• Mineralocorticoids are lifesaving because they maintain Na⁺, Cl⁻, K⁺, extracellular fluid volume, and blood volume.
• Without mineralocorticoids:
  • Na⁺ + Cl⁻ ↓ → large loss from the body.
  • K⁺ ↑ in extracellular fluid → hyperkalemia.
  • ↓ NaCl → ↓ extracellular fluid volume → ↓ blood volume.
  • ↓ blood volume → ↓ cardiac output → shock-like state → death.
  • Complete adrenal cortical hormone loss may cause death within 3–14 days without salt therapy or mineralocorticoids.
• Aldosterone prevents this sequence, so mineralocorticoids are called the acute “lifesaving” portion of adrenocortical hormones.
• Aldosterone is the major mineralocorticoid, producing about 90% of mineralocorticoid activity.
• Cortisol also has mineralocorticoid activity, but:
  • Aldosterone is about 3000× more potent than cortisol.
  • Cortisol concentration is about 2000× higher than aldosterone.
• Cortisol can bind mineralocorticoid receptors, but renal 11β-HSD2 normally prevents this effect by converting:
  • Cortisol → Cortisone
  • Cortisone has little ability to activate mineralocorticoid receptors.
• 11β-HSD2 also helps prevent cortisol from activating these receptors through effects on the cell’s redox state.
• If 11β-HSD2 is genetically deficient, cortisol produces strong mineralocorticoid effects → apparent mineralocorticoid excess (AME).
• AME resembles aldosterone excess, but plasma aldosterone is very low.
• Large amounts of licorice can also cause AME because glycyrrhetinic acid blocks 11β-HSD2.

KEY CONCEPT

Aldosterone protects circulation by preventing NaCl loss and excessive K⁺ accumulation → maintains extracellular fluid and blood volume → prevents shock.

CONCEPTUAL EXAMPLES

• No mineralocorticoid → NaCl loss → ↓ blood volume → ↓ cardiac output → shock → death.
• 11β-HSD2 normal → cortisol → cortisone → mineralocorticoid receptor protected.
• 11β-HSD2 deficient → cortisol acts like aldosterone → AME despite very low aldosterone.
• Licorice → blocks 11β-HSD2 → cortisol acts on mineralocorticoid receptors → AME.

RENAL AND CIRCULATORY EFFECTS OF ALDOSTERONE

• Aldosterone → ↑ Na⁺ reabsorption + ↑ K⁺ secretion mainly in principal cells of collecting tubules, and also in distal tubules and collecting ducts.
• Therefore, aldosterone saves Na⁺ in the body while increasing K⁺ loss in urine.
• Excess aldosterone: Na⁺ loss in urine can fall to only a few mEq/day, while K⁺ loss can temporarily increase several-fold → ↑ body Na⁺ and ↓ body K⁺.
• No aldosterone: Na⁺ loss may reach 10–20 g/day, while K⁺ is strongly retained.
• Although aldosterone strongly retains Na⁺, plasma Na⁺ rises only slightly because retained Na⁺ pulls water with it → ECF volume increases more than Na⁺ concentration.
• Slight ↑ ECF Na⁺ also → ↑ thirst + ↑ ADH → more water intake and renal water reabsorption.
• Excess aldosterone → ↑ ECF volume → ↑ arterial pressure.
• If ECF volume remains elevated for >1–2 days, increased arterial pressure causes:
  • Pressure natriuresis → ↑ Na⁺ excretion.
  • Pressure diuresis → ↑ water excretion.
  • ↓ Angiotensin II + ↑ natriuretic hormones such as ANP → further Na⁺ and water loss.
• Thus, after ECF volume rises about 5–15%, arterial pressure rises about 15–25 mm Hg, and renal Na⁺/water excretion return toward normal despite continued excess aldosterone (Fig. 78.3).
• This return of Na⁺ and water excretion to normal is called aldosterone escape.
• After aldosterone escape, Na⁺ and water intake = output, so further retention stops; however, hypertension persists while aldosterone remains high.
• Severe aldosterone deficiency → ↓ Na⁺ reabsorption → ↑ Na⁺ loss → ↓ ECF volume → ↓ blood pressure → ↓ cardiac output.
• ↓ ECF volume and blood pressure → ↑ ADH + ↑ thirst, which reduce water loss but also contribute to hyponatremia.
• If aldosterone secretion becomes zero, massive Na⁺ loss causes severe dehydration + low blood volume → circulatory shock → death within a few days without treatment.

KEY CONCEPT

Aldosterone saves Na⁺ and loses K⁺ → Na⁺ retention pulls water → ↑ ECF volume → ↑ blood pressure.
Excess → aldosterone escape; deficiency → Na⁺ wasting → ↓ volume/BP → shock.

CONCEPTUAL EXAMPLES

• ↑ Aldosterone → ↑ Na⁺ reabsorption → ↑ water retention → ↑ ECF volume → ↑ BP.
• Excess aldosterone → BP rises → kidneys excrete more Na⁺/water → aldosterone escape.
• ↓ Aldosterone → Na⁺ wasting → ↓ ECF volume → ↓ BP → shock.
• Aldosterone = “Na⁺ saver + K⁺ excreter.”

ALDOSTERONE “ESCAPE” GRAPH

🎯 BIG IDEA

Aldosterone initially saves Na⁺ → water follows → ECF volume ↑ → BP ↑ → kidneys then start dumping ( getting rid of something )Na⁺ again.

👉 This recovery of Na⁺ excretion despite continued aldosterone = ALDOSTERONE ESCAPE.

🟦 First: What do the 3 graphs show?

1️⃣ TOP = 🩸 Mean arterial pressure

During aldosterone infusion:

~98 → ~112 mmHg

➡️ BP rises.

After aldosterone stops:

➡️ BP gradually returns toward normal.

2️⃣ MIDDLE = 💧 Extracellular fluid (ECF) volume

Before infusion:

100% = normal

After aldosterone:

100% → ~110–115%

➡️ Aldosterone causes Na⁺ retention
➡️ Water follows Na⁺
➡️ ECF volume expands

After stopping:

➡️ Volume gradually falls toward normal.

3️⃣ BOTTOM = 🧂 Urinary sodium excretion

This is the most important graph.

Before aldosterone:

➡️ ~250 mEq/day

Day 0–1:

Aldosterone starts.

Na⁺ excretion ↓↓↓

➡️ Kidneys retain sodium.

Then — THE AMAZING PART ⭐

By about Day 2:

Na⁺ excretion rises back toward normal

❗ Even though aldosterone is STILL being infused!

This is the:

🚨 ALDOSTERONE ESCAPE

🧠 WHY DOES ESCAPE HAPPEN?

Think:

Aldosterone

⬇️
Kidney retains Na⁺ 🧂
⬇️
Water follows Na⁺ 💧
⬇️
ECF volume ↑
⬇️
Blood pressure ↑ 🩸
⬇️
Kidneys receive higher pressure
⬇️
More Na⁺ + water excreted 🚽
⬇️

Na⁺ excretion returns toward normal

So the body says:

“Aldosterone is trying to save sodium, but the increased blood pressure makes the kidneys throw sodium out anyway!”

🔥 What do the dashed lines mean?

First dashed line = Day 0

➡️ Aldosterone infusion STARTS

Second dashed line = ~Day 7

➡️ Aldosterone infusion STOPS

The pink region between them = aldosterone is being continuously infused.

⭐ THE MOST IMPORTANT CONTRAST

Early aldosterone:

Na⁺ retention ↑ → ECF ↑ → BP ↑

After ~2 days:

BP ↑ → renal Na⁺ excretion ↑ → “escape” from Na⁺ retention

Therefore:

Aldosterone continues, but sodium retention does NOT continue indefinitely.

🧠 10-SECOND MASTER MEMORY

ALDOSTERONE → Na⁺ SAVE → WATER SAVE → VOLUME ↑ → BP ↑ → Na⁺ LOSS ↑

“Aldosterone holds sodium, but high BP makes the kidney escape.” 🧂➡️💧➡️🩸➡️🚽

⭐ Exam killer point:

Aldosterone escape = return of urinary Na⁺ excretion toward normal despite continued aldosterone administration, mainly because volume expansion and increased arterial pressure promote renal Na⁺ excretion.

Excess Aldosterone Causes Hypokalemia and Muscle Weakness; Aldosterone Deficiency Causes Hyperkalemia and Cardiac Toxicity

• Excess aldosterone → ↑ K⁺ excretion in urine + ↑ K⁺ movement into cells → ↓ plasma K⁺ = hypokalemia.
• Plasma K⁺ may fall from about 4.5 mEq/L → as low as 2 mEq/L.
• When plasma K⁺ falls below about ½ of normal, severe muscle weakness may develop.
• Low K⁺ changes the electrical excitability of nerve and muscle membranes, so normal action potentials cannot be transmitted properly → muscle weakness.
• Aldosterone deficiency → ↓ K⁺ excretion → ↑ plasma K⁺ = hyperkalemia.
• When K⁺ rises 60–100% above normal, serious cardiac toxicity develops:
  • ↓ strength of heart contraction
  • Arrhythmias
  • Further K⁺ rise → heart failure
• Excess aldosterone also increases H⁺ secretion by intercalated cells of the cortical collecting tubules.
• ↑ H⁺ secretion → ↑ renal HCO₃⁻ reabsorption → ↓ H⁺ concentration in extracellular fluid → metabolic alkalosis.

KEY CONCEPT

Too much aldosterone → K⁺ ↓ + H⁺ ↓ → muscle weakness + metabolic alkalosis.
Too little aldosterone → K⁺ ↑ → cardiac toxicity → possible heart failure.

CONCEPTUAL EXAMPLES

• Aldosterone ↑ → K⁺ lost in urine → hypokalemia → muscle weakness.
• Aldosterone ↓ → K⁺ retained → hyperkalemia → arrhythmia/heart failure.
• Aldosterone ↑ → H⁺ secretion ↑ → HCO₃⁻ retention ↑ → metabolic alkalosis.

ALDOSTERONE STIMULATES SODIUM AND POTASSIUM TRANSPORT IN SWEAT GLANDS, SALIVARY GLANDS, AND INTESTINAL EPITHELIAL CELLS

• Aldosterone acts on sweat and salivary glands much like the kidney: it ↑ NaCl reabsorption and ↑ K⁺ secretion in their ducts.
• Sweat glands: aldosterone conserves body salt, especially during hot environments when sweating is high.
• Salivary glands: aldosterone helps conserve salt when large amounts of saliva are lost.
• Intestine, especially colon: aldosterone ↑ Na⁺ absorption, preventing excessive sodium loss in stools.
• Without aldosterone → ↓ intestinal Na⁺ absorption → ↓ absorption of Cl⁻, other anions, and water → diarrhea → further salt loss.

CELLULAR MECHANISM OF ALDOSTERONE ACTION

• Aldosterone is lipid-soluble, so it easily enters tubular epithelial cells.
• Inside the cell, aldosterone binds to a specific mineralocorticoid receptor (MR).
• 11β-HSD2 normally protects MR from cortisol by converting cortisol → cortisone, which does not readily bind MR (Fig. 78.4).
• The aldosterone–receptor complex → nucleus → DNA activation → mRNA formation for proteins involved in Na⁺ and K⁺ transport.
• mRNA → ribosomes → production of:
  • Na⁺-K⁺ ATPase
  • Epithelial Na⁺ channels
  • K⁺ channels
  • Other transport-related enzymes and proteins.
• Na⁺-K⁺ ATPase increases Na⁺/K⁺ exchange at the basolateral membrane.
• Na⁺ channels allow Na⁺ to move from tubular fluid into the cell.
• K⁺ channels allow K⁺ to move from the cell into the tubular lumen.
• Therefore, aldosterone ultimately increases Na⁺ reabsorption and K⁺ secretion.
• Aldosterone does not act immediately because new proteins must first be produced:
  • ~30 min: new RNA appears.
  • ~45 min: Na⁺/K⁺ transport begins increasing.
  • Several hours: effects reach maximum.

KEY CONCEPT

Aldosterone → MR → DNA → mRNA → transport proteins → ↑ Na⁺ reabsorption + ↑ K⁺ secretion.

CONCEPTUAL EXAMPLES

• Hot weather → sweating → aldosterone → ↑ NaCl reabsorption → salt conserved.
• Aldosterone ↑ in colon → ↑ Na⁺ + water absorption → less salt loss in stool.
• Aldosterone enters cell → MR → DNA → new Na⁺/K⁺ transport proteins → transport increases after hours.

Possible Nongenomic Actions of Aldosterone and Other Steroid Hormones

• Aldosterone and other steroids may produce two types of effects:
  • Genomic effects: develop slowly, with a latency of about 45–60 minutes, because they require gene transcription and new protein synthesis.
  • Nongenomic effects: develop rapidly, within seconds to minutes.
• Nongenomic effects are thought to occur when steroids bind to cell-membrane receptors linked to second-messenger systems, similar to peptide hormones.
• Aldosterone can increase cAMP in vascular smooth muscle and renal collecting-tubule epithelial cells in less than 2 minutes → too fast to require new gene transcription and protein synthesis.
• In some cells, aldosterone rapidly activates the phosphatidylinositol second-messenger system.
• The exact receptors responsible for these rapid effects are not yet determined, and their physiological importance is not well understood.
• Overall, nongenomic effects appear much less important than genomic effects in regulating Na⁺, K⁺, and acid-base balance.

KEY CONCEPT

Genomic = slow → genes → new proteins.
Nongenomic = fast → membrane receptors → second messengers.

CONCEPTUAL EXAMPLES

• Aldosterone → gene transcription → new proteins → effect after ~45–60 min = genomic.
• Aldosterone → membrane receptor → cAMP → effect within <2 min = nongenomic.