EDITORIALS INTESTINAL MOTOR ACTIVITY AND BLOOD FLOW

Transcription

1 GASTROENTEROLOGY Copyright 1970 by The Williams & Wilkins Co. Vol. 58, No.4 Printed in U.S.A. EDITORIALS INTESTINAL MOTOR ACTIVITY AND BLOOD FLOW The operating guidelines of scientific thought are often informal generalizations which bridge the space between the few laws and the many facts. One generalization of this type in physiology could be stated as follows: organ function and perfusion are related bidirectionally. By this is meant that changes in the activity of an organ will induce changes in blood flow to the organ and vice versa. One can cite many situations in the physiology of organs which confirm the generalization. In the gastrointestinal tract, for example, increasing activity of secretory organs such as the salivary glands, stomach, and pancreas is accompanied by an increase in blood flow to the organs. l There are three modes by which alteration in the function of an organ could evoke a change in blood flow. These mechanisms can be labeled neurohumoral, local metabolite, and mechanical. The neurohumoral mechanism is evident when autonomic nervous stimulation causes near simultaneous increases in organ function and blood flow. Claude Bernard first described this mechanism in the salivary glands. 2 The mechanism can be seen as well during infusion of neurohumoral mediators such as acetylcholine or catecholamines. The second mechanism involves chemicals derived from cellular activity, substances like adenosine triphosphate, Krebs intermediates, polypeptides, amines, or CO 2 (and hypoxia), which are dilator metabolites for the most part. The great English physiologist, Joseph Barcroft, first Received October 27, Address requests for reprints to: Dr. Eugene D. Jacobson, Department of Physiology and Biophysics, University of Oklahoma Medical Center, Oklahoma City, Oklahoma called attention to this mechanism, again in the salivary glands. 3 The third mechanism is seen in muscular organs like the heart, where activity means generation of high levels of tension in the muscle mass, thereby impeding the flow of blood through the contracting muscles. This mechanical influence on coronary perfusion has been described particularly by members of the Wiggers' school, who demonstrated a higher blood flow in the coronary arteries during relaxation of the ventricles than during systolic contraction. 4,5 On a priori grounds one would expect all three mechanisms to operate when the vagus nerves stimulate intestinal motility. In a lucid speculation about this phenomenon in the gut, Haddy et al. concluded that the circulatory response to motor activity would reflect all three factors, with the cholinergic and metabolic factors tending to increase and intestinal muscle contractions operating to decrease blood flow to the gut. 6 It is not possible at this point in time to prove in detail all aspects of the idea that intestinal perfusion is the vector of these three forces; however, recent work from our laboratory has confirmed the essenti fils of this concept. 7 - lo Early workers were concerned with the relationship between perfusion and wall tension in the gut in terms of an extreme situation, obstruction and ileus leading to ischemic necrosis of the bowel. l1 - l5 They concluded that passive distension of the wall by gas or fluid impeded blood flow and was a significant mechanism in precipitating the gangrenous process. It would be difficult to argue that mechanical resistance evoked by chronic distension is not significant in the pathophysiology of strangulation and gangrene; nevertheless, other

2 576 EDITORIALS Vol. 58, No.4 factors cannot be excluded, especially reflex neurogenic constriction and absorption of toxic substances leading to local and systemic circulatory collapse. The precise place of mechanical slowing of perfusion in a distended gut segment is not clear in terms of a train of events producing tissue necrosis. Subsequently, many physiological studies confirmed the fact that passive distension of the wall diminished the flow of blood through the gut In some of these reports attention also was focused upon increases in wall tension which occur with active contraction of gut musculature This introduces a more complex situation, since active contractions mean increased m e t a b activity o l i ~ of the muscle cells, as well as increased vagomotor and local cholinergic nerve activity. Both of these factors work oppositely from simply increasing wall tension. One of the earlier studies of intestinal circulation focused upon arteriovenous oxygen differences in the distended gut. Lawson and Ambrose 17 concluded that the rate of oxygen consumption was unrelated to changes in blood flow resulting from distension of the gut. Distension nearly always caused an increase in intestinal venous oxygen content and a transient decrease in blood flow, suggesting shunting of blood through non nutritive regions. The transient nature of flow reduction may have been secondary to tissue hypoxia which signaled a later compensatory increase in perfusion. The Lawson-Ambrose study17 is significant because it alone attempted a search into the problem of blood flow distribution within the wall of the gut during distension. The lack of adequate methods to measure tissue blood flow (then and now) kept their conclusions III the speculative state. A more quantitative description of the state of the intestinal wall during distension has been supplied by Scott and Dabney who related the distending luminal volume to intraluminal pressure to provide an estimate of wall compliance. IS Their over-all conclusion was that the net change in blood flow during active or passive muscle movements in the gut wall would be the vector of neurohumoral, local metabolic, and mechanical factors (wall compliance).6 One implication of this view is the unpredidable nature of the circulatory response to active contraction of the wall or to infused drugs. Sidky and Bean studied rhythmic and tonic contractions of the intestinal wall occurring spontaneously in gut preparations They concluded that there were two over-all effects of contractions upon the circulation: (a) tonic contractions diminished blood flow and (b) rhythmic contractions caused a reciprocal periodicity in arterial and venous flows due to a positive pumping action of the visceral musculature on the blood vessels. These studies were carried out on isolated perfused gut segments. More recent work by Geber,28 using an in situ preparation in which perfusion was natural, did not confirm the presence of an intestinal peristaltic pump. Injection of drugs into the mesenteric artery has been used to assess the relationship between intestinal motor activity and blood flow Boatman and Brody27 found that intraarterial acetylcholine caused an initial increase and a later decrease in resistance to blood flow through the gut; the increase in resistance coincided with the contraction of the gut wall induced by the drug. This description of vascular responses was not, however, identical with findings from other 6 -s. 18 investigations of the cholinergic effect. As one looks over the bulk of the work cited in this review, several methodological limitations become apparent. Nearly all studies were conducted on a short segment of small gut whose perfusion was regulated by a constant flow pump or was measured by methods requiring interruption of vascular integrity. Furthermore, the choice of anesthetic was usually pentobarbital, which has strong antivagal properties. Limited intestinal segments may be easy to use technically, but events in one segment of ileum may not be representa-

3 April 1970 EDITORIALS 577 tive of the entire small bowel. A constant flow pump introduces serious artifacts for several reasons, not the least being that Johnson has shown that the normal regulation of mesenteric blood flow depends upon a freely variable blood flow 30 ; fixing flow with a pump dampens the system. Thus, in many investigations into the nature of the intestinal circulatory-motor relationship, a preparation was used in which either blood flow or intestinal muscle action or both were unable to vary freely. In order to obviate these methodological shortcomings, an iii situ preparation was reported in which chloralose was the anesthetic, blood flow was freely variable, vascular integrity was preserved, and the entire small gut and its blood supply were studied. 7, S In these investigations intraarterial infusion of acetylcholine resulted in rhythmic changes in intraluminal pressure (type II waves) accompanied by sizable increases in mesenteric artery blood flow. Intestinal muscle activity also was increased by angiotensin II, which decreased blood flow. s Motor activity and blood flow both were diminished by norepinephrine, whereas blood flow was increased and motor activity decreased by prostaglandin E1. Bradykinin increased both motor activity and blood flow. The authors concluded that the effects of intraarterial vasoactive drugs on intestinal motor function did not correlate with the response of the mesenteric circulation. s Investigations from our laboratory9 have focused upon the apparent discrepancies between earlier experiments which were restricted by various limitations of their intestinal preparations and the more recent in situ studies. From the earlier work, using mainly perfused gut segments, we had concluded that augmented motor activity of the gut impeded blood flow by mechanically compressing the blood vessels. On the other hand, in situ studies indicated that circulatory responses to drugs reflected essentially the vasoactive properties of the infused agent and were independent of intestinal motor activity. Using three quite different intestinal preparations (in vitro metabolically poisoned, in vitro, and in vivo) we found consistent results which permitted these conclusions: (a) passive distension of the gut wall by raismg intraluminal pressure impeded blood flow through the gut; (b) active contractions (induced by acetylcholine) also impeded blood flow if the contractions were sufficiently vigorous; (c) acetylcholine was a vasodilator in the mesenteric circulation and its intraarterial injection resulted in an increased blood flow if contractions of the wall were not too vigorous; (d) there was no evidence of a peristaltic pump effect during rhythmic contraction of the intestinal wall; (e) the impedence to blood flow through the wall during persistent stretch was transient, not unlike the phenomenon of autoregulatory escape described with persistent sympathetic,31 catecholamine,s, 29 or angiotensin s input into the mesenteric circulation. A summary position seems in order from the current vantage point. The intestinal circulation is not independent of motor activity by the muscle mass of the gut wall. Blood flow also is affected during passive stretch of the wall, as by the gas or fluid content of an intestinal segment. The net effect of increased tonus or stretch in the wall is impedence to blood flow through the wall. When the increase in muscle movement has been prompted by acetylcholine or other potent vasoactive drugs, the mesenteric circulation usually will respond mainly to the drug and secondarily to changes in motor activity. The effects of local metabolites and autoregulatory phenomena do not appear to be important during acute motor responses; however, with persistent elevations of wall tension, these occult local vascular processes may be significant in the over-all regulation of blood flow through the motile gut. How does all of this relate to the moment-by-moment circulatory traffic during eating, resting, exercise, or emotional upset? The answer is, "We don't know." Until methods are available to monitor intestinal blood flow continuously in conscious

4 578 EDITORIALS Vol. 58, No.4 man, there has to remain a credibility gap between our esoteric laboratory data and the human situation. E UGENE D. JACOBSON, M.D. GUENTHER F. BROBMANN, M.D. GERHARD A. BRECHER, M.D., PH.D. Department of Physiology and Biophysics University of Oklahoma M edical Center Oklahoma City, Oklahoma REFERENCES 1. J acobson, E. D Secretion and blood flow in the gastrointestinal tract. In C. F. Code [ed.], Handbook of physiology. Sect. 6, Vol. II, p American Physiological Society, Washington, D. C. 2. Bernard, C De I'influence de deux ordres de nerfs qui determinant les variations de couleur du sang vein eux dans les organes glandularies. C. R. Acad. Sci. [D] (Paris) 47: Barcroft, J The gaseous metabolism of the submaxillary gland. III. The effect of chorda activity on the respiration of the gland. J. Physial. (Landon) 27 : E ckstein, R W., M. Stroud, C. V. Dowling, and W. H. Pritchard F actors influencing changes in coronary flow following sympathetic nerve stimulation. Amer. J. Physiol. 162: Gregg, D. E., and L. C. Fisher Blood supply to the heart. In W. F. H amilton [cd.], Handbook of physiology. Sect. 2, Vol. II, p American Physiological Society, Washington, D. C. 6. Haddy, F. J., C. Chou, J. B. Scott, and J. M. Dabney Intestinal vascular responses to naturally occurring vasoactive substances. Gastroenterology 52: Price, W. E., Z. Shehadeh, G. H. Thompson, L. D. Underwood, and E. D. J acobson Effects of acetylcholine on intestinal blood flow and motility. Amer. J. Physiol. 216: Shehadeh, Z., W. E. Price, and E. D. Jacobson Effects of vasoactive agents on intestinal blood flow and motility in the dog. Amer. J. Physiol. 216: Brobmann, G. F., E. D. Jacobson, and G. A. Brecher Effects of distension and acetylcholine on intestinal blood flow in vivo. Angiologica. In press. 10. Jacobson, E. D Effects of histamine, acetylcholine, and norepinephrine on gastric vascular resistance. Amer. J. Physiol. 204: Van Zwalenburg, C Strangulation resulting from distension of hollow viscera. Ann. Surg. 46: Van Beuren, F. T., Jr Relation between intestinal damage and delayed operation in acute mechanical ileus. Ann. Surg. 72: Dragstedt, L. R, V. F. Lang, and R F. Millet The relative effects of distension on different portions of the intestine. Arch. Surg. (Chicago) 18: Gatch, W. D., H. M. Trusler, and K. D. Ayers Effects of gaseous distension on obstructed bowel. Arch. Surg. (Chicago) 14: Gatch, W. D., and C. G. Culbertson Circulatory disturbance caused by intestinal obstruction. Ann. Surg. 102: Lawson, H., and J. Chumley The effect of distension on blood flow through the intestine. Amer. J. Physiol. 131: Lawson, H., and A. M. Abrose The utilization of blood oxygen by the distended intestine. Amer. J. Physiol. 135: U Scott, J. B., and J. M. Dabney Relation of gut motility to blood flow in the ileum of the dog. Cire. R es. 14: suppl. 1, Chou, C., and J. M. Dabney Interrelation of ileal wall compliance and vascular resistance. Amer. J. Dig. Dis. 12: Dabney, J. M., J. B. Scott, and C. C. Chou Effects of cations on ileal compliance and blood flo w. Amer. J. Physiol. 212: Hanson, K. M., and F. T. Moore Pressure-volume relationship and blood flow in the distended colon. Amer. J. Physiol. 217: Hanson, K. M., and F. T. Moore Effects of intraluminal pressure in the colon on its vascular pressure-flow relationship. Proc. Soc. Exp. Bioi. M ed. 131: Bean, J. W., and M. M. Sidky Intestinal blood flow. Fed. Pro e. 9: Bean, J. W., and M. M. Sidky Intestinal blood flow as influenced by vascular and motor reactions to acetylcholine and CO. Amer. J. Physiol. 194: Sidky, M. M., and J. W. Bean Local and general alterations of blood CO.

5 April 1970 EDITORIALS 579 and influence of intestinal motility in regulation of intestinal blood flow. Amer. J. Physwl. 167 : Sidky, M. M., and J. W. Bean Influence of rhythmic and tonic contraction of intestinal muscle on blood flow and blood reservoir capacity in dog intestine. Amer. J. Physiol. 193: Boatman, D. L., and M. J. Brody Effects of acetylcholine on intestinal vasculature of the dog. J. Pharmacol. Exp. Therap. 142: Geber, W. F Intestinal blood flow-pressure responses during control and induced peristalsis. Arch. Int. Pharmacodyn. 157: Ross, G Effects of epinephrine and norepinephrine on the mesenteric circulation of the cat. Amer. J. Physiol. 212: Johnson, P. C Autoregulation of blood flow in the intestine. Gastroenterology 52: Folkow, B Regional adjustments of intestinal blood flow. Gastroenterology 52: