. Postsinusoidal hepatic venules are the critical site, responding initially to the circulating toxin. Using both hemodynamic and metabolic evidence, Bashour concludes that the major splanchnic site suffering from ischemia in shock is the gut, rather than the liver. Lillehei's companion paper covers a great deal of conceptual ground, one of his major points being a unitary view of the hemodynamics of all shock states. My review of this large collection of information and ideas has been intended to stimulate reader interest. The collected papers of this Symposium contain much that has not previously been published. Aside from its novelty, the material represents the authoritative views of the "'expelts" which have been carefully and lucidly expressed. In this sense, it is a vital text on the circulation of the gastrointestinal tract. REFERENCES 1. Visceral circulation elba Foundation Symposium. Little, Brown and Company, Boston.