Endocrine involvement in secondary hypertension Flashcards
What three substances do the adrenal glands secrete that can each be implicated in hypertension? What cells secrete these substances
- ADRENALINE - adrenal medulla - chromaffin cells
- CORTISOL - cortical secretion from fasciculata cells
- ALDOSTERONE - cortical secretion from glomerulosa cells
What is adrenaline released in response to?
- stimulation from pre-ganglionic, ACh secreting sympathetic nerves
Does adrenaline bind alpha or beta receptors with greater potency?
beta
What does adrenaline act on regarding heart and vasculature?
1 - Beta1 in the heart → act to increase
HR(on the SAN) and contractility (on myocardium) - see notes for more info
2 - beta2 on vasculature - Gs → PKA mediated phosphorylation & inactivation of MLCK
3 - alpha1 receptors → vasoconstriction via Gq → IP3 Ca2+ release → Ca-calmodulin -→ activate MLCK
Overall the effect of adrenaline would be to increase blood pressure. However we can debate the extent due to the opposing actions of the adrenoreceptors on vasculature. Indeed the effect on the heart, increasing SV and HR would increase CO and therefore would increase BP. However if there is net vasodilation some of this might become offset, and if there is net vasoconstriction, this increased BP will be exaggerated.
What is the overall effect of adrenaline on the kidneys?
- to produce a net decrease in GFR (to redirect blood flow to more critical organs)
- adrenaline cause net vasoconstriction of the afferent arteriole more than the efferent arteriole, meaning GFR is reduced and filtration is subsequently reduced, in order to reduce the net loss of fluid and electrolytes
Effect of adrenaline on extracellular fluid volume?
- Increased ECV
- RAS activation
- Increase aldosterone
Aldosterone effect on vascular tone
Increases vascular tone due to endothelial dysfunction and enhances the pressor response to catecholamines and up-regulation of angII receptors
Aldosterone action on kidney
Target is the distal convoluted tubule - modulates the epithelial sodium channel ENaC and renal outer medullary potassium channels to induce increased reansorption of sodium and excretion of potassium
- this would lead to volume expansion and raise BP
- INCREASE IN ECV
Describe the effects cortisol has on vascular tone
• Cortisol contributes to increase vascular tone by potentiating the effect of circulating catecholamines to induce vasoconstriction, whilst inhibiting NOS to reduce the action of vasodilators [Nitric Oxide]
• It is known that in Cushing’s syndrome [cortisol excess] there is elevation of Endothelin-1 [potent vasoconstrictor]
Alsopostulated that glucocorticoids down regulate NCX expression in VSM cells. This leads to increase in the cytoplasmic concentration of calcium which causes vasoconstriction.
Describe renal effects of cortisol
• The effect of vasoconstriction would in theory, due to the mechanism of action in potentiating catecholamine action, it would in theory increase afferent tone more than efferent tone and lead to a reduction in GFR
Would also in theory cause vasa recta vasoconstriction to reduce medullary washout and potentiate the effect of sympathetically released ADH
- In excess, cortisol has aldosterone-like effects in the kidney causing salt and water retention
- Increases ECV
What cells release renin?
granular cells/juxtaglomerular cells (located close to the macula densa complex)
What is RAAS activated by?
1 - sympathetic nerve stimulation (acting through beta1 adrenoreceptors on JG cells)
2 - renal artery hypotension (caused by systemic hypotension or renal artery stenosis)
3 - decreased sodium delivery to the distal tubes of the kidney
What cells in the kidney sense concentration of Na and Cl in the tubular fluid?
Macula densa cells
What are some functions of angiotensin II?
- Constricts resistance vessels (via AII [AT1] receptors) thereby increasing systemic vascular resistance and arterial pressure
- Stimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing sodium and water retention by the body
- Acts on the adrenal cortex to release aldosterone, which in turn acts on the kidneys to increase sodium and fluid retention
- Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by the kidneys
- Stimulates thirst centers within the brain
- Facilitates noadrenaline release from sympathetic nerve endings and inhibits noradrenaline re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function
- Stimulates cardiac hypertrophy and vascular hypertrophy
What is a counter-RAAS system?
Natriuretic peptides
What facilitates renin release (IC mechanism)?
It is stimulated by anything that increases cAMP levels due to activation of PKA
Activators therefore include:
- catecholamines
- prostaglanding I2 and E2
- inhibitors of cAMP degradation, such as NO and pharamacological inhibitors cAMP-phosphodiesterases, such as milirone
What inhibits renin release (IC mechanism)?
Increase in cytoplasmic calcium
- angiotensin II and endothelin have the ability to mobilise Ca2+ and inhibit renin release
Describe how tubuloglomerular feedback may inhibit renin release
delivery of NaCl to the macula densa. The macula densa is a
collection of densely packed epithelial cells at the junction of the thick ascending limb and
the distal convoluted tubule. This is taken to be a measure of glomerular filtration rate (GFR)
and is related to the blood pressure and effective circulating volume. NaCl enters apical Na-
K-2Cl cotransporters (NKCC2) which leads to an increase in the osmolarity of these cells.
This causes the cell to swell and ATP escape through a maxi-anion channel. This ATP can
further be converted into adenosine. Adenosine binds to A 1 receptors and this is responsible
for a release of calcium and subsequent inhibition of renin release. This is a process known as
tubuloglomerular feedback.
What is ADH released in response to?
Extracellular fluid hypertonicity - when there is a high concentration of solutes in relative to water
3 main functions of ADH
1 - increased transcription of aquaporin 2 in the apical membrane of collecting tubule and collecting duct epithelial cells - water reabsorption - mediated by V2 receptors
2 - increasing permeablity of the collecting duct to urea → reupake of urea to increase osmolarity to drive water further!
3 - acute increase of sodium absorption across the ascending LOH (via NKCC) which adds to countercurrent multiplication
Describe in more detail how ADH cause APQ2 insertion into apical membrane
Binds Gs coupled V2 receptor
Rise in cAMP
PKA
Phosphorylation of IC proteins leads to targeting of AQP2 perforated vesicles to apical membrane
Through what channels does water leave the cells on the basolateral membrane (re ADH)?
- through AQP3 or APQ4
Describe the secondary effect that ADH has on systemic vasculature
It binds toGq coupled V1 receptors[conversion of PIP2 to IP3 and DAG –> IP3 binds to receptors on the ER –> Ca release and formation of Ca-Calmodulin which activates MLCK] to elicit vasoconstriction and raise blood pressure, through increasing vascular resistance.
Describe Cushing’s syndrome
- caused by excessive cortisol-like medication or a tumour that results in the production of excess cortisol by the adrenals (e.g. pituitary adenoma)
- cause of HBP
