Glucagon, which is present in gnathostomes but absent from agnathans, is a polypeptide molecule consisting of 29 amino acids. It strongly opposes the action of insulin, primarily through a hyperglycemic (blood glucose-raising) effect that results from its promotion of the breakdown of glycogen (glycogenolysis) in the liver, a process that results in the formation of glucose. Glucagon exerts its action by increasing the availability of the enzyme required for the reaction by which glucose units are released from the glycogen molecule. It also reduces the rate of synthesis of glycogen, promotes the breakdown of protein, promotes the use of fat as an energy source, and evokes increased glucose uptake by muscle cells. The last effect, however, may be a consequence of hyperglycemia induced by the increased secretion of insulin.

Another form of glucagon, called gastrointestinal glucagon, is secreted into the blood when glucose is ingested. Its only action appears to be to stimulate insulin secretion, an effect that may provide information to the islet cells of the pancreas about the entry of glucose into the bloodstream. It is also possible that pancreatic glucagon, which is secreted in the islets by the A cells, may directly stimulate the release of insulin from the adjacent B cells without actually entering the bloodstream.

A number of other hormones also influence the release of insulin, mainly through their own actions upon blood sugar levels. For example, growth hormone, thyroxine, epinephrine, and cortisol may increase insulin release because they can promote a rise in blood sugar through effects on carbohydrate metabolism. Growth hormone and cortisol may also act directly on the B cells.

The complexity and delicacy of the control of metabolism by insulin and other hormones in mammals illustrate again the importance of homeostasis, the control of which may not be as well organized in the lower vertebrates. Some of the responses in mammals, however, do occur in lower forms; for example, removal of pancreatic islet tissue from fishes produces hyperglycemia. Thyroxine induces hyperglycemia in amphibians, and corticosteroids promote gluconeogenesis in them. Far more information is needed, however, before the evolution of these remarkable regulating mechanisms can be determined.

Chromaffin tissue of the medulla

The adrenal gland of mammals is composed of an outer region, the cortex, which consists of adrenocortical tissue that secretes steroid hormones (steroids are fat-soluble organic compounds), and an inner region, the medulla, which is composed of chromaffin tissue, so called because its cells contain granules that can be characteristically coloured by certain reagents. Chromaffin tissue secretes two hormones, epinephrine and norepinephrine, which are members of a class of compounds called catecholamines. Both chromaffin and adrenocortical tissues are present in gnathostomes and probably in agnathans (although the evidence on the latter point is not yet decisive), but the tissues vary in the degree to which they are associated, being completely separated in elasmobranch fishes.

Norepinephrine and epinephrine are each composed of a benzene ring containing two hydroxyl (―OH) groups and an amine (NH₂-containing) side chain.

During the synthesis of these hormones, a sequence of enzyme-catalyzed reactions in the chromaffin granules of the secretory tissue transforms tyrosine into a compound commonly called dopa (dihydroxyphenylalanine), which then forms dopamine; dopamine then is hydroxylated (i.e., an ―OH group is added) to form norepinephrine. Epinephrine is formed from norepinephrine by methylation (the addition of a methyl, or ―CH₃, group), a reaction that occurs outside the granules of the chromaffin cells. Norepinephrine (but not epinephrine) is also formed in certain neurons, where it functions as a neurotransmitter.

After their release, both hormones are so rapidly metabolized that they probably remain in the bloodstream only for a few seconds. The first step in the breakdown, which usually occurs in the liver and kidneys, is methylation of one of the hydroxyl groups of the benzene ring. The products (metanephrine or normetanephrine), or compounds derived from them, are excreted in the urine. Small quantities (about 2 to 5 percent of the daily secretion of the gland in humans) of nonmetabolized hormones are also found in the urine.

Epinephrine and norepinephrine evoke diverse and widespread responses but differ from each other in certain of their effects. Both influence the heart and blood vessels in ways which, although opposed to each other in a few respects, generally result in an increase in blood pressure and in output of blood from the heart. Both hormones also have metabolic actions. Epinephrine, for example, like glucagon, stimulates glycogenolysis (breakdown of glycogen to glucose) in the liver, which results in the raising of the level of blood sugar; in addition, it increases oxygen consumption and the output of blood from the heart, probably contributing thereby to the regulation of body temperature in mammals. Epinephrine has effects on the nervous system, which are recognizable subjectively in humans by feelings of anxiety and of increased mental alertness.

The chromaffin tissue is closely related to the sympathetic nerves of the autonomic nervous system, which innervates the components of circulation and digestion and controls their involuntary functions. It is generally assumed that the chromaffin tissue and sympathetic nervous system together act to increase the capacity of the animal for effective action in emergencies. At such times, cardiac output increases, blood is distributed with maximum effectiveness, respiration is enhanced, and the nervous system is stimulated. The sympathetic nerves initiate these reactions and directly promote the release of epinephrine and norepinephrine because these nerves directly innervate the chromaffin cells. The hormones are thus able to develop and prolong an integrated set of responses. Norepinephrine functions both as a neurotransmitter of the sympathetic nervous system and also as a hormone of the chromaffin tissue.

The fact that epinephrine and norepinephrine, which have very similar molecular structures, can exert different actions is probably in part a consequence of the specialization of their target tissues. It has been suggested by some researchers that the target tissues possess two different kinds of receptors—the alpha type, which responds to norepinephrine, and the beta type, which responds to epinephrine. Evidence for this theory is that epinephrine has a vasodilator effect (expands blood vessels), which can be blocked by certain drugs, and norepinephrine has an opposing vasoconstrictor effect, which can be blocked by other drugs. The actions of both hormones are thought to be mediated by CAMP; alpha responses are associated with reduced synthesis of this mediator and beta ones with increased synthesis.

The interpretation of the function of these hormones in mammals has not yet been established as applicable to lower vertebrates in which the hormones are present, but they are known to influence metabolism and heartbeat in some genera. It is possible that in early stages of vertebrate evolution, chromaffin and sympathetic nervous tissues evoked more generalized physiological responses than they do today and that more precise action developed in mammals as part of their high level of homeostatic organization. Laboratory studies show that even in mammals the integrated activity of chromaffin and sympathetic nervous tissues is not essential for life; animals from which these tissues have been removed, however, are much less able to resist environmental stresses.

Adrenocortical tissue of the cortex

The adrenocortical tissue develops from coelomic epithelium (a cell layer surrounding the body cavity, or coelom). In this respect it resembles the endocrine tissue of the gonads, a resemblance emphasized by the fact that both the adrenocortical hormones (corticoids) and the sex hormones are steroids produced by similar metabolic pathways.

Many steroids have been isolated from the adrenal cortex, but in most vertebrate groups only three of them are active as hormones—cortisol (hydrocortisone; compound F), corticosterone (compound B), and aldosterone.

The principal sterol of animals is cholesterol, which is formed by a complex series of reactions from a two-carbon compound (acetate). Progesterone, which is derived from cholesterol, can be used to form either corticosterone and aldosterone or cortisol. All three corticoids are bound to proteins during transfer in the bloodstream to their targets; cortisol, for example, is bound to a glycoprotein called transcortin. Some inactivation of the corticoids takes place in the kidney and in the alimentary tract, but most of it occurs in the liver. The metabolic products, which eventually appear in the urine, provide a basis for determination of the output of adrenocortical hormones in humans.

The normal secretion of the hormones is best determined by direct measurement of the contents of the venous blood leaving the adrenal gland. In humans the daily secretion rates of the hormones as determined by this procedure are cortisol, 20 milligrams; corticosterone, two to five milligrams; and aldosterone, 75 to 150 micrograms (one microgram = one 1,000,000th of a gram). Very small amounts of aldosterone are secreted, because the molecule has a high level of activity.

Animal tissues maintained in culture fluid together with compounds from which the hormones are formed (e.g., acetate, cholesterol, or progesterone containing radioactive isotopes of carbon or hydrogen) show that cortisol and corticosterone are produced in all vertebrates, including the agnathans, although the proportion of each is species-dependent; elasmobranch fishes are unique, however, in having 1-α-hydroxycorticosterone as the principal hormone. Aldosterone is produced by all terrestrial vertebrates. It has also been found in bony fishes, although its function in them has not yet been established as a hormonal one. The presence of aldosterone has not yet been established in elasmobranchs and agnathans, but, whether or not this particular molecule occurs in them, the ability to synthesize corticoids must have evolved very early in vertebrate history.

In contrast to the chromaffin tissue of the adrenal medulla, the adrenocortical tissue is essential for life. Two primary functions of the corticosteroids are distinguishable in mammals. One, which contributes to the regulation of carbohydrate metabolism, is an action of cortisol and corticosterone, which are therefore called glucocorticoids. These hormones promote gluconeogenesis in the liver and are thus important in maintaining normal blood sugar levels, particularly during glucose shortage; lack of them results in low levels of blood sugar and an increase in the sensitivity of the liver to insulin (whose effect there is to decrease gluconeogenesis). In addition, lack of the glucocorticoids is associated with a decrease in the entry of amino acids into muscles and an increase in their uptake by the liver, where enzymes required to convert amino acids to glucose must be synthesized.

In contrast to glucocorticoid action is the so-called mineralocorticoid action of aldosterone, which is manifested in mammals in the regulation of sodium metabolism. In the absence of aldosterone, sodium is lost from the body by excretion in urine; secondary consequences include a decrease in blood volume and in the filtration rate of substances through kidney structures called glomeruli. Cortisol and corticosterone also play a minor part in mineral regulation, so that slight overlap in function occurs between the two corticoid types.

The action of aldosterone is exerted mainly upon the distal segment of the nephron (kidney tubule), where it promotes an increase in the permeability of the tubule membrane to the passage of sodium, and also an increase in the quantity of sodium removed into the blood from the fluid passing through the kidney tubule. At the same time, potassium and hydrogen pass into the fluid from the blood. Aldosterone also exerts other effects. It promotes sodium retention in salivary glands, in sweat glands, and in the colon of the large intestine; it also promotes the excretion of magnesium in the urine. The effects of aldosterone result in an increase in the rate of synthesis of enzymes required to transport these substances through membranes.

Other actions of the corticoids are apparent in patients suffering from Addison disease, which is caused by a general deficiency in corticoid production. A deficiency of corticoids causes disturbances in urinary output and fat metabolism, diminished resistance to stress, muscular weakness, and nervous disturbances manifested by depression and a general lack of mental alertness. The adrenocortical hormones, then, like the hormones of the chromaffin tissue of the medulla, are involved in resistance to stress. It has been postulated that the response to alarm stimuli initially involves both the chromaffin and sympathetic complex and the adrenocortical secretion; then a stage of full resistance occurs that may be followed by mental exhaustion if the alarm stimuli are prolonged. Although a close functional relationship is known to exist between the adrenocortical and chromaffin tissues in mammals, the function of the corticoids in the lower vertebrates has not yet been established. Indications are, however, that the general pattern of action may be similar; for example, the cortisol type of corticoid promotes gluconeogenesis in fish and removal of adrenocortical tissue impairs the metabolism of water and ions in the eel. Any interpretation of corticoid action in teleost, or bony, fishes has to incorporate prolactin, for, as has been noted previously, this hormone also influences the movement of ions.

In contrast to the chromaffin cells, the adrenocortical cells are not innervated. Both cortisol and corticosterone production are regulated by the action of ACTH from the pituitary gland on the zona reticularis and the zona fasciculata. The regulation of aldosterone secretion in the zona glomerulosa, however, is associated with the so-called renin–angiotensin system, which is best characterized in mammals. Renin, an enzyme with a molecular weight of about 40,000, is formed in the kidney and is released into the bloodstream, where it catalyzes the formation of angiotensin, a polypeptide molecule. Angiotensin acts upon smooth muscle and raises blood pressure. In humans it reduces sodium excretion, probably by a direct action on kidney filtration, and may, in fact, be a true hormone, acting to aid sodium retention. In addition, however, angiotensin contributes to sodium retention by increasing aldosterone secretion.