Demo – Physiology

There are three primary stimuli of gastric secretion, each with a specific role to play in matching the rate of secretion to functional requirements. Gastrin is a hormone that is released by G cells in the antrum of the stomach both in response to a specific neurotransmitter released from enteric nerve endings, known as gastrin releasing peptide (GRP, or bombesin), and also in response to the presence of oligopeptides in the gastric lumen. Gastrin is then carried through the bloodstream to the fundic glands, where it binds to receptors not only on parietal (and likely, chief cells) to activate secretion, but also on so-called enterochromaffin-like cells (ECL cells) that are located in the gland, and release histamine. Histamine is also a trigger of parietal cell secretion, via binding to H2 histamine receptors. Finally, parietal and chief cells can also be stimulated by acetylcholine, released from enteric nerve endings in the fundus.
During the cephalic phase of gastric secretion, secretion is predominantly activated by vagal input that originates from the brain region known as the dorsal vagal complex, which coordinates input from higher centers. Vagal outflow to the stomach then releases GRP and acetylcholine, thereby initiating secretory function. However, before the meal enters the stomach, there are few additional triggers and thus the amount of secretion is limited. Once the meal is swallowed, on the other hand, meal constituents trigger substantial release of gastrin and the physical presence of the meal also distends the stomach and activates stretch receptors, which provoke a “vago-vagal” as well as local reflexes that further amplify secretion. The presence of the meal also buffers gastric acidity that would otherwise serve as a feedback inhibitory signal to shut off secretion secondary to the release of somatostatin, which inhibits both G and ECL cells as well as secretion by parietal cells themselves. This probably represents a key mechanism whereby gastric secretion is terminated after the meal moves from the stomach into the small intestine. Gastric parietal cells are highly specialized for their unusual task of secreting concentrated acid. The cells are packed with mitochondria that supply energy to drive the apical H,K-ATPase, or proton pump, that moves H+ ions out of the parietal cell against a concentration gradient of more than a million-fold. At rest, the proton pumps are sequestered within the parietal cell in a series of membrane compartments known as tubulovesicles. When the parietal cell begins to secrete, on the other hand, these vesicles fuse with invaginations of the apical membrane known as canaliculi, thereby substantially amplifying the apical membrane area and positioning the proton pumps to begin acid secretion. The apical membrane also contains potassium channels, which supply the K+ ions to be exchanged for H+, and Cl– channels that supply the counterion for HCl secretion. The secretion of protons is also accompanied by the release of equivalent numbers of bicarbonate ions into the bloodstream, which are later used to neutralize gastric acidity once its function is complete.
The three agonists of the parietal cell—gastrin, histamine, and acetylcholine—each bind to distinct receptors on the basolateral membrane . Gastrin and acetylcholine promote secretion by elevating cytosolic free calcium concentrations, whereas histamine increases intracellular cyclic adenosine 3',5'-monophosphate (cAMP). The net effect of these second messengers are the transport and morphological changes described above. However, it is important to be aware that the two distinct pathways for activation are synergistic, with a greater than additive effect on secretion rates when histamine plus gastrin or acetylcholine, or all three, are present simultaneously. The physiologic significance of this synergism is that high rates of secretion can be stimulated with relatively small changes in availability of each of the stimuli. Synergism is also therapeutically significant because secretion can be markedly inhibited by blocking the action of only one of the triggers (most commonly that of histamine, via H2 histamine antagonists that are widely used therapies for adverse effects of excessive gastric secretion, such as reflux).
(Ganong’s Review of Medical Physiology 23rd Edition)

Spermatogenesis
Maturation of Sperm Begins at Puberty
Spermatogenesis, which begins at puberty, includes all of the events by which spermatogonia are transformed into spermatozoa. At birth, germ cells in the male infant can be recognized in the sex cords of the testis as large, pale cells surrounded by supporting cells. Supporting cells, which are derived from the surface epithelium of the testis in the same manner as follicular cells, become sustentacular cells, or Sertoli cells.
Shortly before puberty, the sex cords acquire a lumen and become the seminiferous tubules.
At about the same time, PGCs give rise to spermatogonial stem cells. At regular intervals, cells emerge from this stem cell population to form type A spermatogonia, and their production marks the initiation of spermatogenesis. Type A cells undergo a limited number of mitotic divisions to form clones of cells. The last cell division produces type B spermatogonia, which then divide to form primary spermatocytes. Primary spermatocytes then enter a prolonged prophase (22 days) followed by rapid completion of meiosis I and formation of secondary spermatocytes. During the second meiotic division, these cells immediately begin to form haploid spermatids. Throughout this series of events, from the time type A cells leave the stem cell population to formation of spermatids, cytokinesis is incomplete, so that successive cell generations are joined by cytoplasmic bridges. Thus, the progeny of a single type A spermatogonium form a clone of germ cells that maintain contact throughout differentiation. Furthermore, spermatogonia and spermatids remain embedded in deep recesses of Sertoli cells throughout their development. In this manner, Sertoli cells support and protect the germ cells, participate in their nutrition, and assist in the release of mature spermatozoa.
Spermatogenesis is regulated by LH production by the pituitary gland. LH binds to receptors on Leydig cells and stimulates testosterone pro- duction, which in turn binds to Sertoli cells to promote spermatogenesis. Follicle-stimulating hormone (FSH) is also essential because its binding to Sertoli cells stimulates testicular fluid production and synthesis of intracellular andro- gen receptor proteins.

Fatigue
Definition
Fatigue is defined as the decrease in muscular activity due to repeated stimuli. When stimuli are applied repeatedly, after some time, the muscle does not show any response to the stimulus. This condition is called fatigue.
Fatigue curve
When the effect of repeated stimuli is recorded continuously, the amplitude of first two or three contractions increases. It is due to the beneficial effect.
Afterwards, the force of contraction decreases gradually. It is shown by gradual decrease in the amplitude of the curves. All the periods are gradually prolonged. Just before fatigue occurs, the muscle does not relax completely. It remains in a partially contracted state. This state is called contracture or contraction remainder.

Causes for fatigue
a. Exhaustion of acetylcholine in motor endplate
b. Accumulation of metabolites like lactic acid and phosphoric acid
c. Lack of nutrients like glycogen
d. Lack of oxygen.
Site (seat) of fatigue
In the muscle-nerve preparation of frog, neuromuscular junction is the first seat of fatigue. It is proved by direct stimulation of fatigued muscle. Fatigued muscle gives response if stimulated directly. However, the force of
contraction is less and the contraction is very slow. Second seat of fatigue is the muscle. And the nerve cannot be fatigued.
In the intact body, the sites of fatigue are in the following order:
a. Betz (pyramidal) cells in cerebral cortex
b. Anterior gray horn cells (motor neurons) of spinal cord
c. Neuromuscular junction
d. Muscle.
Recovery of the muscle after fatigue Fatigue is a reversible phenomenon. Fatigued muscle recovers if given rest and nutrition. For this, the muscle is washed with saline.
Causes of recovery
a. Removal of metabolites
b. Formation of acetylcholine at the neuromuscular junction
c. Re-establishment of normal polarized state of the muscle
d. Availability of nutrients
e. Availability of oxygen.
The recovered muscle differs from the fresh resting muscle by having acid reaction. The fresh resting muscle is alkaline. But the muscle, recovered from fatigue is acidic. So it relaxes slowly. In the intact body, all the processes involved in recovery are achieved by circulation itself. In human beings, fatigue is recorded by using Mosso’s ergograph.

Normally, human blood contains 4000 to 11,000 white blood cells per microliter. Of these, the granulocytes (polymorphonuclear leukocytes, PMNs) are the most numerous. Young granulocytes have horseshoe-shaped nuclei that become multilobed as the cells grow older. Most of them contain neutrophilic granules (neutrophils), but a few contain granules that stain with acidic dyes (eosinophils), and some have basophilic granules (basophils). The other two cell types found normally in peripheral blood are lymphocytes, which have large round nuclei and scanty cytoplasm, and monocytes, which have abundant agranular cytoplasm and kidney-shaped nuclei . Acting together, these cells provide the body with powerful defenses against tumors and viral, bacterial, and parasitic infections

(Ganong’s Review of Medical Physiology 23^rd Edition)

PEAK EXPIRATORY FLOW RATE
„ DEFINITION
Peak expiratory flow rate (PEFR) is the maximum rate at which the air can be expired after a deep inspiration.
„ NORMAL VALUE
In normal persons, it is 400 L/minute.
„ MEASUREMENT
Peak expiratory flow rate is measured by using Wright peak flow meter or a mini peak flow meter.
„ SIGNIFICANCE OF DETERMINING PEFR
Determination of PEFR rate is useful for assessing the respiratory diseases especially to differentiate the obstructive and restrictive diseases. Generally, PEFR is reduced in all type of respiratory disease. However, reduction is more significant in the obstructive diseases than in the restrictive diseases.
Thus, in restrictive diseases, the PEFR is 200 L/minute and in obstructive diseases, it is only 100 L/minute.

Sembuling, K. and Sembuling, P. (2012) Essential of Medical Physiology. 6th Edition, New Jaypee Brothers Medical Publishers, Delhi, India.

Renin
Juxtaglomerular cells secrete renin. Renin is a peptide with 340 amino acids. Along with angiotensins, renin forms the renin-angiotensin system, which is a hormone system that plays an important role in the maintenance of blood pressure.
Stimulants for renin secretion
Secretion of renin is stimulated by four factors:
i. Fall in arterial blood pressure
ii. Reduction in the ECF volume
iii. Increased sympathetic activity
iv. Decreased load of sodium and chloride in macula densa.
Renin-angiotensin system
When renin is released into the blood, it acts on a specific plasma protein called angiotensinogen or renin substrate. It is the α2-globulin. By the activity of renin, the angiotensinogen is converted into a decapeptide called angiotensin I. Angiotensin I is converted into angiotensin II, which is an octapeptide by the activity of angiotensin-converting enzyme (ACE) secreted
from lungs. Most of the conversion of angiotensin I into angiotensin II takes place in lungs. Angiotensin II has a short half-life of about 1 to 2 minutes. Then it is rapidly degraded into a heptapeptide called angiotensin III by angiotensinases, which are present in RBCs and vascular beds in many tissues.
Angiotensin III is converted into angiotensin IV, which is
a hexapeptide.
Actions of Angiotensins
Angiotensin I
Angiotensin I is physiologically inactive and serves only as the precursor of angiotensin II.
Angiotensin II
Angiotensin II is the most active form. Its actions are:
On blood vessels:
i. Angiotensin II increases arterial blood pressure by directly acting on the blood vessels and causing vasoconstriction. It is a potent constrictor of arterioles. Earlier, when its other actions were not found it was called hypertensin.
ii. It increases blood pressure indirectly by increasing the release of noradrenaline from postganglionic sympathetic fibers. Noradrenaline is a general vasoconstrictor.
On adrenal cortex:
It stimulates zona glomerulosa of adrenal cortex to secrete aldosterone. Aldosterone acts on renal tubules and increases retention of sodium, which is also responsible for elevation of blood pressure.
On kidney:
i. Angiotensin II regulates glomerular filtration rate by two ways:
a. It constricts the efferent arteriole, which causes decrease in filtration after an initial increase
b. It contracts the glomerular mesangial cells leading to decrease in surface area of glomerular capillaries and filtration
ii. It increases sodium reabsorption from renal tubules. This action is more predominant on proximal tubules.
On brain:
i. Angiotensin II inhibits the baroreceptor reflex and thereby indirectly increases the blood pressure. Baroreceptor reflex is responsible for decreasing the blood pressure.
Glomerular mesangial cells are phagocytic in nature. These cells also secrete glomerular interstitial matrix, prostaglandins and cytokines.

„ JUXTAGLOMERULAR CELLS
Juxtaglomerular cells are specialized smooth muscle cells situated in the wall of afferent arteriole just before it enters the Bowman capsule. These smooth muscle cells are mostly present in tunica media and tunica adventitia of the wall of the afferent arteriole. Juxtaglomerular cells are also called granular cells because of the presence of secretary granules in their cytoplasm.

Polar Cushion or Polkissen
Juxtaglomerular cells form a thick cuff called polar cushion or polkissen around the afferent arteriole before it enters the Bowman capsule.

„ FUNCTIONS OF JUXTAGLOMERULAR APPARATUS
Primary function of juxtaglomerular apparatus is the secretion of hormones. It also regulates the glomerular blood flow and glomerular filtration rate.
„ SECRETION OF HORMONES
Juxtaglomerular apparatus secretes two hormones:
1. Renin
2. Prostaglandin.
1. Renin
Juxtaglomerular cells secrete renin. Renin is a peptide with 340 amino acids. Along with angiotensins, renin forms the renin-angiotensin system, which is a hormone system that plays an important role in the maintenance of blood pressure.
Stimulants for renin secretion
Secretion of renin is stimulated by four factors:
i. Fall in arterial blood pressure
ii. Reduction in the ECF volume
iii. Increased sympathetic activity
iv. Decreased load of sodium and chloride in macula densa.
Renin-angiotensin system
When renin is released into the blood, it acts on a specific plasma protein called angiotensinogen or renin substrate. It is the α2-globulin. By the activity of renin, the angiotensinogen is converted into a decapeptide

ii. It increases water intake by stimulating the thirst center
iii. It increases the secretion of Corticotropin-releasing hormone (CRH) from hypothalamus. CRH in turn increases secretion of adrenocorticotropic hormone (ACTH) from pituitary
iv. It increases secretion of antidiuretic hormone (ADH) from hypothalamus.
Other actions:
Angiotensin II acts as a growth factor in heart and it is thought to cause muscular hypertrophy and cardiac enlargement.
Angiotensin III
Angiotensin III increases the blood pressure and stimulates aldosterone secretion from adrenal cortex. It has 100% adrenocortical stimulating activity and 40% vasopressor activity of angiotensin II.
Angiotensin IV
It also has adrenocortical stimulating and vasopressor activities.

Sembuling, K. and Sembuling, P. (2012) Essential of Medical Physiology. 6th Edition, New Jaypee Brothers Medical Publishers, Delhi, India.

Tubuloglomerular Feedback
Tubuloglomerular feedback is the mechanism that regulates GFR through renal tubule and macula densa. Macula densa of juxtaglomerular apparatus in the terminal portion of thick ascending limb is sensitive to the sodium chloride in the tubular fluid.
When the glomerular filtrate passes through the terminal portion of thick ascending segment, macula densa acts like a sensor. It detects the concentration of sodium chloride in the tubular fluid and accordingly alters the glomerular blood flow and GFR. Macula densa detects the sodium chloride concentration via Na+K+ 2Cl– cotransporter (NKCC2). When the concentration of sodium chloride increases in the filtrate
When GFR increases, concentration of sodium chloride increases in the filtrate. Macula densa releases adenosine from ATP. Adenosine causes constriction of afferent arteriole. So the blood flow through glomerulus decreases leading to decrease in GFR. Adenosine acts on afferent arteriole via adenosine A1 receptors. There are several other factors, which increase or decrease the sensitivity of tubuloglomerular feedback.
Factors increasing the sensitivity of tubuloglomerular feedback:
i. Adenosine
ii. Thromboxane
iii. Prostaglandin E2
iv. Hydroxyeicosatetranoic acid.
Factors decreasing the sensitivity of tubuloglomerular feedback:
i. Atrial natriuretic peptide
ii. Prostaglandin I2
iii. Cyclic AMP (cAMP)
iv. Nitrous oxide.

When the concentration of sodium chloride decreases in the filtrate

When GFR decreases, concentration of sodium chloride decreases in the filtrate. Macula densa secretes prostaglandin (PGE2), bradykinin and renin. PGE2 and bradykinin cause dilatation of afferent arteriole. Renin induces the formation of angiotensin II, which causes constriction of efferent arteriole. The
dilatation of afferent arteriole and constriction of efferent arteriole leads to increase in glomerular blood flow and GFR.
Sembuling, K. and Sembuling, P. (2012) Essential of Medical Physiology. 6th Edition, New Jaypee Brothers Medical Publishers, Delhi, India.

Pituitary gland or hypophysis is a small endocrine gland with a diameter of 1 cm and weight of 0.5 to 1 g. It is situated in a depression called ‘sella turcica’,
present in the sphenoid bone at the base of skull. It is connected with the hypothalamus by the pituitary stalk or hypophyseal stalk.
„ DIVISIONS OF PITUITARY GLAND
Pituitary gland is divided into two divisions:
1. Anterior pituitary or adenohypophysis
2. Posterior pituitary or neurohypophysis.
Both the divisions are situated close to each other. Still both are entirely different in their development, structure and function. Between the two divisions, there is a small and relatively avascular structure called pars intermedia. Actually, it forms a part of anterior pituitary.
„ DEVELOPMENT OF PITUITARY GLAND
Both the divisions of pituitary glands develop from different sources. Anterior pituitary is ectodermal in origin and arises from the pharyngeal epithelium as an upward growth known as Rathke pouch.
Posterior pituitary is neuroectodermal in origin and arises from hypothalamus as a downward diverticulum. Rathke pouch and the downward diverticulum from
hypothalamus grow towards each other and meet in the midway between the roof of the buccal cavity and base of brain. There, the two structures lie close together.
Sembuling, K. and Sembuling, P. (2012) Essential of Medical Physiology. 6th Edition, New Jaypee Brothers Medical Publishers, Delhi, India.