Lecture 10 - Cardiovascular Pharmacology Flashcards
Describe RAAS?
Feedback system involving BP, blood volume and electrolyte homeostasis. Implicated in many pathologies. Two main enzymes in series = renin and ACE. Stimulated by decreased renal perfusion.
Renin and ACE
Renin = proteolytic enzyme secreted by juxtaglomerular cells in response to low sodium conc, decreased renal perfusion pressure, renal sympathetic nerve activity, B-adrenoreceptor agonists and prostaglandin I2. SECRETION INHIBITIED BY ANGII and ANP.
ACE = membrane bound dipeptidyl carboxylase which cleaves C-terminal peptides in Ang I and bradykinin (inacitvates bradykinin).
Fyhrquist, 2008?
Other angiotensin peptides exist, derived from Ang I/II by actions of other proteolytic enzymes.
Ang III/IV/1-7 appear to have biological effects that oppose action of Ang II.
Angiotensin receptors?
GPCRs - multiple subtypes, main actions of AngII mediated by AT1R/AT2R - similar affinity.
Acute effects of AT1R?
Vasoconstriction (40x more than NE)
Increased NE release from sympathetic neurons
Stimulation of proximal tubular Na+ reabsorption
Aldosterone secreted from adrenal cortex
Chronic effects of AT1R?
Vascular growth (hyperplasia and hypertrophy) Fibrosis and increased oxidative stress
Effects of AT2R?
Anti hypertrophic and anti hypertensive effects
Effects of Ang 1-7? (SANTOS, 2003 and 2006)
MAS1 oncogene = GPCR that binds Ang 1-7 and opposes effects of AT1R. Suggested that MAS receptor antagonists have similar therapeutic effects as AT1R antagoinsts.
AT4R? (Vanderheyen, 2009)
Membrane bound insulin regulated aminopeptidase
How does AT1R mediated vasoconstriction happen?
AngII binds receptor - Gq –> PLC cleaves PIP2 to IP3 and DAG –> PKC and Ca2+ release –> activates MLCK –> MLC –> contraction
Aldosterone?
Steroid hormone from outer section of adrenal cortex - controls BP by acting on distal tubules and collecting ducts of nephron. Promotes Na+/H2O retention.
RECEPTOR = nuclear receptor
Mechanism of action of aldosterone?
- Upregulates and activates basolateral Na+/K+ pumps: pumps 3 Na+ out for 2 K+ resulting in Na+ (and H2O) reabsorption in blood and secretion of K+ in urine.
- Upregulates epithelial sodium channels (ENaCs) - increased apical membrane permeability for Na+.
- Cl- reabsorbed with Na+ to maintain electrochemical balance.
When dysregulated –> pathogenic and contributes to CV/renal disease.
4 types of drug targeting RAAS?
Renin inhibitors
ACE Inhibitors
AT1R antagonists
Aldosterone receptor antagonists
Renin inhibitors?
prevent cleavage of angiotensinogen –> Ang I.
Essential hypertenson.
Few side effects. Contraindicated with ACEi and ARBs.
ALISKIREN
ACE Inhibitors?
Inhibits cleavage of Ang I to Ang II.
Hypertension and HF.
Adverse effects = hypotension (after 1st dose), dry cough, angioedema (accumulating circulating bradykinin), hyperkalaemia and renal failure (renal artery stenosis).
RAMIPRIL
