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The Renin-Angiotensin System
1. ↓ Renal Perfusion
Pressure
2. ↓ Na at Macula
Densa cells
3. ↑ Sympathetic
nerve activity (ß-1)
Non-ACE
(eg. Chymase
in heart)
Angiotensinogen
±PG
+
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
1 2
3
7
8 9 10
Renin
Angiotensin I
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2
3
7
8 9 10
ACE
Angiotensin II
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2
3
7
8
Aminopeptidase
Angiotensin III
Angiotensin 1-7
Releases ADH; ↑ PG;
Natriuretic; ↓ RVR;
↓ BP (brain stem inj.)
? Role in effects of ACEI
NH2-Arg-Val…Pro-Phe-COOH
2
3
7 8
ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE
Cardiac & Vascular
Hypertrophy
↑ Cardiac
Contractility
Sympathetic
Facilitation:
Central
Nerve terminal
(ganglionic ?)
Vasoconstriction
Direct Renal
Sodium Retention
Angiotensin II
Aldosterone
Secretion
↑ Thirst
ADH Release
All known physiologic effects are mediated
by the angiotensin II type 1 receptor
Angiotensin Converting
Enzyme Inhibitors

Large number of drugs available differ
mainly in the following:
1.
Potency
Route of elimination
Duration of action
Being prodrugs or active drugs
2.
3.
4.

Similar therapeutic indications, adverse
effects and contraindications
Adverse Effects
• Hypotension
• Renal Insufficiency (if bilateral renal artery
stenosis)
• Hyperkalemia – special group of patients (Na
restricted, on K-sparing diuretic, COX inhibitors)
• Cough (20 %)
Kinin-related (?)
• Angioedema
• With captopril especially: neutropenia, nephrotic
syndrome, skin rash, taste disturbances (SH grouprelated).
Binds to Zn ion
Binds to active site
Enalapril
Binds more strongly
to Zn – more active
Lisinopril
ACE Inhibitors and Left Ventricular Hypertrophy
ACE Inhibitors and Left Ventricular Hypertrophy
ACE Inhibitors after Myocardial Infarction
ACE Inhibitors in Heart Failure
Study of LV Dysfunction (SOLVD)
Asymptomatic Patients with EF<40%
ACE Inhibitors in Severe Heart Failure
Probability of Sudden Death
Placebo
Captopril
Probability of Survival
Mortality Rate
Survival and Ventricular Enlargement Trial (SAVE)
Captopril
Hydralazine
Patients with Severe Heart Failure
Placebo
Enalapril
Cooperative New Scandinavian
Enalapril Survival Study (CONSENSUS)
Enalapril
Metoprolol
Metoprolol
Enalapril
ACE Inhibitors – Effect on
Progression of Diabetic
Nephropathy
ACE Inhibitors – Effect on
Progression of Non-Diabetic
Nephropathy
Therapeutic Uses
• Anti-hypertensive
• Prevent or reverse LVH
• Protect against sudden death and second
myocardial infarction after acute MI
• Improve survival and hemodynamics in
patients with congestive heart failure
• Protect against progression of diabetic and
non-diabetic nephropathy
Angiotensin II Type 1 Receptor Blockers
Losartan
Valsartan
Candesartan
Angiotensin Receptor Blockers
e.g. Losartan
• Block only the AT-1 subtype
• Comparable effects to ACE Inhibitors in almost all
situations.
• Less decrease in GFR in volume depleted states
Kinins
• Less side effects especially cough, angioedema,
(?)
rash
• Block all AII effects and not dependent on
particular pathway
3 month mortality (%)
P: Placebo
E: Enalapril
L: Losartan
C: Captopril
P
E
P
L
SOLVD
US +Int’l
Exercise
(n=2569)
(n=736)
C
L
ELITE
(n=722)
Fig. 3: 3-month mortality in three different studies
ELITE STUDY GROUP (Evaluation of Losartan in the Elderly) –
Losartan better than captopril in patients with heart failure (chance finding?)
ELITE STUDY GROUP
Losartan Superior to Captopril (? Chance Finding)
Probability of Survival
Losartan
Captopril
Follow-up (days)
ELITE II STUDY GROUP (3,152 patients for 1.5 y)
No Difference between Captopril and Losartan
Probability
Of Survival %
Event-free
Probability %
Lancet. 2000;355:1582-7.
Hypertensive Patients with Nephropathy
AII Receptor Blocker
ACE Inhibitor
Blocks formation
Blocks Kininase II
of AII incompletely
↓ AII effects
& aldosterone
Blocks
AT-1R
AT-2R
Free
↑ Kinins More complete Preserve
Inhibition
of AII effects
PROTECTION
Antiproliferative
effect