Gastrointestinal Defence Mechanisms: Satellite Symposium of the 28th International Congress of Physiological Sciences, Pécs, Hungary, 1980

defence

CIRCULATORY RESPONSES TO CHANGES OF INTESTINAL CONTENTS

G. Szabó and I. Benyó,     Traumatological Research Unit and Third Department of Surgery, Semmelweis University Medical School, Budapest, Hungary

Publisher Summary

This chapter discusses experimental results on circulatory responses to changes of intestinal contents. The maximal increase in mesenteric blood flow is 150–200% but usually the augmentation is well below 100%. The blood flow has been measured to the gastrointestinal tract as a whole. The composition of the ingested food and its degree of digestion might be an important factor in the production of the gastrointestinal flow response. The concentration of nutrients in the jejunal lumen must exceed a certain value to produce local hyperemia and, generally speaking, the greater the concentration of nutrients in the chyme, the greater the resultant hyperemia. It has been reported that gastrointestinal hormones might play an important role in the postprandial intestinal vascular alterations. Shunts do not exist and accordingly, the redistribution of flow cannot occur. During vasodilatation elicited by intraluminal glucose or food, the spheres impacted in the deeper layer might migrate to the mucosa and consequently produce an apparent redistribution of intestinal blood flow.

Metabolic and circulatory changes during digestion and absorption of food were analysed already by Brodie et al. in 1910. Many studies have since confirmed that blood flow in the superior mesenteric vascular bed increases following a meal. This postprandial mesenteric hyperaemia has been observed in man /Brandt et al., 1955; Degenais et al. 1966/, conscious primate /Vatner et al. 1974/, anaesthetized and conscious dogs /Burns and Schenk, 1969; Fronek and Stahlgren, 1968; Varro et al., 1967; Vatner et al. 1970/ and rats /Reininger and Sapirstein, 1957/. The blood flow through the superior mesenteric artery in dogs starts to increase within 5 to 15 min following food intake, reaches a maximum in 30–90 and lasts for 3–7 h /Burns and Schenk, 1969; Fronek and Stahlgren, 1968; Vatner et al. 1970/. If food constituents are introduced directly into the duodenum the circulatory reaction begins in less than 10 min /Chou et al. 1976/.

The maximal increase in mesenteric blood flow is 150-200% but usually the augmentation is well below 100%. This seems to be a rather moderate increase because propranolol e.g. may produce a much greater augmentation of flow /Lundgren 1967/. There might be several reasons for the moderateness of this prostprandial vasodilatation. In the above studies the blood flow was measured to the gastrointestinal tract as a whole. It seems unlikely, however, that maximal vasodilatation occurs simultaneously in ever part of it. The vasodilatation might be localized to the mucosa with no or only moderate changes in the perfusion of the muscular layer. It seems that intestinal motility as such does not increase significantly total intestinal blood flow /Lundgren 1967/ and that the absorption of certain foods may not induce any conspicious flow changes /Brand et al. 1955/. The composition of the ingested food and its degree of digestion might be an important factor in the production of the gastrointestinal flow response. Moreover, certain food constituents may increase the blood flow in some part of the gastrointestinal tract, but be without effect on the circulation of other parts. Let us see a few examples for the above propositions.

While undigested food introduced into the duodenal or jejunal lumen failed to increase venous outflow from the exteriorized intestinal loop, digested food or its supernatant increased it significantly by 13% and 11%, respectively /Chou et al. 1976, 1978/. In the jejunum bile alone had no effect, but introduced in the ileal lumen it increased local blood flow and it also markedly enhanced the hyperaemic effect of digested food in the jejunum. Glucose solution increased the circulation of the isolated jejunal loop in the dog /Varró et al. 1967/. The intestinal hyperaemia is limited, however, only to the perfused teritory /Van Heerder et al. 1968/ and the increase of flow occurs mainly in the mucosal layer /Yu and al. 1975/. Intraduodenal fat augmented flow in the cat superior mesenteric artery by 50-100% /Fara and al. 1969/. At physiological postprandial concentrations in the jejunum micellar solutions of oleic acid and monoolein increased flow, but 16 common dietary amino acids did not. The hyperaemic effect of lipids required the presence of taurocholate /Chou and al. 1978/.

The concentration of nutritients in the jejunal lumen must exceed a certain value to produce local hyperaemia and, generally speaking, the greater the concentration of nutritients in the chyme the greater the resultant hyperaemia. The differences in circulatory effects are, however, not due to differences in the osmolarity of the solutions since an unabsorbeable substance with the same osmotic concentration does not increase intestinal blood flow /Kvietys and al. 1976/.

It seems, however, that the composition of the ingested food is not the only factor leading to haemodynamic changes. It was only recently realized that the cardiovascular system responds to feeding in two distinctly different phases. During presentation and ingestion of food cardiac output, heart rate arterial pressure and vascular resistance in various vascular beds are altered in a pattern similar to that observed at the increase in sympathetic neural activity. Within 5ndash;30 min, however cardiac output, heart rate, arterial pressure, the perfusion of the kidney and of the myocardium return to control levels, while mesenteric blood flow starts to rise. In humans anticipated feeding increases also vagally mediated gastric acid secretion /Moor and Motoki, 1979/. Pure psychic stimulation may be as effective stimulant as feeding. The observations suggest that in the first phase the anticipation and/or ingestion of food elicit a secretory and generalized cardiovascular reaction, in the second phase i.e. during the digestion when the ingested food reaches the intestines there is a circulatory response confined to the digestive organs /Burns and Schenk, 1969; Fronek and Fronek, 1970; Vatner et al., 1970, 1974/. On the other hand some textbooks state that there are nervous receptors in the walls of the duodenum stimulated by high concentration of hydrogen ions and that the acidification of the duodenal contents leads even in absence of any food to marked changes in gastrointestinal macro- and micromotility and secretory activity. The automatic movements of the intestinal villi are stimulated and their capillaries are dilated /Ludany et al. 1959/. The hepatic blood flow, measured with coupled thermoelements, hydrogen wash-out technique or BSP-clearance is significantly increased /Benyó et al., 1965, 1966, 1974/.

In the studies about the effect of various nutritients on gastrointestinal circulation usually only the superior mesenteric artery flow /SMAF/ has been measured. There are only a few informations available concerning the effect of a meal on coeliac artery flow, which supplies the liver, stomach, duodenum and pancreas. In order to gain information about the flow changes in the whole splanchnic vascular bed in the first series of our experiments we have studied in dogs with non-cannulating electromagnetic flow probes the effect of acidifying the duodenal contents on the blood flow in the hepatic artery and in the portal vein.

In 13 mongrel dogs the basal blood flow in the hepatic artery /HAF/ was 13.6 (SEM ± 1.3) ml / min/100 g tissue weight in the portal vein /PVF/ 46.6 ± 7.0 and total hepatic blood flow /HBF/ was 53.5 ± 6.3 ml/min/kg. After the introduction of 3 ml/kg body weight 0.1 M hydrochloric acid into the duodenal lumen HAF increased by 24.7%, PVF by 31.3% and HBF by 29.2%. Maximum HAF change was attained in 2 to 7 min and the reaction lasted 8 to 30 min. The arterial and venous reaction:-were usually not entirely synchronous. In the first minute after acid introduction there was usually a drop in arterial blood pressure, after which it returned to nearly control level. At the same time there was a small increase in portal venous pressure. Hepatic artery inflow resistance decreased by 11%. The most prominent change was the 32.5% drop in mesenteric arteriolar resistance. /Fig. 1, Fig 2/

Fig. 1 Effect of duodenal instillation of 0.1 and 0.5 M hydrochloric acid on hepatic artery /AHF/, portal vein /VPF/ and total hepatic blood flow /HBF/ in anaesthetized dogs.

F: blood flow, ml/min/100 g organ weight. White columns: before acid introduction; Shaded columns: after acid.

Fig. 2 The effect of duodenal acid introduction /arrow/ on arterial pressure /AP/, portal venous /PVF/ and hepatic artery blood flow /HAF/.

These experiments have shown that the introduction of acid into the duodenum leads to a transitory increase in mesenteric blood flow lasting about 30 min. If it is supposed that the flow reaction is due to chemoreceptor stimulation, it can be assumed that a stronger stimulus would elicit a greater response and that a prolonged stimulation leads to a sustained flow reaction. Actually in 5 dogs 3 ml/kg 0.5 M hydrochloric acid introduced into the duodenum increased HAF by 42% and PVF by 40%. In the same animals 0.1 M HCl produced only a 20% and 25% rise. A further group of animals received after the standard 3 ml/kg 0.1 M HCl dose a sustaining intraduodenal infusion of acid at a rate of 0.2–0.3 ml/min/kg. In these animals a prolonged flow reaction was observed, HAF and PVF remained high during the duration of acid infusion.

Next the question was raised whether the postulated chemoreceptors are confined to the duodenum or are they present also in some other part of the intestine. In 7 dogs after the introduction of the standard hydrochlorid acid dose into the upper jejunum HAF rose by 11% VPF by 16%, and HBF by 14%. In the same animals the increase in HBF after intraduodenal acid injection was 29%. This speaks in favor of the presence of receptors in the jejunal wall. The possibility cannot be excluded, however, that the flow reaction is a consequence of the regurgitation of the acid jejunal contents into the duodenum. Actually the vascular response was absent in the experiments where regurgitation was prevented by clamping the jejunum. But in this preparation the reaction could not be elicited even by the intraduodenal injection of concentrated, 0.5 M acid solution./Fig. 3./

Fig. 3 Effect of duodenal and jejunal introduction of 0.1 M HCl on hepatic artery /AHF/ portal venous /PVF/ and hepatic artery blood flow /HAF/.

Is the vascular reaction due to the stimulation of specific pH-sensitive chemoreceptors? Andrews and Andrews /1971/ investigated in rabbits the effect of introducing acid into the lumen of the duodenum on the frequency of action potentials in the afferent nerves. Hydrochloric acid, 0.1 and 0.5 M and acid sodium citrate, buffered with HCl to a pH less than 2, induced action potentials in the distal portions of cut mesenteric nerves coming from the part of duodenum exposed to the acid. Two types of response were noted. The authors therefore postulate the presence of two types of nerve receptors in the wall of the duodenum of rabbits which may be stimulated by acid in the lumen and they suggest that the concentration of hydrogen ions is the important factor. Two kinds of receptors were found also in anaesthetized sheep, where samples of single fibre activity were recorded from the cervical vagi whilst mechanical, chemical and electrical stimuli were applied to the surgically exposed mucosa of the fundus, pylorus and proximal duodenum /Harding and Leak 1972/. Both types, namely slowly adapting mechanoreceptors and rapidly adapting mechanoreceptors with chemoreceptor properties were found in all three locations. The first were briefly stimulated by tapping and brushing the mucosa. Steady high frequency spike dischanges were evoked by maintained strech of the stomach or the duodenum. Acid and alkali solutions did not affect the discharge. Similar stretch receptors have been described also in cat stomach and duodenum /Paintal, 1956; Iggo, 1957/. The second type of receptors were also stimulated by stroking but not by pressing the mucosa. In most cases these receptors were excited by acid and/or alkali solutions. Units responding to 0.05 M HCl gave after a longer latency comparable dischanges to various organic acids. Isotonic and hypertonic solutions of sucrose and NaCl were ineffective. It was concluded, that these receptors respond to both alkali and acid solutions by mechanisms affected by their normalities and their molecular weights or diffusion coefficients, but actually independent of their pH or pK values.

Whether the stimulation of alkali sensitive receptors may actually elicit vascular reactions remains to be proved. The activation of some mechano- or stretch receptors was ruled out in our experiments by the observation that the introduction of the same volume, i.e. 3 ml/kg physiological saline solution into the duodenum has no effect on HBF and PVF. On the other hand, after the introduction of 3 ml/kg 30% glucose solution HAF remained unchanged, but PVF increased by 8%. This change was not significant. The intraduodenal injection of 3 ml/kg of a 3.3% solution of a mixture of amino acids /hydrolized casein/ increased HAF by 5.6% and PVF by 13.6%. In the same animals 0.1 M HCl lead to a 18% and 32% increase, respectively. The response to amino acid administration may be due to a intraduodenal pH change because, the amino acid solution had a low pH. A 0.15 M phosphate buffer solution of the same pH increased HAF by 7.5% and PVF by 6%. Essentially, all these observations can be explained by the stimulation of acid sensitive intraduodenal chemoreceptors. It should be mentioned, however, that the parenteral administration of amino acid solutions also increases HBF /Hallberg and Soda, 1974/. /Fig. 4./

Fig. 4 Blood flow changes after the intraduodenal instillation of 0.1 M hydrochloric acid, 3.3% hydrolised casein solution /aminosol/ and 30% glucose.

The receptors in the duodenal mucosa can be blocked by the application of a local anaesthetic. This was shown in experiments where 5 min before acid administration 1 ml/kg of 1% lidocain solution was introduced into the duodenal lumen. The subsequent injection of 3 ml/kg 0.1 M hydrochlorid acid had no effect on HAF and PVF. In the same animals the introduction of the standard dose of acid increased before receptor blockade HAF by 20% and PVF by 29%. /Fig. 5./

Fig. 5 Effect of intraduodenal instillation of a local anaesthtetic on the circulatory response elicited by the acidification of duodenal contents.

White columns: blood flow before acid introduction; Shaded columns: flow after acidification. Δ%: per cent flow changes elicited by acidification before and after lidocain administration.

The flow response is elicited not exclusively by acidification. Fat, i.e. milk or corn oil introduced into the cat duodenum increased superior mesenteric artery blood flow by as much as 50 to 100%. The effect is due to the lipid component and it was reported that it can be blocked by vagatomy and atropine /Fara et al. 1969, 1970, 1972/.

In our experiments the vascular reaction to intraduodenal acid could not be blocked by bilateral cervical vagatomy. In these animals superior mesenteric artery flow /SMAF/ and PVF were measured with electromagnetic flowmeters. In the 11 dogs the standard dose of acid increased both SMAF and VPF by about 20%. After vagatomy acid introduction increased SMAF by 13.3% and PVF by 21.8%. Eight.dogs received after vagatomy 3 mg/kg atropine intravenously. In these animals the response to intraduodenal acid before atropine administration was a 18.9% increase in SMAF and a 19.1% increase in PVF. After parasympathetic blockade SMAF increased only by 7.4 and PVF by 15.8%. Accordingly, the response has been significantly reduced in the SMAF but remained nearly unchanged in other territories drained by the portal vein, i.e. in the organs supplied by the coeliac artery and in part also by the inferior mesenteric artery. In the SMAF arteriolar resistance which decreased after acid administration by 16% in normal and by 12% in vagotomized animals changed after atropine only by 9% and total splanchnic arteriolar resistance, which decreased in consequence of duodenal acidification in normals and in vagotomized animals by 19% and 15% respectively was reduced in the atropinized animals by intraduodenal acid by 14%. This difference was not significant /p > 0.05/. /Fig. 6. /

Fig. 6 Effect of vagatomy and vagatomy + atropine on the blood flow and vascular resistance changes after intraduodenal hydrochloric acid instillation. SMAF: superior mesenteric artery flow. PVF:. portal vein blood flow. RSMA: arteriolar resistance in the superior mesenteric territory. RSA: splanchnic arteriolar resistance. White columns: per cent changes after hydrochloric acid introduction before the intervention. Shaded columns: changes after acid introduction in the animals after vagotomy or vagotomy + atropine.

It could be shown, that the vascular response is actually due to changes in sympathetic vasomotor tone. In 9 dogs anaesthetized with pentobarbital the n. splanchnicus maior was transsected and the coeliac ganglion was denervated by cutting all pre- and postganglional nerve fibres. In these animals HAF was increased by intraduodenal acid prior to the denervation by 19% and PVF by 30.5%. After denervation there was no reaction to acid introduction. Neither was there any reaction to intraduodenal acid after the blockade of sympathetic α-receptors by phenoxybenzamine. In 7 animals before the α-receptor blockade 3 ml/kg 0.1 M hydrochloric acid increased HAF by 17.4% and PVF by 37%. After the intravenous administration of 2 mg/kg phenoxybenzamine acid introduction elicited only a small, not significant decrease in HAF. Interesting conclusions can be drawn from the analysis of the resistance changes: Surgical sympathetic denervation decreased arterial blood pressure by an average 19 mmHg, but HAF remained unchanged and PVF decreased by 11%. Hepatic artery and total mesenteric arteriolar resistance decreased by 17% and 13,5% respectively. Duodenal acidification did not lead to any further resistance change. In the same animals before denervation acidification decreased the resistances by 16% and 20% respectively. /Fig. 7, 8./

Fig. 7 Effect of denervation on the circulatory response elicited in the dog by intraduodenal acidification. White columns: blood flow before intraduodenal instillation of 3 ml/kg 0.1 M HCl. Shaded columns: blood flow after acidification.%: percent flow changes elicited by acid introduction.

Fig. 8 Effect of chemical sympathetic α-receptor blockade on the blood flow changes elicited by intraduodenal acidification.

The chemical blockade of α-receptors lead to a marked drop in arterial blood pressure from 139 to 80 mmHg. At the same time HAF decreased by 30% but PVF did not change significantly. The sympathetic blockade reduced significantly vascular resistance in the splanchnic vascular bed. HA inflow resistance was decreased by 17% and mesenteric arteriolar resistance by 42%. Acidification did not lead to any further decrease of vascular resistance. In the same animals before phenoxybenzamine administration intraduodenal acid reduced HA inflow resistance by 17% and mesenteric arteriolar resistance by 37%.

It can be concluded that the surgical and chemical sympathetic denervation both prevent the haemodynamic response to intraduodenal acid. Both interventions reduce, however, markedly the neurogenic vasomotor tone. In the first instance the loss of sympathetic tone is only regional and in the second it is generalized. Accordingly after surgical denervation the consequent haemodynamic changes are reflected by a moderate decrease in systemic arterial blood pressure and after chemical blockade by a marked pressure drop. In both instances splanchnic vasomotor tone decreased to about the same level as after duodenal acidification. The absence of subsequent reaction to acid instillation in the denervated animals suggests that the haemodynamic changes elicited by the stimulation of duodenal chemoreceptors are due to the reduction or abolition of the sympathetic vasomotor tone in the splanchnic vasculature.

The gastrointestinal vascular response to food intake may be governed by humoral agents. It is now generally recognized, that the mucosa of the gastrointestinal tract is the largest endocrine organ of the body /Johnson, 1977/. The gastrointestinal hormones are located in endocrine cells scattered throughout the gastrointestinal mucosa but their distribution is variable. For instance maximum gastrin concentration has been detected in the antral mucosa, GIP, motilin and most importantly CCK and secretin are restricted to the duodenum, jejunum and ileum. A large number of gastrointestinal polypeptide hormones has been isolated and purified and it became possible to analyse their effects by injecting the pure hormone. This lead to the realization that each hormone affected almost every function of every target organ, including secretion, motility and even mucosal growth.

The effect of the principal hormones on gastrointestinal blood flow has been also extensively studied. It was shown, that secretin, cholecystokinin and and GIP increase blood flow in the SMA and in the small intestine /Burns et Schenk, 1967; Fara et al. 1972; Ross, 1970; Fara and Salazar, 1978/. The possible role of a hormonal component in the postprandial mesenteric hyperaemia was suggested by Burns and Schenk /1967/. It was shown, that the increase of SMAF elicited in cats by the intraduodenal instillation of milk or corn oil could be mimicked by the intravenous injection of cholecystokinin /Fara and al. 1970/. The development of radioimmunoassay has made possible the ready measurement of the concentration of several hormones in blood plasma. It is now well established e.g. that the principal stimulus to gastrin release is feeding but it is Inhibited by acid in the lumen of stomach and duodenum /McGuigan and Trudeau, 1970; Yalow and Berson, 1970/. On the other hand the release of CCK-pancreozymin is stimulated by hydrochloric acid, fatty acids and amino acids. Its highest concentrations are found in the jejunum with smaller concentrations in the duodenum and ileum /Bloom and Bryant, 1973/. Secretin has its greatest concentrations in the duodenum and jejunum. Secretin release is elicited by the reduction of duodenal luminal pH to 4.5 or below /Johnson and Grossman 1968; Lee et al. 1970/ but in most studies it has not been possible to demonstrate secretin release after feeding /Kolts and McGuigan, 1977; Rayford et al. 1978; Lee et al. 1976/. Feeding or intraduodenal acidification is, however, the stimulus for the release of several other hormones, e.g. gastric inhibitory peptide /GIP/ /Ebert et al. 1976; Brown et al. 1975/ motilin /Brown, 1974/, pancreatic polypeptide /Polak et al.,1976/ and others.

This brief review shows that most hormones are widely distributed in the gastrointestinal mucosa, the release of many hormones is stimulated by the presence of various food constitutents in the lumen or by the change of luminal hydrogen ion concentration and that the parenteral introduction of some hormones increases SMAF or intestinal blood flow. An attempt was therefore made to demonstrate that physiological intraduodenal stimuli, such as food and its components, release sufficient endogenous hormones /in the first place CCK and secretin/ to account for the observed intestinal vasodilatation /Fara et al. 1972/. In this study in dogs the intraduodenal instillation of corn oil, 1-phenylalanine or hydrochloric acid induced increases in SMAF, pancreatic secretion and gall bladder and duodenal motility. All changes were mimicked by the intravenous infusion of low doses of CCK and secretin. In crossperfusion experiments after intraduodenal Instillation of fat in the donor animal a comparable mesenteric vasodilatation was seen in the recipient animal. It is believed that the hypothesis that Intraduodenal agents mediate the mesenteric vascular response through the release of intestinal hormones is further supported by the observation that the vascular reaction is blocked by vagotomy or atropine that interferes with the release of intestinal hormones. The vasodilatation occurs mainly in the intestinal and pancreatic vascular bed with a simultaneous increase in local O2 consumption. It is therefore suggested that the vascular changes are secondary to the metabolic effect of the hormones. This assumption is believed to be supported by the observation that secretin and CCK have in vitro no direct effect on the vascular wall /Fara,