I. Definition

Homeostasis (from Greek homeo- = sameness; -stasis = standing still) is the dynamic state of relative stability or equilibrium of the body’s internal environment, often referred to as the milieu intérieur.

• The body's physiological systems work to maintain the physical and chemical composition around its constituent cells—the internal environment—within narrow limits.

• Physiology is fundamentally the study of the homeostatic mechanisms.

• Homeostasis requires the coordination and regulation of numerous complex activities in all component systems of the body.

• Vital parameters that are tightly controlled include body core temperature, arterial pressure, blood volume, and plasma levels of oxygen, glucose, potassium ions (K+), calcium ions (Ca 2+), and hydrogen ions (H+).

II. History

The understanding of homeostasis evolved through the observations of key physiologists:

• Claude Bernard (1813–1878)(oncept of Homeostasis): Considered the originator of modern physiology. He observed that the milieu intérieur (internal environment) remains remarkably constant despite changing conditions in the external environment.

• Walter Cannon (1871–1945): Coined the term homeostasis in 1897. In his 1932 book, The Wisdom of the Body, he suggested that the various mechanisms of physiological regulation share the single purpose of maintaining internal constancy.

• James Hardin (early 1950s): Proposed that homeostatic mechanisms maintain each physiological variable within a normal range by comparing its value to a desired reference value, or set point.

III. Mechanism: Control Systems and Feedback Loops

Homeostasis is achieved through complex regulatory systems, primarily involving feedback control mechanisms.

A. The Negative Feedback Loop

The most common and fundamental theme in physiology for maintaining constancy is the negative feedback mechanism. It requires at least four elements:

1. Sensor (Receptor): Detects the change in the vital parameter (input signal).

2. Integrating Center (Control Center): Compares the input signal with the internal reference value, the set-point, forming a difference signal (error signal).

3. Output Signal: Produced by multiplying the error signal by the gain (proportionality factor) (e.g., release of insulin).

4. Effector Mechanism: Activated by the output signal, it produces a response that opposes the original deviation, moving the vital parameter back toward the set-point.

Examples of Negative Feedback Mechanism

1- Body Temperature-Falls too low-Shivering increases heat production-Sweating is induced when temperature is too high.

2- Blood Pressure-Falls rapidly-Baroreceptors trigger neural and hormonal responses (e.g., sympathetic activation) to increase heart rate and vasoconstriction.-The sino-aortic mechanism can increase or decrease BP as required by affecting cardiac output (CO) and peripheral resistance (PR).

3- Plasma Osmolality-Increases (becomes concentrated)-Osmoreceptors in the hypothalamus stimulate thirst and trigger the release of Antidiuretic Hormone (ADH) (vasopressin) from the posterior pituitary.-ADH promotes water retention by the kidneys, maintaining normal osmolality and blood volume.

4- Cellular Basis- Homeostasis relies heavily on membrane-mediated processes at the cellular level. Cells regulate their volume and the concentrations of ions (Na+, Ca2+, H+) using transport mechanisms like passive diffusion, osmosis, and mechanisms dependent on protein machinery (ion channels, solute transporters, and ATPases or "pumps") residing in cellular membranes.

5- Central Regulatory Systems- The body’s activities are coordinated by two major communication and control systems:

1. Nervous System (Neural Regulation): This is the quick-reaction system concerned with the immediate, short-term maintenance of homeostasis. Examples include vagovagal (long) reflexes in the GI tract and the sino-aortic mechanism (baroreceptor reflex) for moment-to-moment regulation of blood pressure (BP).

2. Endocrine System (Hormonal Regulation): This system maintains long-term homeostasis. It involves hormones secreted in response to specific chemical stimuli, regulating metabolism, growth, and fluid balance over days, months, and years.

B. The Positive feedback loops 

The positive feedback loops are mechanisms that can temporarily exist within the body, often serving to amplify a change rather than oppose it, and are typically part of a larger, overall negative feedback mechanism that eventually restores homeostasis.

Definition of Positive Feedback

Positive feedback is a self-reinforcing and explosive mechanism where the action of the effectors amplifies those changes that initially stimulated the effectors.

• In contrast to negative feedback, where the effector produces changes opposite in direction to the initial stimulus, in positive feedback, the effector produces changes in the same direction.

• Positive feedback mechanisms confer instability to a system, meaning "something has to give".

• While rare in comparison to negative feedback, positive feedback can be crucial because it quickly amplifies a small initial change into a major, often decisive, event.

Examples of Positive Feedback Mechanism

1. Generation of an Action Potential (Action Potential Upstroke)

The rapid rising phase of the action potential (AP) in excitable cells (neurons, muscle cells, and some endocrine cells) is a classic example of positive feedback.

• Mechanism: Membrane depolarization opens voltage-gated Na+channels, which increases Na+conductance (gNa​). The resulting Na+ influx (inward current) further depolarizes the membrane. This greater depolarization then opens more Na+ channels, leading to a self-reinforcing, explosive cycle.

• Outcome: Once initiated by reaching the threshold potential, this explosive response cannot be stopped (it is all-or-none) and drives the membrane potential (Vm) rapidly toward the Na+ equilibrium potential (ENa). This process is terminated shortly thereafter when the Na+channels rapidly inactivate (close) and K+channels open, leading to repolarization (negative feedback).

2. Regulation of Hormone Secretion (Luteinizing Hormone Surge)

The surge of Luteinizing Hormone (LH) that occurs just before ovulation in the menstrual cycle is a result of positive feedback.

• Mechanism: Rising secretion of estradiol (estrogen) from the ovaries stimulates the anterior pituitary gland to secrete a "surge" of LH. LH then acts on the ovaries, causing more estrogen secretion.

• Outcome: This stimulatory, positive feedback effect creates the LH surge that triggers ovulation. It is important to note that later, higher levels of estradiol revert to exhibiting the opposite effect—negative feedback inhibition—on LH secretion.

3. Contraction of the Uterus During Childbirth

Contraction of the uterus during labor (parturition) is enhanced through a positive feedback loop involving the hormone oxytocin.

• Mechanism: Contraction of the uterus is stimulated by oxytocin, a hormone released from the posterior pituitary. The secretion of oxytocin is increased by sensory feedback received from the cervix and vagina, which are stimulated by the uterine contractions during labor.

• Outcome: This mechanism increases the strength of uterine contractions, ensuring the completion of the birthing process.

4. Blood Clotting (Coagulation Cascade)

The process of blood clotting involves positive feedback to ensure rapid cessation of blood loss (hemostasis).

• Mechanism: Blood clotting occurs through the sequential activation of clotting factors; the activation of one factor rapidly results in the activation of many more in a positive feedback cascade.

• Outcome: This amplification process produces a blood clot quickly. The formation of the clot eventually stops further blood loss, demonstrating the completion of the overall negative feedback loop that restores blood volume and pressure homeostasis.

Positive Feedback and Hemorrhagic Shock

Severe blood loss (hemorrhage) can trigger latent positive feedback mechanisms that exaggerate the hypotension, potentially leading to death if not quickly resolved (hemorrhagic shock).

• These decompensatory mechanisms, such as cardiac failure and central nervous system depression, may initiate vicious circles.

• Whether a vicious circle develops depends on the gain of the feedback mechanism: a gain greater than 1 means that the secondary change evoked by the mechanism is greater than the initiating change, causing the condition to worsen at an accelerating rate.

• In minor blood loss, negative feedback gains are high, and positive feedback gains are low. In severe hemorrhage, the converse is true, increasing the likelihood of a total gain greater than 1, leading to irreversible shock.

The feedforward mechanism 

The feedforward mechanism is a critical component of homeostatic regulation, serving as an anticipatory response that allows the body to prepare for, and thereby prevent, potentially large fluctuations in physiological parameters.

Mechanism and Function

The core function of the feedforward mechanism is anticipation. Instead of waiting for a change to occur and then correcting it (which is the basis of a feedback loop), a feedforward mechanism anticipates the future needs of the individual and adjusts physiological output proactively.

• This type of response prevents large changes in physiological parameters that could be detrimental to optimal function.

• It is considered a key component of the regulation of homeostasis during stress.

• A system relying purely on feedback could produce a response that is delayed or out of phase with the stimulus. The feedforward response helps the body respond rapidly and more efficiently to a threat or physiological challenge.

Examples in Physiology

1. Regulation during Exercise: A classic example of feedforward is observed in cardiovascular and respiratory adjustments during exercise.

◦ When a person begins to exercise, sympathetic output increases before the increase in metabolic need.

◦ This central command, originating from cerebrocortical activation, produces cardiac acceleration, increased myocardial contractile force, and peripheral vasoconstriction.

◦ Because of this anticipatory response, alveolar ventilation rises to such an extent that blood levels of carbon dioxide, a byproduct of exercise, actually drop at the onset of exercise. This drop is the opposite of what would be expected if the body worked purely through feedback loops, where an obligatory increase in levels would precede the increase in respiratory output.

◦ Similarly, in a trained athlete, heart rate begins to increase several seconds before the start of a dash, demonstrating anticipation of future activity.

2. Gastrointestinal (GI) System: The GI system integrates signals to maintain homeostasis (as noted in the context of the previous notes section), but specific actions can have anticipatory elements. For example, the regulation of gastric acid secretion involves enterogastrones (like Secretin and Cholecystokinin) released in response to the arrival of acid or fatty acids in the duodenum. This prepares the downstream pancreas and gallbladder for the arrival of chyme by stimulating their secretions, though the sources do not explicitly label this a feedforward loop.

3. Renal Physiology (Related Concepts): While not explicitly labeled as feedforward, the kidney exhibits anticipatory maintenance mechanisms. For instance, the concept of Glomerulotubular (G-T) balance is a mechanism of self-regulation where changes in the glomerular filtration rate (GFR) lead to proportional changes in proximal tubule reabsorption. This immediately minimizes changes in sodium (Na+) filtration, helping maintain urinary excretion constant until other mechanisms (like tubuloglomerular feedback) return GFR to normal 

IV. Applied Physiological and Clinical Aspects

Homeostasis is essential to survival; failure of these mechanisms leads to disease (pathophysiology).

A. Fluid and Electrolyte Homeostasis (Renal System)

The kidneys are crucial regulatory organs that maintain the constant volume and composition of the body’s fluids, particularly the Extracellular Fluid (ECF) volume and NaCl balance, despite wide variations in daily intake.

• ECF Volume Regulation: Changes in Na+balance alter ECF volume. The effective circulating volume (ECV) is monitored by volume sensors (baroreceptors) in the vascular system, which send signals (like the Renin-Angiotensin-Aldosterone System, ANP, and BNP) to the kidneys to regulate NaCl excretion.

• Acid-Base Balance: The pH of body fluids is maintained within a narrow range (7.35–7.45) by the coordinated function of the lungs and kidneys. The HCO3−​  buffer system is critical in the ECF. The kidneys contribute by balancing acid and alkali excretion, regulating HCO3−​reabsorption, and forming new HCO3−​(Renal Net Acid Excretion, RNAE).

B. Gastrointestinal Homeostasis

The GI system's secretory, motility, and absorptive functions are integrated to digest food, absorb nutrients, and maintain homeostasis between meals.

• Gastric Acid Regulation: Gastric acid secretion is inhibited by hormones called enterogastrones (e.g., Secretin, Cholecystokinin, Gastric Inhibitory Peptide) released from the duodenal mucosa in response to acid, fatty acids, or hyperosmotic solutions. This homeostatic mechanism ensures gastric contents are delivered to the small bowel at a rate suitable for digestion and absorption, and prevents damage to the duodenal mucosa.

• Hemostasis: This is a vital homeostatic mechanism to prevent blood loss after vascular injury, involving vasoconstriction, platelet plug formation, and coagulation.

C. Pathophysiological Consequences of Homeostatic Failure

If homeostatic mechanisms fail or are severely impaired, pathological conditions arise:

• Diabetes Mellitus: Failure of the homeostatic mechanism regulating blood glucose, where insulin does not adequately lower the concentration in response to a rise.

• Hypertension (High BP): If there are repeated episodes of high BP (due to stress, etc.), the sino-aortic baroreceptors may become "reset" to maintain blood pressure at a higher level, leading to a state of chronic hypertension.

• Orthostatic/Postural Hypotension: Failure of the autonomic nervous system to make the necessary quick adjustments (like increased heart rate and vasoconstriction) upon standing, causing arterial pressure to fall significantly.

• Edema: Results from an imbalance in Starling forces (capillary hydrostatic and oncotic pressures) controlling fluid exchange between capillaries and the interstitial fluid. This can occur in conditions like heart failure.