Gordens Hypertension Syndrome Flashcards
What is Hypertension?
Is the sustained elevation of blood pressure
What is systolic blood pressure?
> 140 mm Hg
Systolic pressure> cuff pressure
What is diastolic blood pressure?
> 90 mm Hg
Diastolic pressure> cuff pressure.]
What is normal blood flow?
No occlusion of blood flow
What is Blood Occlusion?
cuff pressure blocks blood flow
What is the normal blood pressure?
120/80
What is the blood pressure for pre-hypertension?
120-139/80-88
What is the blood pressure for stage 1 hypertension?
140-159/90-99
What is the blood pressure for stage 2 hypertension?
> 160/100
From what blood pressure does cardiovascular disease risk start to double with each increment of 20/10mmHg?
115/75
What are the environmental risk factors which contribute to hypertension?
Smoking, bad diet and stress.
What are the genetic risk factors which contribute to hypertension?
Mitochondrial genome - signalling - energy transduction - cell death Nuclear genome - arterial factors - kidney and RAAS - mutations - metabolic and local hormonal factors -CNS
What is Gordons Syndrome?
Rare familial form of hypertension; monogenic; fully penetrant- sporadic cases have been reported.
Alternative names - Pseudohypoalsteronsim type II
Familial H& H
What are the features of Gordons syndrome?
Hypertenison
Hyperalkalaemia
Normal renal function
Very sensitive to thiazide diuretics.
How is hypertenision affected in Gordons Syndrome?
Low-renin type - salt dependent
- Aldosterone levels low for degree of hyperkalaemia.
Alternate names
FHHt + PHA2
How is hyperkalaemia affected in Gordons Syndrome?
High serum potassium,
- May be severe (>8mmol/l)
- Metabolic acidosis/ hyperchloraemia(Cl-)
- Muscle weakness
What is the treatment goal in Gordons Syndrome?
Is to reduce the overall cardiovascular risk factors and control BP by the least intrusive means possible.
BP<140/90
In patients with diabetes or renal disease the goal is <130/80
What are the complications of hypertension?
Target organ diseases
can occur in the heart brain, kidney and eyes.
What can causes kidney diseases?
High blood pressure
How does the kidney control salt levels?
The Sodium chloride co-transporter
Sodium potassium chloride cotransporter.
There activity, defines salt concentration in urine,
Affecting the blood volume and arterial pressure,
Could be inhibited by loop or thiazide-type diuretics,
How much of the blood pumped to the heart is filtered?
20%
What does the Sodium chlorine transporter do?
NCC -
Transports sodium and chlorine into the blood. which also maintains ion homeostasis in the blood.
NCC - transmembrane protein.
What happens at the N-terminus of the NCC?
Phosphorylated by SPAK/OSR1, which binds to the RFX1 domain
What is TAL?
Thick accendini loop
Where is the NKCC2? and what does it do?
In the Thick ascending loops.
It extracts Sodium potassium and chlorine from the urine to be reabsorbed into the blood.
Analysis of NCC phosphorylation in the DCT cells
Culture the cells in dishes and treat it with hypotonic low Cl-, The cells are phosphorylated, then in osmotic stress
What would the radio active sodium uptake assay?
To measure the activity
What does Gordons Syndrome entail?
Severe hypertension
High serum levels
Increased Na reabsorption
Sensitivity to thiazide diuretics, antagonists of the Na-Cl co-transporter (NCC).
What has sequence similarity with the MEKK-like kinases?
The kinase domain of WNK
How does WNK 1/4 phosphorylation and activates SPAK and OSR1?
Activation is mediated by T-loop phosphorylation
SPAK and OSR1 are 68% identical, what does this effect?
Possess a highly similar kinase catalytic domain
what does the CC terminal domain on the SPAK/OSR1 bind too?
The RFQV motif on the NKCC2, and the RFTI motif on the NCC, Leucine 502 is important for the binding, and is very conserved.
How does WNK1 signalling pathway work?
- Osmotic stress activates WNK1 by phosphorylation, which phosphorylated SPAK/OSR1, on the T-loop.
- Which regulates the ion channels through phosphorylation NKCC1 NKCC2 NCC
Ubiquitination System
- E1 Activates ubiquitin at the C-terminus through adenylation
- And transfers it to the E2 (Ubiquitin-conjugating enzyme) by transthiolation
- E2 and E3 come together forming a complex, Called ubiquitin ligase.
- E3 binds to degron in the protein, E3 ligates the c-terminus carboxyl group of the ubiquitin to a lysine group on the protein more are added, which can then be recognised by the proteasome.
What is the Proteasome?
Compartmentalised protease, which active sites are sequestered (Inaccessible without admission into its proteolytic chamber)
How does the proteasome work?
- Ubiquitin receptor holds the protein in place.
- Ubiquitin hydrolase (cleaves Ubiquitin from substrate proteins.
- AAA proteins form a hexametric protein unfoldase, it requires ATP, protein is unfolded, Nucleophile attacks bonds in aa.
What mutations cause Gordons Syndrome?
KLHL3 and CUL3
A patient has high blood pressure and high potassium levels what disease could they have?
Gordons Syndrome
A patient with low blood pressure and low serum levels, are likely to have what disease?
Gitelman
What affect does thiazide diuretic have on the body?
Increase renal excretion of Sodium, Potassium and Hydrogen ions (causing metabolic alkalosis)
Decreases renal excretion of calcium
What are the treatments of Gordons trying to do?
Decrease the phosphorylation of NCC
