„ INTRODUCTION Medulla is the inner part of adrenal gland and it forms 20% of the mass of adrenal gland. It is made up of interlacing cords of cells known as chromaffin cells. Chromaffin cells are also called pheochrome cells or chromophil cells. These cells contain fine granules which are stained brown by potassium dichromate. Types of chromaffin cells Adrenal medulla is formed by two types of chromaffin cells: 1. Adrenaline-secreting cells (90%) 2. Noradrenaline-secreting cells (10%). „ HORMONES OF ADRENAL MEDULLA Adrenal medullary hormones are the amines derived from catechol and so these hormones are called catecholamines. Catecholamines secreted by adrenal medulla 1. Adrenaline or epinephrine 2. Noradrenaline or norepinephrine 3. Dopamine. „ PLASMA LEVEL OF CATECHOLAMINES 1. Adrenaline : 3 μg/dL 2. Noradrenaline : 30 μg/dL 3. Dopamine : 3.5 μg/dL „ HALF-LIFE OF CATECHOLAMINES Half-life of catecholamines is about 2 minutes. „ SYNTHESIS OF CATECHOLAMINES Catecholamines are synthesized from the amino acid tyrosine in the chromaffin cells of adrenal medulla (Fig. 71.1). These hormones are formed from phenylalanine also. But phenylalanine has to be converted into tyrosine. Stages of Synthesis of Catecholamines 1. Formation of tyrosine from phenylalanine in the presence of enzyme phenylalanine hydroxylase 2. Uptake of tyrosine from blood into the chromaffin cells of adrenal medulla by active transport 3. Conversion of tyrosine into dihydroxyphenylalanine (DOPA) by hydroxylation in the presence of tyrosine hydroxylase 440 Section 6tEndocrinology FIGURE 71.1: Synthesis of catecholamines. DOPA = Di- hydroxyphenylalanine, PNMT = Phenylethanolamine-N- methyltransferase. 4. Decarboxylation of DOPA into dopamine by DOPA decarboxylase 5. Entry of dopamine into granules of chromaffin cells 6. Hydroxylation of dopamine into noradrenaline by the enzyme dopamine beta-hydroxylase 7. Release of noradrenaline from granules into the cytoplasm 8. Methylation of noradrenaline into adrenaline by the most important enzyme called phenylethanolamine- N-methyltransferase (PNMT). PNMT is present in chromaffin cells. „ METABOLISM OF CATECHOLAMINES Eighty five percent of noradrenaline is taken up by the sympathetic adrenergic neurons. Remaining 15% of noradrenaline and adrenaline are degraded (Fig. 71.2). FIGURE 71.2: Metabolism of catecholamines. COMT = Catechol-O-methyltransferase, MAO = Monoamine oxidase. Stages of Metabolism of Catecholamines 1. Methoxylation of adrenaline into meta-adrenaline and noradrenaline into metanoradrenaline in the presence of ‘catechol-O-methyltransferase’ (COMT). Meta-adrenaline and meta-noradrenaline are together called metanephrines 2. Oxidation of metanephrines into vanillylmandelic acid (VMA) by monoamine oxidase (MAO) Removal of Catecholamines Catecholamines are removed from body through urine in three forms: i. 15% as free adrenaline and free noradrenaline ii. 50% as free or conjugated meta-adrenaline and meta-noradrenaline iii. 35% as vanillylmandelic acid (VMA). „ ACTIONS OF ADRENALINE AND NORADRENALINE Adrenaline and noradrenaline stimulate the nervous system. Adrenaline has significant effects on metabolic functions and both adrenaline and noradrenaline have significant effects on cardiovascular system. „ MODE OF ACTION OF ADRENALINE AND NORADRENALINE – ADRENERGIC RECEPTORS Actions of adrenaline and noradrenaline are executed by binding with receptors called adrenergic receptors, which are present in the target organs. Chapter 71tAdrenal Medulla 441 Adrenergic receptors are of two types: 1. Alpha-adrenergic receptors, which are subdivided into alpha-1 and alpha-2 receptors 2. Beta-adrenergic receptors, which are subdivided into beta-1 and beta-2 receptors. Refer Table 71.1 for the mode of action of these receptors. „ ACTIONS Circulating adrenaline and noradrenaline have similar effect of sympathetic stimulation. But, the effect of adrenal hormones is prolonged 10 times more than that of sympathetic stimulation. It is because of the slow inactivation, slow degradation and slow removal of these hormones. Effects of adrenaline and noradrenaline on various target organs depend upon the type of receptors present in the cells of the organs. Adrenaline acts through both alpha and beta receptors equally. Noradrenaline acts mainly through alpha receptors and occasionally through beta receptors. 1. On Metabolism (via Alpha and Beta Receptors) Adrenaline influences the metabolic functions more than noradrenaline. i. General metabolism: Adrenaline increases oxygen consumption and carbon dioxide removal. It increases basal metabolic rate. So, it is said to be a calorigenic hormone ii. Carbohydrate metabolism: Adrenaline increases the blood glucose level by increasing the glycogenolysis in liver and muscle. So, a large quantity of glucose enters the circulation iii. Fat metabolism: Adrenaline causes mobilization of free fatty acids from adipose tissues. Catecholamines need the presence of glucocorticoids for this action. 2. On Blood (via Beta Receptors) Adrenaline decreases blood coagulation time. It increases RBC count in blood by contracting smooth muscles of splenic capsule and releasing RBCs from spleen into circulation. 3. On Heart (via Beta Receptors) Adrenaline has stronger effects on heart than nor- adrenaline. It increases overall activity of the heart, i.e. i. Heart rate (chronotropic effect) ii. Force of contraction (inotropic effect) iii. Excitability of heart muscle (bathmotropic effect) iv. Conductivity in heart muscle (dromotropic effect). 4. On Blood Vessels (via Alpha and Beta-2 Receptors) Noradrenaline has strong effects on blood vessels. It causes constriction of blood vessels throughout the body via alpha receptors. So it is called ‘general vasoconstrictor’. Vasoconstrictor effect of noradrena- line increases total peripheral resistance. Adrenaline also causes constriction of blood vessels. However, it causes dilatation of blood vessels in skeletal muscle, liver and heart through beta-2 receptors. So, the total peripheral resistance is decreased by adrenaline. Catecholamines need the presence of glucocor- ticoids, for these vascular effects. 5. On Blood Pressure (via Alpha and Beta Receptors) Adrenaline increases systolic blood pressure by increasing the force of contraction of the heart and cardiac output. But, it decreases diastolic blood pressure by reducing the total peripheral resistance. Noradrenaline increases diastolic pressure due to general vasoconstrictor effect by increasing the total peripheral resistance. It also increases the systolic blood pressure to a slight extent by its actions on heart. The action of catecholamines on blood pressure needs the presence of glucocorticoids. TABLE 71.1: Adrenergic receptors Receptor Mode of action Response Alpha-1 receptor Activates IP3 through phospholipase C Mediates more of noradrenaline actions than adrenaline actions Alpha-2 receptor Inhibits adenyl cyclase and cAMP Beta-1 receptor Activates adenyl cyclase and cAMP Mediates actions of adrenaline and noradrenaline equally Beta-2 receptor Activates adenyl cyclase and cAMP Mediates more of adrenaline actions than noradrenaline actions IP3 = Inositol triphosphate 442 Section 6tEndocrinology Thus, hypersecretion of catecholamines leads to hypertension. 6. On Respiration (via Beta-2 Receptors) Adrenaline increases rate and force of respiration. Adrenaline injection produces apnea, which is known as adrenaline apnea. It also causes bronchodilation. 7. On Skin (via Alpha and Beta-2 Receptors) Adrenaline causes contraction of arrector pili. It also increases the secretion of sweat. 8. On Skeletal Muscle (via Alpha and Beta-2 Receptors) Adrenaline causes severe contraction and quick fatigue of skeletal muscle. It increases glycogenolysis and release of glucose from muscle into blood. It also causes vasodilatation in skeletal muscles. 9. On Smooth Muscle (via Alpha and Beta Receptors) Catecholamines cause contraction of smooth muscles in the following organs: i. Splenic capsule ii. Sphincters of gastrointestinal (GI) tract iii. Arrector pili of skin iv. Gallbladder v. Uterus vi. Dilator pupillae of iris vii. Nictitating membrane of cat. Catecholamines cause relaxation of smooth muscles in the following organs: i. Non-sphincteric part of GI tract (esophagus, stomach and intestine) ii. Bronchioles iii. Urinary bladder. 10. On Central Nervous System (via Beta Receptors) Adrenaline increases the activity of brain. Adrenaline secretion increases during ‘fight or flight reactions’ after exposure to stress. It enhances the cortical arousal and other facilitatory functions of central nervous system. 11. Other Effects of Catecholamines i. On salivary glands (via alpha and beta-2 receptors): Cause vasoconstriction in salivary gland, leading to mild increase in salivary secretion ii. On sweat glands (via beta-2 receptors): Increase the secretion of apocrine sweat glands iii. On lacrimal glands (via alpha receptors): Increase the secretion of tears iv. On ACTH secretion (via alpha receptors): Adrenaline increases ACTH secretion v. On nerve fibers (via alpha receptors): Adrenaline decreases the latency of action potential in the nerve fibers, i.e. electrical activity is accelerated vi. On renin secretion (via beta receptors): Increase the rennin secretion from juxtaglomerular apparatus of the kidney. „ REGULATION OF SECRETION OF ADRENALINE AND NORADRENALINE Adrenaline and noradrenaline are secreted from adrenal medulla in small quantities even during rest. During stress conditions, due to sympathoadrenal discharge, a large quantity of catecholamines is secreted. These hormones prepare the body for fight or flight reactions. Catecholamine secretion increases during exposure to cold and hypoglycemia also. „ DOPAMINE Dopamine is secreted by adrenal medulla. Type of cells secreting this hormone is not known. Dopamine is also secreted by dopaminergic neurons in some areas of brain, particularly basal ganglia. In brain, this hormone acts as a neurotransmitter. Injected dopamine produces the following effects: 1. Vasoconstriction by releasing norepinephrine 2. Vasodilatation in mesentery 3. Increase in heart rate via beta receptors 4. Increase in systolic blood pressure. Dopamine does not affect diastolic blood pressure. Deficiency of dopamine in basal ganglia produces nervous disorder called parkinsonism (Chapter 151). „ APPLIED PHYSIOLOGY – PHEOCHROMOCYTOMA Pheochromocytoma is a condition characterized by hypersecretion of catecholamines. Cause Pheochromocytoma is caused by tumor of chromophil cells in adrenal medulla. It is also caused rarely by tumor of sympathetic ganglia (extra-adrenal pheochromocytoma). Chapter 71tAdrenal Medulla 443 Signs and Symptoms Characteristic feature of pheochromocytoma is hyper- tension. This type of hypertension is known as endocrine or secondary hypertension. Other features: 1. Anxiety 2. Chest pain 3. Fever 4. Headache 5. Hyperglycemia 6. Metabolic disorders 7. Nausea and vomiting 8. Palpitation 9. Polyuria and glucosuria 10. Sweating and flushing 11. Tachycardia 12. Weight loss. Tests for Pheochromocytoma Pheochromocytoma is detected by measuring meta- nephrines and vanillylmandelic acid in urine and Cathecolamines in olasma

Silk Road

A vast network of trade routes created during the Han Dynasty in China that connected the East to the West.

Han Dynasty

The Chinese dynasty during which the Silk Road was established.

Silk

A valuable fabric that was one of the main goods traded along the Silk Road.

Trade routes

Paths or networks over which goods and services are traded.

Spices

Valuable goods exchanged along the Silk Road, used for flavoring and preserving food.

Tea

A beverage made from the Camellia sinensis plant, traded along the Silk Road.

Porcelain

A fine ceramic material that was another valuable trade item along the Silk Road.

Precious metals

Gold and silver that were traded on the Silk Road.

East to West

The geographical direction that the Silk Road connected through trade.

Valuable goods

Items of high worth, such as silk, spices, and porcelain, that were traded on the Silk Road.

Cultural exchange

The sharing of ideas, products, and culture as a result of trade along the Silk Road.

Merchants

Traders who traveled along the Silk Road to exchange goods.

Caravans

Groups of travelers, often merchants, who traveled together for safety along the Silk Road.

Silk production

The process of creating silk, primarily developed in ancient China.

Caravanserais

Roadside inns along the Silk Road providing lodging for merchants and travelers.

Economic impact

The influence of the Silk Road on trade and commerce in ancient economies.

Cultural diffusion

The spread of cultural beliefs and social activities from one group of people to another through the Silk Road.

Goods transported

Items moved from one location to another along the Silk Road.

Traders' routes

Paths taken by merchants while traveling the Silk Road.

Marketplaces

Trading centers where goods exchanged hands along the Silk Road.

Exotic goods

Rare items such as spices and silk that were highly sought after on the Silk Road.

Ancient civilizations

Historical societies involved in trade along the Silk Road, such as those in China, India, and Persia.

Silk trade

The commerce involving silk, a crucial part of the economic transactions on the Silk Road.

Westward expansion

The movement of people and goods towards the Western regions facilitated by the Silk Road.

Imports and exports

Goods brought into a region and those sent out, significant in Silk Road trade.

Buddhism

A religion that spread from India to China along the Silk Road.

Cultural artifacts

Objects made and used by humans that reflect the culture and history, often exchanged on the Silk Road.

Political influence

The power to affect decisions and policies, seen in regions impacted by Silk Road trade.

Silk Road cities

Important towns and cities situated along the Silk Road where trade flourished.

Trade alliances

Agreements made between merchants to facilitate trade along the Silk Road.

Economic exchange

The act of trading resources and goods, prevalent across the Silk Road.

Innovation

The introduction of new ideas and technologies as a result of interactions along the Silk Road.

Globalization

The process of interaction and influence among people and countries, seen historically with the Silk Road.