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Drugs: From Molecules to Man - Lecture 13 (12/03/18)
PHYSIOLOGICAL CONTROL OF BLOOD PRESSURE:
SLOW 'COMPENSATORY' CONTROL: FAST CONTROL:The slow control system is provided by the Renin Angiotensin Aldosterone System.
This system acts via both the kidneys and the vasculature to increase blood pressure. It is therefore a major drug target for treating hypertension.
PHYSIOLOGICAL ROLE OF ALDOSTERONE:Acts on specific receptors in collecting duct/tubule
Aldosterone (mineralocorticoid) increases sodium absorption by:
Genomic effects - increasing number of Na+/K+ ATPases
- increasing number of Na+ channels
- stimulating Na+ channels via protein mediator
GENERATION OF ANGIOTENSIN HORMONES:The renin angiotensin system is peptide signally pathway that involves several steps.
Renin itself is a protease that cleaves the precursor of angiotensin, angiotensinogen to produce angiotensin I.
This decameric peptide is inactive, but is further acted upon by the enzyme angiotensin converting enzyme (ACE) to produce the active octomer, angiotensin II.
Angiotensin II can be further cleaved by various enzymes to yield further active products.
Angiotensin II binds to two main receptors. The most important one is the AT receptor type 1 (AT1R). This receptor stimulates aldosterone release from the adrenal cortex and causes vasoconstriction.
PHYSIOLOGICAL CONTROL OF RENIN SECRETION:-
Renin is secreted into the circulation from a distinct set of cells in the juxtaglomerular apparatus.
Its release can be stimulated by:
decreased blood pressure in the kidney
decreased Na+ in the distal convoluted tubule.
TISSUE DISTRIBUTIONS OF
RENIN AND ACE:Renin - discrete (juxtaglomerular apparatus)
"global control" - secreted into circulationglobal control" - secreted into circulationACE - found in many tissues
local production of angiotensins, therefore ACE is locally regulated
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