Diabetes Mellitus and Angiotensin Converting Enzyme Inhibitors
Dr.Almoutaz Alkhier Ahmed
Saudi Arabia/Gurayat North
Gurayat General Hospital / Diabetic Center
Diabetes mellitus is one of the diseases that affect different systems in the body. The kidneys are an example for those organs affected by diabetes. The long the duration of the disease, the more effects on the body organs. Diabetic nephropathy is a term used to define the kidney affection by diabetes.Microalbuminurea is the early manifestation of diabetic nehropathy.Angiotensin Converting Enzyme inhibitors (ACEI) were the first class of antihypertensive drugs that shown to reduce the vascular complications among diabetics independent of blood pressure reduction (1).
The reno-protective effects of ACEIs were not only benefited by those with overt nephropathy(stage of macroalbuminuria), but also extend to cover those with incipient nephropathy (stage of microalbuminuria) even if they were not hypertensive (2). Slow deterioration in the renal functions should not discourage the use of the ACEIs in patients with renal insufficiency (3).On the other hand rapid progressive rise in Serum Creatinine following initiation of ACEIs should prompt the immediate discontinuation of the agent and further evaluation of the patient for advanced renovascular disease(3). The development of the orally active Angiotensin Receptor Blockers (ARBs) has been added an alternative method to inhibit the effect of angiotensin II.
Several effects of the ACEIs that may contribute to renal protection have been related to the association of rise in Kinins which is also responsible for some of the side effects associated with ACEIs therapy such as dry cough (4). The renal protection effect is related to the antihypertensive effects in normal and hypertensive patients, renal vasodilatation resulting in increased renal blood follow and dilatation of the efferent arterioles.
History of Angiotensin Converting Enzyme Inhibitors:
In 1954,Skeggs and coworkers start to recognized substrates participated on the physiology of the rennin-angiotensin system (5) .
In 1956 Skeggs et al potentially purified the enzyme responsible for conversion of the inactive Angiotensin I to the active vasoconstrictor angiotensin II in the presence of chloride ion from horse plasma (6).
In 1965,Ferreira showed that non toxic ethanol extract of the venom of Brazilian viper- Bothrops Jararaca- potentiated smooth muscle contraction, hypotension and increased capillary permeability induced by bradykinin (7).View years passed before it become clear that Angiotensin Converting Enzyme was bradykininase inhibited by the Bradykinin potentiating factor (BPF).In 1968,Bakhle reported that BPF was a potent inhibitor of angiotensin converting enzyme of dog lung homogenate, and the long delayed purification of the active components of BPF was initiated by two groups (8). The first one led by Ferreira in 1970 (9) and the second group was led by Ondetti in 1971 (10). Structure –activity correlation among analogs of BPF suggested that these snake venom peptide inhibitors compete with substrates for binding to the active site of ACE.
In early 1974, the efficacy of converting-enzyme inhibitors as antihypertensive drugs had been demonstrated, but it was early to be presented in an oral form for use in chronic therapy. In the early 1980, the efforts was succeed by Squibb to develop the oral form and receive the approval from the FDA (11) .Captopril was the first ACEI to be appear in the market with a trade name Capoten (11).Since that date a series of discoveries of other members of the group of ACEIs were started to appear in which they differ in their pharmacokinetic.
Physiology of Angiotensin-Renin-System (ARS):
The Angiotensin-Renin-System (ARS) is one of the greatest gifts of our god. The ARS is located mostly in our kidneys . The system plays a major role in maintaining blood pressure, fluid and electrolytes in our body (12) (13).
The system composed of two parts. The first one is the functional part which contains the hormones and enzymes mediate the functions of the system. The second part is the anatomical part which contains the anatomical structures form this system (Figure 1).
A) The functional part:
The Renin is a glycoprotein synthesized as long preprohormone with 406 amino acid residues. The active Renin contains 340 amino acid residues and it is primarily and exclusively produces by the kidneys. The active rennin is formed in the secretory granules of the Juxtaglomerular cells in the kidneys.
The function of the rennin is to split Angiotensin - I from Angiotensinogen or the Renin substrate (14).
It is a protein synthesized in the liver .It is composed of 453 amino acid residues with characteristic 32 amino acids signal sequence that is removed in the endoplasmic reticulum (15).
It is a physiologically inactive decapeptide produced by splitting Angiotensinogen by Renin (15).
It is a physiologically active octapeptide known previously as Hypertensin or Angiotonin.It is rapidly metabolite in the circulation. Its half life is 1-2 minutes (15).
It is physiologically active heptapeptide resulting from metabolism of Angiotensin II (15).
Angiotensin Converting Enzyme (ACE) or Kininase II:
It is a dipeptidyl carboxpeptidase that converts Angiotensin I to Angiotensin II (15).
The Bradykinin which is one of the vasodilator hormones is inactivating by the same enzyme . Most of the converting enzyme that forms Angiotensin II in the circulation is located in endothelial cells (16). Most of the conversion occurs as the blood passes through the lungs. Conversion is also occurs in many other parts of the body.
Angiotensins have different functions in the human body (table 1).
B) The anatomical part:
Angiotensin II receptors (17):
There are at least two classes of Angiotensin II receptors (AT).One of them is the Angiotensin recptor 1 (AT1).The gene for this receptor is located on chromosome 3. The other receptor (AT2) is less important than the previous one. Its gene is located on chromosome X. The effect on the same receptor may differ from tissue to tissue. Example for this is the AT1 receptors in arterioles and AT1 receptors in adrenal cortex .They are regulated in opposite way. An excess of angiotensin II will down regulates the vascular receptors but up regulates the adrenal cortical receptors making the gland more sensitive to Aldosterone stimulating effect.AT1 receptor is classified into two subtype,AT1A is located mainly in the blood vessel walls, the brain and other organs. It mediates most of the known effects of Angiotensin (18).
The AT1B is found in the anterior pituitary and the adrenal cortex.
AT2 receptors are more plentiful in fetal and neonatal life, but they persist in brain and other organs in adults.AT2 receptors are important in fetal kidney development, modulation of pressure-natriuresis,angiotensin II-induced renal production of nitric oxide and renal conversion of prostaglandin E2 to prostaglandin F2alpha (19).In addition,experimental evidences suggests that AT2 receptors may counterbalance some of the effects mediated by AT1 receptors.
The juxtaglomerular apparatus:
Renin is produced by the juxtaglomerular cells. These cells are epitheloid cells located in the media of the afferent arterioles as they enter the glomeruli.It is also found in granular Lacis cells that are located in the junction between the afferent and efferent arterioles.
The macular densa is a modified region of tubular epithelium located at the beginning of the distal convoluted tubule in proximity to the juxtaglomerular cells.
The juxtaglomerular cells in combination to macula densa cells are called the juxtaglomerular apparatus.
How can the Renin-Angiotensin-System stimulated in diabetes mellitus?
The Diabetic patients need to stimulate their sympathetic nervous system more than non diabetics due to their need:
- To increase the secretion of insulin from the beta cells through stimulation of beta2 receptors.
- Their need to dilate the renal arterioles through stimulation of beta1&2 receptors.
Why do diabetics need to dilate their renal arterioles?
Diabetes as a multisystem disease has different progressive effects on human body organs. The kidneys are one of those victims. Different pathological changes occurred in kidneys. The sum of these pathological changes may lead to deteriorate renal functions due to vascular and interstitial changes (figure 2).
The renal affection in diabetes will stimulate the Angiotensin-Renin - System (ARS). Deterioration of the diabetes control itself will add more to the degree of stimulation of the ARS.
In addition recent researches found that the tissue ARS can be present in abundant in some tissues such as adipose tissue. Investigations of Angiotensin in adipose tissue began in 1987 when angiotensin-mRNA was found in periaortal brown adipose tissue and in cells found within the rat aorta wall (20).Also recent studies showed solid evidences for the existence of intrinsic angiotensin generating system in the pancrease.Recent epidemiological data showed that administration of ACEI in hypertensive patients may exert protective role in prevention the occurrence of diabetes (21). This fact explains why some antidiabetic drugs such as Thiazoladinodiaone can decrease blood pressure in obese diabetics when it is used.
ACEI in the recommendations of the international health bodies:
The clinical recommendations and the guidelines of many medical and diabetic societies or associations include the recommendation of using ACEI in diabetes.
The European Society of hypertension-European Society of cardiology guidelines for the management of arterial hypertension indicates the use of ACEI in the following conditions:
- Congestive heart failure, left ventricular dysfunction
- Post-myocardial infarction
- Non- diabetic nephropathy
- Type 1 diabetic nephropathy, proteinuria
But they indicate Angiotensin Receptor blocker in the following conditions:
- Type 2 diabetic nephropathy
- Diabetic microalbuminurea
-Left ventricular hypertrophy
- ACEI induce cough
Superiority of ACEI in preventing the aggregate of major cardiovascular events is limited to two trials, one against diuretics/beta blockers and the other against Calcium antagonist.
Canadian Hypertension Education Program recommendations.
ACEI is recommended in initial therapy for the following conditions:
- Diabetes mellitus with nephropathy
- Diabetes mellitus without nephropathy
- Prior myocardial infarction
- Heart failure
- post cerebro-vascular accident or transient ischemic attack
- Renal disease
- Left ventricular hypertrophy
The American diabetes association clinical recommendations.
The ADA state that all diabetic patients older than 55 years with or without hypertension, or with or without but with another cardiovascular risk factor (history of cardio-vascular diseases, dyslipidaemia, microalbuminuria or smoking) an ACEI should consider to be use.
Combination of ACEI and ARBs can be use in treatment of albuminuria and diabetic nephropathy.
The 7th report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure.
This report indicates the use of ACEI in the following conditions:
- Hypertension with acute coronary syndromes (unstable angina and myocardial infarction)
- Post myocardial infarction
- Heart failure
- Diabetic hypertension
- Chronic kidney disease. Limited increase in serum creatinine of as much as 35% above the baseline with ACEI or ARBs is acceptable and should be a reason to withhold treatment unless hyperkalaemia develops.
- Cerebrovascular disease.
Management of high blood pressure in African Americans.
All antihypertensive drug classes can be use by African American to lower their blood pressure. in terms of efficacy, there is no rational for using the race as reason to avoid certain classes of agents in African American patients with high blood pressure .when prescribing ACEI for blacks,clinican should note that compared with whites, African American appear to be at increased risk for ACEI associated angioedema or cough or both.
Clinical trials assess the use of ACEI in diabetic and non diabetics:
In these trials, patients with type 2 diabetes mellitus have been randomized to receive ACEI as initial therapy and compare the out come of these patients with the other group receive other antihypertensive drugs.
1) The UK prospective diabetes study (UKPDS-1998).Compared the effect of Captopril versus Atenolol (22)
2) Micro-Hope Diabetic substudy (2000) of the larger heart outcomes prevention evaluation study (23).Compared the use of Ramipril versus Placebo.
3) The Appropriate Blood Pressure Control in Diabetes (ABCD-1998) trial (24).Compared the use of Enalapril versus Nisoldipine
4) Captopril Prevention Project (CAPPP-2000).Compared the use of Captopril versus diuretic or beta-blockers (25)
5) Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET-2000).This trial compared the use of Fosinopril versus Amlodipine (26).
Angiotensin Converting Enzyme inhibitors is a class of antihypertensinve drugs which should be recommended to be use by all diabetic patients especially those with type 2 diabetes mellitus .It is not used only as antihypertensive drug but it is also use as renal protective drug.
1) Lewis EJ,Hunsicker LG,Bain RP,Rohde RD,for the collaborative study group:the effect of angiotensin-converting enzyme inhibition on diabetic nephropathy Engl J Med 1993,329:1456-1462.
2) The ACE inhibitors in diabetic nephropathy trialist group:should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin – converting enzyme inhibitors? Ameta-Analysis of individual patient data.Ann intern med 2001,134:370 – 379.
3) Bakris GL,Weir MR: ACE inhibitors-assocoaited elevations in serum Creatinine:is this a cause for concern?.Arch intern med 2000,160:685 – 693.
4) Israili ZH,Hall WD:Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy:A review of the literature and pathophisiology.Ann Intern Med 117:324-242,1992.
5) Skeggs,L.T.,Jr.,Marsh,W.H.,Kahn,J.R.,and Shumway,N.P.1954.The existence of two forms of hypertensin.J Exp Med 99:275-282.
6) Skeggs, L.T., Kahn, J.R., and Shumway, N.P.1956.The preparation and function of the hypertensin converting enzyme..J Exp Med 103:295-299.
7) Ferreira,S.H.1965.A bradykinin-poteniating factor (BPF) present in the venom of Bothrops jararaca.Brit J Pharmacol 24:163-169.
8) Bakhle,Y.S.1968.conversion of angiotesin I to angiotensin II by cell free extracts of dog lung.Nature 220:919-921.
9) Ferreira,S.H.Bartel,D.C. and Greene,L.J.1970.Isolation of bradykinin-poteniating peptides from Bothrops Jararaca venom.Biochemistry 9:2583-2593.
10) Ondetti,M.A,Williams,N.J,Sabo,E.F.,Pluscec,J.Weaver,E.R.,and Kocy,o.1971.Angiotensin-converting enzyme inhibitors from the venom of Bothrops Jararaca.Isolation,elucidation of structure,and synthesis.Biochemistry 10:4033 – 4039.
11) Reichert, J. M., Milne, C.-P. (2002) Public and private sector contributions to the discovery and development of ‘impact’ drugs Tufts Center for the Study of Drug Development Boston MA.
12) Page IH&Bumus FM 1974 Angiotensin.New York:Springer Verlag.
13) Fitzimons JT 1998 Angiotensin,thirst and sodium appetite.Physiological Reviews 78 583-686.
14) Menard J,Clauser E,Bouhnik J & Corvol P 1993 Angiotensinogen:biochemical aspects. In the Renin Angiotensin System,pp 8.1-8.10.Eds JIS Robertson & MS Nichollas.London:Gower Medical Publishing.
15) William F.Ganong.Review of medical physiology 19th edition.Appleton & Lange 1999.
16) Caldwell PRB,Seegal BC,Hsu KC,Das M & Soffer RL 1976 Angiotensin-converting enzyme:vascular endothelial localization.Science 191 1050-1051.
17) De Gasparo M ,Catt KJ,Inagami T,Wright JW & Unger TH 2000 angiotensin II receptors. Pharmacological Reviews 52 412-472.
18) Chung O,Kuhl H,Stoll M,Unger T: physiology and pharmacological imilications of AT1 versus AT2 receptors.Kidney Int 54(Suppl 67):S95-S99,1998.
19) Siragy HM,Carey RM:the subtype 2 (AT2) angiotensin receptor regulates renal prostaglandin F2 alpha formation in conscious rats.Am J Physiol 273:R1103-R1107,1997.
20) Campbell DJ,Habener JF.Cellular localization of AGT gene expression in brown adipose tissue and mesentry:quantification of messenger ribonucleic acid abundance using hybridization in site.Endocrinology.1987;121:1616-1626.
21) Stern MP 1995 Diabetes and cardiovascular disease:the common soil hypothesis.diabetes 44 369-374.
22) EEficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes:UKPDS 39.UK prospective diabetes study group.BMJ.1998;317(7160):713-720.
23)Effects of Ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus:result of HOPE study and MICRO-HOPE substudy.Heart Outcome Prevention Evaluation study investigators.Lancet 2003;355(9200);253-259.
24) Villarosa IP,Bakris GL.The appropriate blood pressure control in diabetes (ABCD) trial Human Hypertension 1998 Sep;12(9):653-5
25) Scheen AJ.Clinical study of the month.The CAPPP Study:the Captopril Prevention Project.Rev Med Liege 1999;54(3):197-9
26) Tatti P,Pahor M,Byington RP,Di Mauro P,Guarisco R,Strollo F.outcome results of the Fosinopril versus Amlodipine Cardiovascular events Randomized Trial (FACET) in patients with hypertension and NIDDM.Diabetes Care.1998;21 (4):597-603.