4. Endocrine physiology (Part 4).pptx

Do you stay and fight OR do you turn and run away? These are "Fight or Flight" responses

The Adrenal Glands:

Medulla (28%)

Cortex

• _{Essential for life}

• _{Glucocorticoid} (cortisol)

• Mineralocorticoid (Aldosterone)

• Androgen

deal with emergencies

• _Epinephrine

• _{Norepinephrine}

• _Dopamine

Adrenal medulla

• _{The medulla can be considered a sympathetic nervous system}

ganglion, which, in response to preganglionic sympathetic neuron stimulation, release of acetylcholine, and its binding to a cholinergic receptor in chromaffin cells,

stimulates the production and release of catecholamines.

The medulla is extremely vascular and consists of large chromaffin cells arranged in a network.

These cells synthesize and secrete the catecholamines

Catecholamine Transport

•

The half-life of circulating catecholamines is short

(< 2 minutes).

•

Most (>50%) of the catecholamines released

•

The physiologic effects of catecholamines are mediated

by binding to cell membrane

G protein–coupled

adrenergic receptors

distributed widely throughout the

body.

• _{Catecholamines have differential}

Effects of Epinephrine

& Norepinephrine:

- emotional stress (with which the individual is familiar)  NE

- in situations in which the individual does not know what

to expect  epinephrine

• _{Exert their effects on a group of plasma membrane receptors:}

β1, β2, α1 & α2. Epinephrine reacts well with β1 and β2 receptors but has less potency with α receptors.

1. they increase the force and rate of contraction of the isolated heart through β1 receptor medication (They also increase myocardial excitability, causing extrasystole and more serious arrythmias occasionally).

2. Through α1 receptors norepinephrine produce

vasoconstriction in most organs but epinephrine dilates the blood vessels in skeletal muscles and the liver through β2

receptor. So the total peripheral resistance falls.

Effects of Epinephrine & Norepinephrine

:

3. They

increase alertness

equally although in humans

epinephrine usually produces more anxiety and fear.

4. they

stimulate glycogenolysis in the liver

through

β

receptor also stimulate

gluconeogenesis

, by activation

of

α

receptors on the liver cells and increase muscle

glycogenolysis which increase plasma lactate levels.

Also epinephrine inhibits insulin mediated glucose

5. Epinephrine

increases basal metabolic rate

by

7-15%

6. Catecholamines

increase rennin release

by

stimulation of β receptors in the kidney. This

increases aldosterone secretion which enhances Na

retention.

7. Thyroid hormone secretion is enhanced by

Alpha adrenergic receptor

•

The increase in intracellular

Ca2+

calmodulin kinase–

mediated phosphorylation

of

myosin

light-chain kinase

in smooth muscle produces

contraction in vascular,

Summary:

Catecholamine

physiologic effect

• _{Most of the events involved in coping with a stressful situation require}

the expenditure of energy.

• _{Catecholamines ensure substrate mobilization from the liver, muscle,}

and fat (elevations in plasma glucose, glycerol, and free fatty acid

levels).

• _{Injected dopamine produces renal vasodilatation and also}

vasodilatation in the mesentery.

• _{Elsewhere it produces vasoconstriction it has a positively}

inotropic effect on the heart by an action on β1 receptors.

• _{(So dopamine is useful in the treatment of traumatic and}

cardiogenic shock).

Regulation of Adrenal Medullary Secretion

:

• _{Epinephrine and NE cause almost the same effects as direct}

stimulation of the sympathetic nerves in all parts of body.

• _{Thus perception or even anticipation of danger or harm}

(anxiety), trauma, pain, hypovolemia from hemorrhage or fluid loss, hypotension, anoxia, hypoglycemia, very high

temperature and severe exercise cause rapid secretion of them

• _{These stimuli are sensual at various higher levels in the SNS and}

Adrenal Cortex:

This is divided into three zones: 1. Zona Glomerulosa: the

outermost and makes up to 15% of the mass of adrenal gland and secretes aldosterone

(Mineralocorticoid).

2. Zona Fasciculata: 50% cortisol (75% of adrenal cortex) and secretes (Glucocorticoid).

Chemistry of the Adrenocortical Hormones:

• _{All the adrenocortical hormones are steroid compounds. They}

Transport and Fate of the Adrenal

Hormones

:

Adrenocortical Hormones are Bound to plasma PTN

approximately 90 to 95 % of the cortisol in the plasma binds

especially to a globulin (called cortisol-binding globulin or transcortin) and, to a lesser extent, to albumin.

This high degree of binding to plasma proteins slows the

elimination of cortisol from the plasma; therefore, cortisol has a relatively long half-life of 60 to 90 mins.

Only about 60 percent of circulating aldosterone combines with the plasma PTN, so about 40 percent is in the free form; as a

Functions of Mineralocorticoids

Aldosterone

:

1. Renal and Circulatory Effects:

Aldosterone causes

absorption of Na & excretion of K by the tubular epithelial cells especially in the collecting tubule

• _{So aldosterone causes Na to be conserved in the extracellular}

fluid while more K is excreted into the urine. So there is osmotic absorption of almost equivalent amounts of water & will

increase ECF volume without many changes in Na.

 _{Hypokalemia from excessive aldosterone some time reaches to}

• _{if high aldosterone secretion remain for 1-2 days and if ECF}

volume has increased to about 10-15% above normal in response to great excess of aldosterone the BP also has increased some 15-25 mmHg

which leads to greatly increased kidney excretion of both

water and salt and called pressure diuresis & natriuresis, and this returns the renal output of water & salt to normal despite excess aldosterone and this is called aldosterone escape.

• _{In contrast if aldosterone secretion become zero, very large}

amounts of salt are lost in the urine, the result is severe

To a much smaller extent, aldosterone causes

tubular secretion

of hydrogen ions

in exchange for Na. so, decreased H+

concentration in the ECF with a mild degree of alkalosis.

2. Effects of Aldosterone on Sweat Glands, Salivary

Glands and Intestinal Absorptoin:

It has the same effect by greatly increasing the reabsorption of NaCl and the secretion of K by the ducts so it’s important in sweat glands to conserve body salt in hot environments and in salivary glands to conserve salt when excessive quantities of saliva are lost. Aldosterone also increases Na absorption by the intestine.

Cellular mechanism of aldosterone action

• _{Genomic effect (main effect): increase PTN formation:}

• _{1. increase enzyme Na-K ATPase} • _{2. Increase Na channels}

• _{Thus, aldosterone does not have a major immediate effect on sodium}

transport;. About 30 minutes is required before new RNA appears in the cells, and about 45 minutes is required before the rate of sodium

transport begins to increase; the effect reaches maximum only after

several hours

• _{Other effect (non-genomic): within few sec.s or min.s, believed to be}

Regulation of Aldosterone Secretion

:

•

Zona glomerulosa cells function almost independently of

the zona reticularis & zona fasciculata.

•

Four different factors are known to play essential roles in

the regulation of aldosterone, these are:

1 .

K+ _{concentration of the extracellular fluid} . 2 . Renin-Angiotensin system . 3 .

Na+ _{ion concentration in the extracellular fluid}

.

4 .

Adrenocorticotropic hormone (ACTH)

.

*

• _{The first two are the most potent regulator:}

•

An increase in the plasma K

+

level

_{of only 1 mEq/L or less} stimulate aldosterone secretion. It stimulates the conversion of cholesterol to pregnenolone and the conversion of corticosterone to aldosterone.

•

Renin-Angiotensin system:

Angiotensinogen (synthesized in the liver). Renin (secreted from the juxtaglomerular cells of kidney) will split the angiotensin I from the angiotensinogen.

• _{Angiotensin I which is physiologically inactive will convert to}

Angeotensin II action

• _{Angiotensin II (AngII) is one of the most potent vasoconstrictors}

known.

• _{It also acts directly on the adrenal cortex to increase the}

secretion of aldosterone (the renin-angiotensin system is a major regulator of aldosterone secretion).

• _{it also acts on the brain to increase BP, increase water intake and}

increase the secretion of vasopressin (ADH) and ACTH.

Functions of the Glucocorticoids:

• _{At least 95% of the glucocorticoid activity results from the}

secretion of cortisol also known as hydrocortisone

1. Effect of Cortisol on Carbohydrate Metabolism:

• _{Cortisol stimulates gluconeogenesis 6-10 folds by the liver by}

activation of DNA transcription in the liver cell nuclei for the enzymes required to convert amino acids into glucose

• _{also cortisol mobilize amino acids from muscle to plasma to}

enter into the gluconeogenesis process of the liver.

• _{Increased gluconeogenesis leads to a marked increase in}

• _{Cortisol also causes a moderate decrease in the rate of glucose}

utilization by the cells everywhere in the body.

• _{The net result is increased the blood glucose concentration,}

occasionally 50% or more above normal and called adrenal diabetes

2. Effects on Protein Metabolism:

• _{Cortisol reduces protein stores in all body cells except liver by}

decreased protein synthesis and increased catabolism of protein in the cells (due to decrease a.a transport to the cell and depress formation of RNA) especially in the muscle and lymphoid tissues.

3. Effects on fat metabolism:

• _{Cortisol promotes mobilization of fatty acids from adipose}

tissue. With increased free fatty acid concentration in plasma, it also increase use of fatty acid for energy and enhances oxidation of fatty acids in the cells as well (part of this is by decreased

mobilization of glucose to fat cells).

• _{Cortisol also has a ketogenic effect which occurs only under}

4. Anti inflammatory effects:

when tissues are damaged by

trauma, by infection with bacteria or in any other way they almost always become inflamed. In some conditions the inflammation is more damaging than the trauma or disease itself. Cortisol:

•

Blocks the early stages of the inflammation process:

- _{It cause stabilization of the lysosomal}

membranes

- _{decreased permeability of capillaries}

- _{suppress migration of WBC, specially}

T lymphocytes in the inflamed area

•

If inflammation has already

begun, it

causes rapid resolution

of the inflammation

&

increase

rapidity of healing

.

• _{Cortisol blocks the inflammatory}

response to allergic reaction and

• _{cortisol decreases the number of eosinophils and lymphocytes in}

the blood and administration of large doses of cortisol causes

significant atrophy of all the lymphoid tissue throughout the body and both T-cells and antibodies from the lymphoid tissue will

decrease as a result the level of immunity is decreased.

• _{On the other hand this effect makes glucocorticoids most useful to}

prevent immunological rejection of transplanted organs as kidney.

• _{Cortisol increases RBC production and in excess cortisol}

polycythemia occurs.

Functions of Cortisol in Different Types of Stress:

• _{Almost any type of stress, physical or}

neurogenic, will cause an immediate and marked increase in ACTH secretion and

within minutes increased cortisol secretion.

• _{These probably occur because}

glucocorticoid causes rapid mobilization of

Some of different types of stress that

increase cortisol release are the following:

• _{Trauma of almost any type.} • _Infection

• _{Intense heat and cold.}

• _{Injection of norepinephrine and other sympathomimetic drugs.} • _{Surgical operations}

• _{Injection of necrotizing substances beneath the skin.} • _{Almost any debilitating disease.}

• _{Stress causes increase in plasma glucocorticoids to high}

Permissive Action of Glucocorticoids

:

•

Small amounts of glucocorticoids must be present for a

number of metabolic reactions to occur, although they

don’t produce the reaction by themselves, e.g.

glucocorticoid required for calorigenic effect of glucagons

and catecholamine.

•

Another example is for

catecholamine

to produce

Regulation of Cortisol Secretion

:

• _{Secretion of cortisol is controlled almost entirely by ACTH}

which also enhances the production of adrenal androgens and increases the sensitivity of the adrenal to subsequent dose of ACTH.

• _{High circulating levels of free glucocorticoids inhibit ACTH}

secretion the effect exerted at both the pituitary and the

Control of ACTH Secretion:

• _{CRH secreted by hypothalamus in anterior pituitary stimulates}

ACTH secretion. ACTH release is affected by:

• _{Circadian rhythm: highest level on waking in morning, lowest}

level on going to bed at night. This results from a 24 hour cyclic alteration in the signals from the hypothalamus. When a person changes daily sleeping habits. The cycle changes correspondingly

• _{Stress which is dominant control, e.g. trauma, pain, fever,}

hypoglycemia can lead within minutes to greatly enhanced ACTH

secretion.

• _{Negative feedback lowering cortisol levels as in primary adrenal}