Understanding the Human Machine - A Primer for Bioengineering - Max E. Valentinuzzi

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	SG	S	M
	St	G	St	GJ
				Pe
	D			Pa
			PJ
				L
			B	GB
	SI	CCK-PZ
			Se

Figure 2.57. MAIN SECRETIONS OF THE GIS. SG = salivary glands; Sa = saliva; M = mouth. The stomach, St, secretes gastrin, G, which in the same stomach stimulates the production of gastric juice, GJ, and pepsin, Pe. SI = small intestine secretes chole- cystokinin-pancreozymin, CCK-PZ, and secretin, Se, to stimulate pancreatic juice secretion and the gall bladder contraction, respectively. The liver, L, sends bile into the gall bladder, GB, and the latter into the duodenum, D.

Figure 2.57 summarizes in a block diagram the main secretions (hormones and juices) of the gastrointestinal system. There are several websites that can be visited to fetch detailed information about this subject.

One good piece is http://www.kutchai/medphys/handouts/gi-secr.doc, www.hsc.virginia.edu/med-ed/phys/pdf/Gi_secr.pdf .

2.5.4. Perfusion

Mesenteric circulation and splanchnic circulation are terms many times used as synonims, however, the former actually refers specifically to the intestinal vasculature while the latter encompasses the blood flow to all the viscera within the abdominal cavity.

Figure 2.58 summarizes the main avenues giving also some numerical values. It can be observed that the liver receives blood from two important inputs: from the hepatic artery, to take care of its tissue needs, and from the portal vein, to supply via its exchanger the hepatic parenchyma with the substances to be metabolized and stored in it. The first one, supplying in the order of 700 mL of blood/min, feeds the hepatic artery, HA, which carries into the liver 500 mL/min to satisfy the tissue needs of this organ, and distributes also blood to the stomach, St, the spleen, Sp, and the pancreas, Pa. The SMA carries another 700 mL/min with ramifications to the pancreas, the small intestine, SI, and the colon, Co. Finally, the IMA, with 400 mL/min, completes the blood supply to the colon. The

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TO THE RIGHT HEART
HV	AORTA
PV	HA
L
St	CA
Sp
Pa
SI	SMA
CO	IMA

Figure 2.58. SIMPLIFIED DIAGRAM OF THE SPLANCHNIC CIRCULATION. The descending abdominal aorta gives off three main branches: the celiac (CA), the superior mesenteric (SMA) and the inferior mesenteric (IMA) arteries.

portal vein, PV, high in nutritive contents loaded mainly through the small intestinal capillaries, returns blood to the liver at a rate of 1,300 mL/min, by far much more than its tissue needs because this blood goes into the delicate hepatic sinusoids. The liver parenchyma is the place of essential metabolic and storing processes. The hepatic veins, HV, return blood to the vena cava and, from there, on to the right heart.

The liver is an essential station for the sustenance of life. Claude Bernard, around 1860, already recognized its importance. Any substance, good or bad, that we ingest is metabolized in the liver. Nutrients, among them —such as glucose— are metabolized, elaborated and stored in the liver to be delivered later on to satisfy body needs. The liver acts, for example, as a glucostat to regulate the blood sugar level.

To think about: Many times, say at mid-afternoon, we feel some dizziness and headache, especially when already tired after some demanding work. However, by sheer will we keep on going and soon the headache and weakness vanish. It was hypoglycemia, that is, our sugar level went down. We could have quickly solved the discomfort by taking a cup of tea with a couple of cookies to restore the normal glycemia, but we did not, and the liver sensing the deviation released glucose into the blood stream from its glycogen reserves. Thus, it was an “internal cup of tea” served by the liver. The student is advised to dig further into the meanings of glucose, glycemia, glycogen, and glucostat.

No wonder then that knowledge of the hepatic blood supply is of paramount significance. Based on a simple linear model, similar to that de-

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veloped previously for the kidneys, a method for its determination will be outlined (Valentinuzzi, 1971b). Let us remind the definition of a portal system, schematically represented in Figure 2.54, as one that connects two capillary exchangers, in this case the intestinal network with the hepatic sinusoids.

Figure 2.59 depicts succinctly the procedure: The liver is considered a node where the continuity principle can be applied under steady state conditions, that is,

φaCa +φpCp =φhCh +Qo

(2.106)

where φa, φp, and φh are, respectively, the average blood flows of the hepatic artery, portal vein and hepatic veins, while Ca, Cp, and Ch stand for the corresponding concentrations of the indicator. A fraction Qo, expressed in mg/min, is the amount of indicator coming out of the biliary duct.

The indicator is constantly infused via a peripheral vein at a rate of Qi mg/min until the stationary condition is reached when Qi = Qo, that is,

		HL
samples					HA	φa Ca
		L			PV	φp Cp
HV φhCh
			BC		Qo
										IC
Samples

PC

Qi

Figure 2.59. HEPATIC BLOOD FLOW DETERMINATION. The heart-lung HL supplies blood through the aorta (above). One of its branches is the hepatic artery HA going into the liver. It carries a flow φa , in mL/min, which has a concentration Ca of an indicator substance, in mg/mL. The indicator is constantly infused via a peripheral vein at a rate of Qi mg/min. The intestinal capillaries IC are represented by the loop on the lower right, receiving blood from the arterial supply and converging into the portal vein PV, with flow φp carrying a concentration Cp of indicator. From the liver exits also the biliary canal BC which dumps bile into the intestine at a rate of Qo mL/min.

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such substance (as sulphobromophtalein sodium) must not be taken up by any tissue and only has to be excreted through the liver to the intestine through the biliary duct. Besides, and for the same reason, the arterial and portal concentrations are constant and equal, that is, Ca = Cp = C. As a consequence, equation (2.106) simplifies to

(φa +φp)C =φhCh +Qi			(2.107)
from which the hepatic blood flow φh can be solved for as
φh =	Qi		(2.108)
	[C − C h ]

because φa +φp = φh . Notice that the latter equation is nothing but the

dilution principle already described in the Cardiovascular Section. The numerical value of Qi is the rate of indicator administration, C is obtained by analyzing blood samples removed from a peripheral vein and Ch requires catheterization of one of the hepatic veins or a surgical procedure. In the dog, a typical value is 35 mL/min per kg of body weight, i.e., a 30 kg animal is expected to have an hepatic flow of about 1 L/min. Since cardiac output is in the order of 8%–9% of body weight (or 2.5 L/min, at rest), hepatic flow would represent 40% of the total cardiac outflow. In man, hepatic flow is about 25 to 35% of cardiac output in resting adults.

More detailed information on the liver, especially on its pathologies, can be obtained from Howard J. Worman, Division of Digestive and Liver Diseases, Departments of Medicine and of Anatomy and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, E-mail: [e-mail]. He has an excellent INTERNET site.

2.5.5. Exchangers

The gastrointestinal exchanger is highly complex and, actually, is divided in two sections: the intestinal exchanger, with its capillary network, and the hepatic sinusoids or hepatic capillaries, both connected by the portal vein. The portal blood, especially after a meal, is well loaded with nutritive substances (carbohydrates, aminoacids and lipids). Transport from the intestinal lumen to the capillary blood is essential for life. This is the absorptive function of the intestine.

Such function takes place mainly at the level of the jejunum and ileum, with a total length of about 6.5 m in the adult. The caliber goes from 3

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cm in the duodenal-jejunal angle, decreasing gradually to 2 cm at the beginning of the large intestine. The ileocecal valve marks the limit between both intestinal sections. After that, the large intestine becomes much larger in diameter. Several hundred grams of carbohydrates are being absorbed per day plus 100 or more grams of fatty acids, including monoglycerides and cholesterol, 50 to 100 g of aminoacids, 50 to 100 g of different ions (such as Na, K, Mg and the like) and 8 to 10 liters of water. However, the absorptive capacity of the small intestine is much greater than these values.

The intestinal mucosa acts as an amplifier. Its surface area is approximately 100 times the skin body surface, that is, it is in the order of 200 m2 (an adult’s body surface area ranges from 1.5 to 2 m2, typically 1.75). Such enormous contact area is attained by successive convolutions: intestinal loops, mucosal convolutions, intestinal cilia or villi, and epithelial microcilia. Each villus has a capillary network with a small arterial input, a small output venula and a central exit lymphatic vessel, everything in a countercurrent arrangement to improve the exchange efficiency (see the Renal System). Intestinal lymphatics play a significant role in the absorption of fatty acids. Absorptive mechanisms are passive and active and many are still not well understood.

Using the GOOGLE searching engine and the words “intestinal absorption”, an interactive computer-simulation of experiments that may be performed on one of the classical in vitro preparations — the isolated, everted intestinal sac of the rat — can be found. The authors are David Dewhurst, Jake Broadhurst, Peter and Jacqueline Hardcastle, who are part of the 2000 Sheffield Bioscience Programs, in England (David Dewhurst, [e-mail]).

2.5.6. Control and Regulation

Control and regulation of the GI system recognize different origins without existing at all a unique center to collect and integrate the information. There are autonomic nervous factors as well as hormonal and local ones. Also, the central nervous system plays an important role.

The autonomic system — both parasympathetic (with the vagus nerves as major representatives) and sympathetic branches — innervates the stomach and the intestine. Besides, there are two nervous plexuses — Auerbach and Meissner — intrinsic to the gastrointestinal tract. The

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plexuses are interconnected and contain nerve cells with processes that originate in receptors in the wall of the gut or the mucosa. They are responsible for peristaltic contractions while coordinated motor activity occurs in the total absence of extrinsic innervation. Generally speaking, cholinergic stimulation (typically of vagal origin) increases intestinal activity while the adrenergic discharge (typically sympathetic) has an opposite effect.

Reflexes play a definite role in GI control and regulation. Let us briefly review the most important. Details can be found in specialized bibliography or in INTERNET:

Deglutition or swallowing. It is controlled via the vagus nerves and a center in the medulla oblongata. Initiation is voluntary after collection of the oral content. Thereafter, a wave of involuntary pharyngeal muscle contractions is triggered that pushes the bolus into the esophagus. Inhibition of respiration and glottic closure are part of the reflex response.

Enterogastric reflex. The entry of chyme into the duodenum stimulates duodenal chemo and mechanoreceptors. This inhibits gastric motility by inhibiting the vagal nuclei in the medulla, thus slowing the transport of material from the stomach. It also activates sympathetic fibers that cause the pyloric sphincter to tighten. The intrinsic plexuses mediate the inhibitory effects, by long autonomic pathways and by the release of several duodenal hormones (such as secretin and other inhibitory hormones known collectively as enterogastrones). In other words, since the duodenum is full and has a small capacity, the reflex provides a protective mechanism to prevent further food entry into the small intestine.

Gastroileal reflex. Enhanced activity of the stomach initiates the gastroileal reflex, which is a long reflex that enhances the force of segmentation in the ileum. When the gastric content leaves the stomach, the ileocecal valve relaxes letting chyme get from the ileum — last portion of the small intestine — into the ascending colon. Presumably, this is a reflex mediated by vagal activity.

Gastrocolic reflex. This reflex is the colon’s equivalent to the gastroileal reflex in the small intestine, and is responsible for initiating mass movements. Distension of the stomach trigger contractions of the colon and rectum and, frequently, it leads to defecation. Every mother knows well the quick baby’s response after nursing or feeding it the bottle. Babies do

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not yet have the social inhibitions of the adults. Apparently, the reflex is not neurally mediated and may be due o the action of gastrin on the colon.

Defecation. It is a complex action requiring coordination and sequential activation of a large number of muscles. It is controlled by the autonomic nervous system, but is also under voluntary control. Defecation is initiated by distension of the rectum by feces arriving from the sigmoid colon. This sensation leads to a chain of events that ends in expulsion of feces from the anus. The act of defecation is voluntarily controlled in healthy, normally functioning people.

A mechanism of intestinal blood flow regulation. Blood flow to the intestinal bed is essential for normal activity but highly variable depending on the activity of the individual. After a heavy meal, when there is predominance of the parasympathetic vasodilating discharge, it is highly increased and playing a football game is not advisable nor the subject feels

	Glucose, AA and Na
	absorption
	Increased Metabolic
	Activity of Enterocytes
	Relative local hypoxia	Negative
	Release of dilating metabolites
		Feedback
Arteriolar	Precapillary Sphincters
Relaxation
	Relaxation
Increased	Increase in	More O2
Blood Flow	Circulating Nutrients	Availability
	Increased Washout of
	Dilating Metabolites

Figure 2.60. MESENTERIC BLOOD FLOW REGULATION. This interesting mechanism links the intestinal absorption of glucose, aminoacids (AA) and sodium to the amount of blood supplied to the region. The relative local hypoxia generated by the metabolic activity of the ciliary enterocytes plus the release of dilating metabolites are central actors in the process.

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like doing it. Conversely, when ready to perform a heavy exercise or during it, the sympathetic activity is enhanced with a consequent vasoconstrictor action on the splanchnic region and all the reflexes described above are inhibited.

There is a neat feedback coupling between the absorptive intestinal activity and the amount of blood to the region (Jacobson, 1982). The activity of the ciliary enterocytes during absorption of glucose, aminoacids and sodium generates a relative local hypoxia and the release of dilating metabolites (Figure 2.60). The latter induce arteriolar and capillary presphincter relaxation, which, in turn, increase the blood flow to the intestinal bed. This results in a better circulation of nutrients, more oxygen availability plus the washout of the same initial dilating metabolites. The end result is the compensatory effect of the triggering local hypoxia. Thus, the system keeps balancing from hypoxia to normoxia according to the enterocytes absorptive activity while the arterioles and capillary sphincters change their calibers to regulate the blood supply to the region.

2.5.7. Closing Remarks of Section 5

All the GIS activity aims at the exchange of substances that in the end must sustain viable cells and tissues. The exchanger is actually divided in two separated sections: an absorptive one — intestinal — and a metabolic exchanger — hepatic — the latter storing in its parenchymal cells a number of essential compounds. The portal vein connects both sections. It is easy then to understand the harmful and even lethal effects of the socalled malabsorption syndromes (due, for example, to the lack of certain enzymes or to surgical partial ablation). By the same token, hepatic degenerative processes (as cirrhosis) can also lead to serious and sometimes irreversible conditions.

Since we have here introduced already the concept of secretion, it is a good time to better clarify the current recognized types and their respective definitions. They will be useful. They are also referred to as types of chemical communication or mediation. The suffix –crine derives from the Greek word krinein, to separate or elaborate products, and is attached to a prefix that modifies its meaning. Etymologically, ‘secretion’ is the Latin equivalent and has exactly the same meaning. These substances can also be considered as mediators. Thus,

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Exocrine secretion or mediation: Since exo means ‘outside’, it is a secretion that goes out, usually via a duct. Saliva, pancreatic juice and bile are typical examples we have mentioned above. The student is encouraged to find other examples.

Endocrine secretion or mediation: Since endo means ‘inside’, it is substances secreted into the blood vessels to act on distant target cells. They are called collectively ‘hormones’ and the paragraphs above have already introduced a few of them, such as secretin, which was the first to be discovered.

Intracrine secretion or mediation: It regulates intracellular events. Examples are the second messenger systems.

Autocrine secretion or mediation: The prefix means ‘self’. They are substances secreted outside the cell that influence the same cell. Thus, there are autoreceptors.

Paracrine secretion or mediation: The prefix here means ‘near’ or ‘from the side of’. They are substances that influence adjacent cells. Neurotransmitters are typical examples.

Ectocrine secretion or mediation: The prefix means ‘outside’. They are substances released into the environment to communicate with other individuals. Examples are the pheromones. Smell is usually the detecting organ (a male animal follows the track of a female in heat).

For the time being, learn well the first two concepts and just read the four latter and know they exist. In due time, they will show up again and in more detail. To complement the concepts of this section, there are in the libraries several textbooks of recent editions (Rhoades & Tanner, 1995; Guyton & Hall, 1996; Henderson, 1996; Cormack, 1998; Fox, 1999; Christensen, 2001, the latter via INTERNET).

A last historical tip: William Beaumont (1785–1853) was a pioneer investigator in the area of gastric physiology. A rather attractive and colorful piece of history frame his significant contributions. In 1809, Beaumont began “reading” under Dr. Benjamin Moore. There were few medical schools in the U.S., so it was common to be trained by reading medical subjects under the direction of an established physician. In 1812, the Medical Society of Vermont approved William to practice surgery. That same year, Beaumont enlisted as a surgeon's mate in the U.S. Army. That event in his life marked for many years to come his interests and activities.

On June 6, 1822, in the American Fur Company on Mackinac Island, a French–Canadian voyageur named Alexis Saint Martin was accidentally shot in the upper left abdomen. The

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musket wound was “more than the size of the palm of a man's hand,” Beaumont wrote after examining the patient, “and affected part of a lung, two ribs, and the stomach”. Beaumont was unsuccessful in fully closing the hole. The patient was now unable to work as a voyageur, so in April 1823, Beaumont hired him as the family's live-in handyman (would you do a thing like this?). A voyageur's job was to paddle a canoe to pick up furs from Indian trappers to deliver to the fur company. The hole in St. Martin's side was a permanent open gastric fistula, large enough that Beaumont could insert his entire forefinger into the stomach cavity.

It was not until 1825 that Beaumont began his experiments with St. Martin, becoming the first person to observe human digestion as it occurs in the stomach. Beaumont tied pieces of food to the end of a silk string and dangled the food through the hole into St. Martin's stomach. Beaumont pulled out the string one, two, and three hours later, to observe the rate of digestion for the different foods. He even took samples of gastric juice to observe the rate of digestion of a piece of meat, while also placing the same-sized piece of meat directly into the stomach. The stomach digested the meat in two hours; the vial of gastric juice took 10 hours. The experiments shown that gastric juice has solvent properties. Saint Martin returned to Canada, so Beaumont was unable to experiment on him further at this time.

In June 1829, Alexis St. Martin returned to the Beaumonts, this time bringing his family. One set of observations was to try to determine any relation between digestion and weather. By observing St. Martin on different days and times and in varying weather conditions, Beaumont saw that dry weather increases stomach temperature, and humid weather lowers it. He also learned that gastric juice needed heat to digest (cold gastric juice has no effect on food). Beaumont found that vegetables are less digestible than other foods. St. Martin sometimes became irritable doing experiments, and Beaumont observed that being angry can hinder one's digestion. In April 1831, St. Martin and his family left for their home in Canada.

Beaumont located Alexis St. Martin in October 1832 and traveled with him to Washington, D.C., where he again tried different foods. Beaumont focused on gastric juice, but did not study the importance of saliva on digestion. Another limitation on Beaumont's work is that he could not obtain a chemical analysis of the gastric juice, as chemical analysis was severely limited in the mid-nineteenth century. Beaumont published in 1833 his results in a famous book, “Experiments and Observations on the Gastric Juice and the Physiology of Digestion”. Sometime later, St. Martin left for Canada; he expected to rejoin Beaumont for more experiments, but as it turned out, St. Martin and Dr. Beaumont never again saw each other.