2. INTRODUCTION
ANGIOTENSIN-CONVERTING ENZYME (ACE) is a dipeptidyl peptidase transmembrane
bound enzyme.
A soluble form of ACE in plasma is derived from the plasma membrane-bound form
by proteolytic cleavage of its COOH-terminal domain.
There are two distinct isoforms of ACE: somatic and testicular. They are transcribed
from a single gene at different initiation sites.
The somatic form of ACE is a large protein (150 –180 kDa) that has two identical
catalytic domains and a cytoplasmic tail. It is synthesized by the vascular endo-thelium
and by several epithelial and neural cell types.
The testicular form of ACE is a 100- to 110-kDa protein that has a single catalytic
domain corresponding to the COOH terminal domain of somatic ACE and is only found
in developing spermatids and mature sperm where it may play a role in fertilization.
5. ANGIOTENSINOGEN
ANGIOTENSIN I
ANGIOTENSIN II
ANGIOTENSIN III
Renin
ACE
Aminopeptidase
Non-ACE
(eg. Chymase
in heart)
Angiotensin 1-7
Releases ADH; ↑ PG;
Natriuretic; ↓ RVR;
↓ BP (brain stem inj.)
? Role in effects of ACEI
1 2 3 7 8 9 10
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2 3 7 8
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2 3 7 8
NH2-Arg-Val…Pro-Phe-COOH
2 3 7 8
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
+
1. ↓ Renal Perfusion
Pressure
2. ↓ Na at Macula
Densa cells
3. ↑ Sympathetic
nerve activity (ß-1)
±PG
The Renin-Angiotensin System
6. MECHANISM
ACE inhibitor amplified the effects of bradykinin in vessels that
lacked measurable ACE activity
ACE inhibitors also directly activate the bradykinin B1 receptor,
acting at the Zn-binding pentameric consensus sequence HEXXH of
the B1 receptor
A motif that is present in the active center of ACE but absent
from the B2 receptor
ACE inhibitors also induce phosphorylation of the ACE
intracellular tail (Ser1270) via CK2, resulting in outside-in signaling
that enhances expression of ACE and cyclooxy-genase-2
The effect of the ACE inhibitor on COX-2 is due to the
transcription factor activator prot-ein-1(AP-1). This results in
increased release of prostacyclin and prostaglandin E2 by the
endothelial cells that is independent of local accumulation of
kinins
Competitive
inhibition of ACE
reduces generation
of angiotensin II and
consequently
reduces the release
of aldosterone .
9. The venom peptide teprotide, a long-acting
angiotensin-converting enzyme (ACE) inhibitor,
initiated research that led to the development of
captopril and subsequently lisinopril. These drugs
were designed to bind to a 'classical model' of the
ACE active site (underlined in red) in the same
manner as predicted for the venom peptide
analogue, and to be orally active. The recently
obtained crystal structure of the ACE–lisinopril
complex provides the first high-resolution
template that could allow the design of improved
ACE inhibitors for the treatment of cardiovascular
diseases. A space-filling model of lisinopril (red)
co-crystallized in the active site of ACE is shown
on the left, with its bound conformation
highlighted in expanded view on the right,
confirming the Phe/S1 and Pro/S2' interactions
originally predicted by the classical model.
An experimentally derived model of a snake toxin
(-cobratoxin; shown in red) docked onto the 7
nicotinic acetylcholine receptor. Interestingly, the
key binding residues (shown in expanded view on
the right) are clustered in loop 2 of the snake
toxin (shaded portion on the left). By engineering
a structural clip (dashed line) that works in
synergy with the crucial disulphide bond (light
yellow) at the tip of loop 2, it might be possible to
achieve this conformation in a smaller
peptidomimetic. However, agonists rather than
antagonists are typically needed for the
treatment of a diverse range of neurological
diseases. Whether this approach can be extended
to the development of subtype-specific, orally
active agonists remains to be seen
12. PHARMACOKINETICS OF ACE INHIBITORS
• Some are primany eliminated by kidney.
• Others are eliminated in bile and feces.
• Useful in selection of patients – Reduced
Kidney Function Or Liver Function.
• Except CAPTORIL (capoten) and LISINOPRIL
(prinivil, zestril) all other are inactive.
13. CONDITIONS FOR ACE INHIBITORS USAGE
• Stroke.
• Hypertension.
• Antihypertensive.
• Reverse left ventricular hypertrophy and vascular disease.
• Prevent remodeling after myocardial infarction.
• Slow progression of heart failure.
• Slow progression of renal disease (diabetes, microal buminuria).
• Prevent diabetes.
• Prevent cancer and slow the aging process.
14. Uses of ACE inhibitors
• Treatment of hypertension .
• Treatment of heart failure .
• Secondary prevention after myocardial infarction .
• Diabetic nephropathy in insulin dependent diabetes .
15. Side effects of ace inhibitors
•Dizziness
•Headache
•Drowsiness
•Diarrhea
•Low blood pressure
•Weakness
•Cough dry
•Rash
•Many cause birth defects
•Swelling of tissues
16. References:-
Hecker M, Blaukat A, Bara AT, Mu¨ ller-Esterl W, and Busse R. ACE inhibitor
potentiation of bradykinin-induced venoconstriction. Br J Phar-macol 121: 1475–1481,
1997.
Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, and Erdo¨ s EG. Activation of bradykinin
B1 receptor by ACE inhibitors. Int Immunophar-macol 2: 1787–1793, 2002.
Peng H, Carretero OA, Vuljaj N, Liao T-D, Motivala A, Peterson EL,and Rhaleb N-E.
Angiot -ensin-converting enzyme inhibitors: a new mech-anism of action.
Young ME, Leighton B. 1998. Evidence for altered sensitivity of the nitric oxide/cGMP
signalling cascade in insulin-resistant skeletal muscle. Biochem J 329:73–79.
Roberts CK, Barnard RJ, Scheck SH, Balon TW. 1997. Exercise-stimulated glucose
transport in skeletal muscle is nitric oxide dependent. Am J Physiol Endocrinol Metab
273:E220–E225.
Cartee GD, Douen AG, Ramlal T, Klip A, Holloszy JO. 1991. Stimulation of glucose
transport in skeletal muscle by hypoxia. J Appl Physiol 70:1593–1600.
