L11: Secondary Hypertension: new clinical syndromes

Question 1

Definition of hypertension

Answer 1

sustained elevation of systolic and diastolic blood pressure > 140/90 mmHg

Question 2

Causes of secondary hypertension

Answer 2

• renal disease (salt/H2O imbalance)
• adrenal tumours (aldosterone) - tumours that secrete substances that effect RAAS pathway
• aortic coarctation (narrowing of aorta)
• Steroids, drugs, Rx

Question 3

What are determinants of secondary hypertension?
(the causes of 2 hypertension)

Answer 3

< 10% of cases with high blood pressure

• Renal diseases (e.g. Glomerulonephritis, diabetic nephropathy)
• Vascular causes (e.g. Renal artery stenosis)
• Hormonal abnormalities (e.g. Conn’s syndrome, - Cushing’s syndrome, Pheochromocytoma)
• Drugs (Contraceptive pill; liquorice)
  -Pregnancy (Pre-eclampsia)
• Genetic disorders

Question 4

What is this?

Answer 4

GLOMERULONEPHRITIS

Gross features = Inflammation of glomeruli + shrinkage of kidney

• autoimmune
• Acute or chronic
• Kidney is contracted and granular – due to cortical atrophy
• Apoptosis;
• granulation (due to increased fibrosis)
• Causes fluid imbalance -> swelling in the lower limbs- due to filtration issues -> increased BP

Question 5

How can the endocrine system affect BP? (endocrine hypertension)

Answer 5

Adrenal cortex:
- Adrenal adenoma producing aldosterone (Conn’s syndrome) – can be due to benign tumour
- Adrenal hyperplasia – can be due to benign tumour
- Cushing’s syndrome excess cortisol increasing adrenalin’s VASOCONSTRICTIVE effect

Adrenal medulla
- Pheochromocytoma (adrenalin secreting tumour(benign))

Question 6

Drugs that induce hypertension

Answer 6

• NSAIDs
• Oral contraceptives
• Alcohol
• Cocaine
• Erythropoietin
• Glucocorticoids
• Ginseng, yohimbin
• Tyramine and MAO inhibitors (antidepressants)
• Angiogenesis inhibitors

Question 7

How do we know angiogenic inhibitors induce hypertension?/ how does anti-angiogenic induced hypertension occur?

Answer 7

• Angiogenesis: formation of new blood vessels essential for solid tumour growth & metastasis
• Regulated by proangiogenic soluble mediators e.g. vascular endothelial growth factor (VEGF)
• Antiangiogenic drugs that block the VEGF signalling pathway prolong progression free survival in several cancers and are now in broad clinical use
• Hypertension is the most common VS toxicity of this therapeutic class

Question 8

characteristics of kidney cancer?

Answer 8

Highly angiogenic
and highly metastatic

anti-angiogenic drugs used to inhibit growth

Question 9

Evidence that VEGF is involved in maintaining vascular tone

Answer 9

• Hypertension - Low VEGF/VEGF inhibited
• Hypotension - High VEGF

VEGF binds to its receptor KDR (VEGF receptor 2)

Question 10

VEGF signalling: ligands and their receptor

Answer 10

• VEGF (VEGF-A) binds to VEGFR-1 (FLT-1) + VEGFR-2 ((FLK-1/KDR) role in cell signalling)
• Neuropilins (NRP1, NRP2) are VEGF co-receptors but can also signal independently
• VEGF-B has restricted angiogenic activity e.g. in heart
• VEGF-C + VEGF-D involved in vasculogenesis + lymphangiogenesis

Question 11

VEGF signalling pathways - role of endothelium in VEGF + downstream effects of VEGF.

Answer 11

VEGF binds to VEGFR 2-> multiple pathways activated:
Endothelial cell induces relaxation effect through NO = causes vasodilation
Angiogenesis induced through PIP2 calcium signalling
Protein Kinas B pathway activated – cell survival increased, apoptosis reduced
RAS/RAF/MEK/MAPKinaes pathway activated – increases gene expression, transcription + cell proliferation of endothelial cells, can induce angiogenesis
Blocking VEGF binding blocks a lot of these processes – NO induction prevented, vascular tone increases