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121

- All are chemical modifications of cholesterol
4 rings with 21 carbons

- Progesterone, glucocorticoids, and mineralocorticoids are 21-carbon steroids
- Androstanes are 19-carbon steroids
- Estranes (produced primarily in the ovaries) are 18-carbon steroid

Adrenocortical hormones

122

Mnemonic

21 - pregnanes
19 - androstanes
18 - estranes

123

Synthesis of adrenocortical hormones

- Each layer is specialized to synthesize particular hormones

- Depending on the presence or absence of enzymes
(17,20- lyase in zona fasciculata: androgenic steroid
Aldosterone synthase in zona glomerulosa: aldosterone)

124

The rate-limiting reaction in steroidogenesis is the __ because cholesterol is stored in the cytoplasm and CYP11A1 (cholesterol desmolase) is located in the inner mitochondrial membrane

transfer of cholesterol from the outer to the inner mitochondrial membrane

125

- Principal mineralocorticoid
- Synthesized only by the zona glomerulosa
Due to presence of aldosterone synthase
Cannot synthesize glucocorticoids

- Regulated primarily by RAAS (Minimally influenced by ACTH)

Aldosterone

126

Aldosterone: Transport and metabolism

- Only ~60% bind to plasma proteins, 40% in free form
- half-life: ~20 mins
- Almost all inactivated by the liver in one pass(Conjugated especially to glucuronic acid and to a lesser extent sulfates)
- Excretion
Bile then feces: ~25%
Urine: remaining

127

Aldosterone: Physiologic actions

Three actions on the late distal tubule and collecting ducts of the kidney:

1. Increases Na+ reabsorption (principal cells)
2. Increases K+ secretion (principal cells)
3. Increases H+ secretion (α-intercalated cells)

128

Aldosterone: Physiologic actions 2

Excess increases ECF Volume and arterial pressure but has only small effect on plasma sodium concentration.
>>Simultaneous osmotic absorption of almost equivalent amounts of water
>>Stimulate thirst and increased water intake

129

- Excess causes hypokalemia and muscle weakness

- Too little causes hyperkalemia and cardiac toxicity
Stimulates transport of potassium into ICF
Alters the electrical excitability of the nerve and muscle fiber membranes
Weakness of heart contraction, development of arrhythmia, heart failure

Physiologic Action of Aldosterone

130

Physiologic Action of Aldosterone in Colon, salivary glands and sweat glands

- Promotes Na+ and water absorption
- Effect on salivary glands: for conservation of salt when excessive quantities of saliva are lost
- Effect on sweat glands: for conservation of salt in hot environments

131

- has a proinflammatory, profibrotic effect on the cardiovascular system, causes LVH and remodeling
- Binds to mineralocorticoid receptor (MR), an intracellular receptor
- Similar to cortisol (alters gene expression)

Aldosterone

132

Cellular Mechanism of Aldosterone

- Aldosterone diffuses readily to the interior of the tubular epithelial cells (Lipid soluble)

- Combines with receptor protein

133

Has a stereomolecular configuration that allows only aldosterone or very similar compounds to combine with it

receptor protein

134

Cellular Mechanism of Aldosterone 2

- Aldosterone-receptor complex diffuses into the nucleus

- mRNA, in conjunction with the ribosomes, causes protein formation.
(1) one or more enzymes and (2) membrane transport proteins required for sodium, potassium, and hydrogen transport through the cell membrane

135

Aldosterone: Regulation of secretion

- Almost entirely independent of regulation of cortisol and androgens by zona fasciculata and reticularis

136

Major stimuli for aldosterone production

1. Increased angiotensin II
2. Increased serum [K+]

137

What is the effect of increased sodium ion concentration in aldosterone secretion?

very slightly decreases aldosterone secretion

138

- is necessary for aldosterone secretion but has little effect in controlling the rate of secretion in most physiological conditions

ACTH

139

Major actions of angiotensin II on the adrenal cortex

1. Specifically increase output of aldosterone
2. increased growth (hypertrophy) and vascularity of the zona glomerulosa; no effect on other two zones
3. increased StAR and aldosterone synthase enzyme activity

140

- Principal naturally occring glucocorticoid in humans
- Synthesized in zona fasciculata/ reticularis
- ≥ 95% of glucocorticoid activity of the adrenocortical secretions (Small but significant: corticosterone)

Cortisol

141

Cortisol is bound predominantly (>90%) when in circulation. Where?

1. cortisol-binding globulin (i.e. transcortin)
2. Albumin (5-7%)

142

Circulating half-life of cortisol?

60-90 minutes; Because of the high degree of binding in circulation

143

- predominant site of steroid inactivation
- inactivates cortisol and conjugates them so that they can be excreted more readily by the kidney

Liver

144

Mechanism of action

Acts through glucocorticoid receptor (GR)

145

How does Cortisol increase gene transcription?

1. Rapid translocation of the cortisol-GR complex into the nucleus
2. Cortisol-GR complex interacts with glucocorticoid response elements (GREs) in the DNA
3. Recruitment of coactivator proteins
4. Assembly of general transcription factors

146

How does Cortisol decrees gene transcription?

1. Rapid translocation of the cortisol-GR complex into the nucleus
2. Interaction with negative glucocorticoid response elements (GREs)
3. Recruitment of corepressor proteins; OR interference with ability of transcription factors to activate gene expression

147

Metabolic Action of Cortisol

- Catabolic and diabetogenic
- ↑ blood glucose
- Increase lipolysis

148

How does Cortisol increase blood glucose?

1. Stimulates gluconeogenesis in liver
- Enhance gene expression of hepatic gluconeogenic enzymes

2. Inhibit protein synthesis, ↑ proteolysis in muscle
- Provide rich source of carbon for hepatic gluconeogenesis

149

How does Cortisol promotes glucose sparing?

1. Decreases glucose utilization by tissues

2. Decreases insulin sensitivity of adipose tissue

3. ↓ Glut4-mediated glucose uptake
- Potentiates effects of catecholamines on lipolysis

150

How does Cortisol Act on Cardiovascular?

1. Permissive actions on catecholamines - Good cardiac output and blood pressure

2. Stimulates EPO synthesis