• Converts Angiotensinogen to Angiotensin I --> rate-limiting step
• It is secreted by the kidney, more specifically the juxtaglomerular cells

• Converts Angiotensin I to Angiotensin II
• Expressed in lung endothelium

1. stimulates zona glomerulosa cells of the adrenal cortex to secrete aldosterone
2. directly stimulates renal proximal tubule reabsorption of NaCl
3. causes efferent arteriolar vasoconstriction which increases intraglomerular pressure and thereby increases GFR
4. stimulates hypothalamic thirst centers and promotes ADH secretion

1. chronic Na depletion upregulates nNOS  -> nNOS increases NO production -> NO reacts with O₂^- to form peroxynitrite -> peroxynitrite activates COX-2 -> COX-2 converts Arachidonic Acid to Prostaglandins -> PGs diffuse to nearby juxtaglomerular cells and stimulate AC via PG receptors (EP₄ and IP) -> [cAMP]_i increase and this augments renin release
2. Increased NaCl transport depletes ATP -> Adenosine levels increase in the macula densa -> ADO diffuses to nearby juxtaglomerular cells and activates the AT₁-G_i pathway -> AC is inhibited and [cAMP]_i decrease -> renin release is inhibited
3. Circulating catecholamines bind to beta1 receptors on the juxtaglomerular cells -> beta1 receptors are coupled with G_s -> AC is activated and converts ATP to cAMP -> [cAMP]_i increase and this augments renin release
4. Circulating angiotensin II binds to AT₁ receptors -> AT₁ receptors are coupled with G_q -> PLC is activated and converts PIP₂ to IP₃ and DAG -> IP₃ binds to IP₃-R on the endoplasmic reticulum -> [Ca²⁺]_i increase and this decreases renin release

• block the formation of angiotensin II and inhibit the breakdown of bradykinin, a vasodilator
• the antihypertensive action of ACEI is primarily caused by a reduction in peripheral vascular resistance
• ACEI decrease both arterial and venous pressure
• by reducing angiotensin-stimulated aldosterone secretion, ACEI prevent the compensatory increase in Na retention and plasma volume
• in patients treated with ACEI, renal Na retention is decreased, whereas renal K retention is increased

1. can cause fetal and neonatal morbidity and mortality when administered to pregnant women
2. can cause renal failure in patients who have bilateral renal artery stenosis
3. most common side effect is dry, non-productive cough caused by increased bradykinin levels
4. rash (captopril increased likelihood, due to SH group)
5. angioedema; painful swelling of lips, face, and throuat
6. abnormal taste sensation (due to -SH group

• the antihypertensive action of ACEI is augmented by diuretics
• ACEI can interact with K-sparing diuretics and K supplements to increase serum K levels and cause hyperkalemia
• ACEI can also increase serum lithium levels and provoke lithium toxicity in patients receiving lithium for the treatment of bipolar disorder
• NSAIDs can reduce the effects of ACEI

• drug of choice for diabetics and patients with chronic renal disease and left ventricular hypertrophy
• ACEI decrease cardiac afterload, increase CO, and reduce the risk of death in patients with heart failure
• in diabetic patients who exhibit early signs of renal impairment, ACEI exert a renoprotective effect

1. hypertension
2. left ventricular systolic dysfunction
3. acute myocardial infarction
4. diabetic nephropathy

• located in vascular and myocardial tissue, brain, kidney, adrenal cortex
• mediates feedback inhibition of renin release
• mediates aldosterone release

• located in the adrenal medulla, kidney, brain, fetal vascular smooth muscle
• mediate vascular development

1. ARBs reduce activation of AT1 receptors more effectively than ACEI
2. In contrast with ACEI, ARBs permit activation of AT2 receptors
3. ACEI increase the levels of a number of ACE substrates (i.e. bradykinin)

• selective for AT1 receptor subtypes (10,000 fold selective)
• block binding of angiotensin II to AT1 receptor
• by preventing effects of angiotensin II, these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume
• cough, an adverse effect of ACEI, has not been associated with angiotensin II antagonists

1. hypotension
2. hyperkalemia
3. reduced renal function
4. should not be administered to patients who are pregnant and breast feeding

• major advantage over ACEI is the low incidence of cough
• angioedema is rare
• it takes 3 - 6 weeks to have the full effects of angiotensin II antagonists on BP
• if BP is not controlled by an angiotensin II antagonist alone, a low dose of a HCTZ or other diuretic may be added

1. hypertension
2. heart failure

• Aliskiren is the first drug of the class of non-peptide, orally active renin inhibitors
• blocks the first rate-limiting step of the renin-angiotensin-aldosterone system
• may present an advantage over ACEIs and ARBs
• Does not affect kinin metabolism

1. may cause fetal and neonatal morbidity and mortality
2. head and neck angioedema
3. hypotension: an excessive fall in BP
4. hyperkalemia
5. renal dysfunction
6. cough; slight increase as compared to placebo

reduce the blood concentrations of furosemide when aliskiren was given with furosemide

so far, combination therapies with diuretics and ARBs have been studied

• ACEI increase the levels of angiotensin I
• ARBs increase the levels of the angiotensin II
• Renin Inhibitors block both angiotensin I and II

Sulfhydryl-Containing ACEI

Phosphate-Containing ACEI