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 longer the duration of the disease, the more effects on the body organs. Diabetic nephropathy is a term used to define the kidney affected by diabetes. Microalbuminurea is the early manifestation of diabetic nephropathy. Angiotensin Converting Enzyme inhibitors (ACEI) were the first class of antihypertensive drugs shown to reduce the vascular complications among diabetics, independent of blood pressure reduction ⁽¹⁾.

The reno-protective effects of ACEIs were not only beneficial to 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 renal function should not discourage the use of ACEIs in patients with renal insufficiency ⁽³⁾.On the other hand a 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 orally active Angiotensin Receptor Blockers (ARBs) has been added as an alternative method to inhibition of the effect of angiotensin II.

Several effects of ACEIs that may contribute to renal protection and have been related to the association of rise in Kinins which is also responsible for some of the side effects associated with ACEI 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.

The objective of this article is to highlight the points which are not known by most physicians using the ACEIs, such as the history of ACEIs and the base evidence for the use of this group of medications.

In 1954,Skeggs and co-workers start to recognize substrates participated in the physiology of the renin-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⁾. A few 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 effort succeeded, by Squibb to develop the oral form and receive approval from the FDA ⁽¹¹⁾ .Captopril was the first ACEI to 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 started to appear, and in which there were differences in pharmacokinetic activity.

The Angiotensin-Renin-System (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 is composed of two parts. The first is the functional part which contains the hormones and enzymes that mediate the functions of the system. The second part is the anatomical part which contains the anatomical structures. (Figure 1)

A) The functional part:

Renin:
Renin is a glycoprotein synthesized as long preprohormone with 406 amino acid residues. The active Renin contains 340 amino acid residues and primarily and exclusively is produced by the kidneys. The active renin is formed in the secretory granules of the Juxtaglomerular cells in the kidneys.
The function of the renin is to split Angiotensin - I from Angiotensinogen or the Renin substrate ⁽¹⁴⁾.

Angiotensinogen:
Is a protein synthesized in the liver .It is composed of 453 amino acid residues with a characteristic 32 amino acids signal sequence that is removed in the endoplasmic reticulum ⁽¹⁵⁾.

Angiotensin I:
Is a physiologically inactive decapeptide produced by splitting Angiotensinogen by Renin ⁽¹⁵⁾.

Angiotensin II:
Is a physiologically active octapeptide known previously as Hypertensin or Angiotonin. Its half life is 1-2 minutes ⁽¹⁵⁾.

Angiotensin III:
Is a physiologically active heptapeptide resulting from metabolism of Angiotensin II ⁽¹⁵⁾.

Angiotensin Converting Enzyme (ACE) or Kininase II:
Is a dipeptidyl carboxpeptidase that converts Angiotensin I to Angiotensin II ⁽¹⁵⁾.
The Bradykinin which is one of the vasodilator hormones is inactivated 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 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. An example of this is the AT1 receptors in arterioles and AT1 receptors in adrenal cortex .They are regulated in opposite ways. An excess of angiotensin II will down regulate the vascular receptors but up regulate the adrenal cortical receptors making the gland more sensitive to Aldosterone stimulating effect. AT1 receptor is classified into two subtypes. 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 evidence 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 with macula densa cells are called the juxtaglomerular apparatus.

How is the Renin-Angiotensin-System stimulated in diabetes mellitus?
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.
  
• dilate the renal arterioles through stimulation of beta 1 & 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 these. Different pathological changes occurr in kidneys. The sum of these pathological changes may lead to deterioration of renal functions due to vascular and interstitial changes (figure 2).

The renal affection in diabetes will stimulate the Angiotensin-Renin - System (ARS). Deterioration of diabetes control itself will add more to the degree of stimulation of the ARS.

In addition recent research has found that the tissue ARS can be present in abundance in some tissues such as adipose tissue. Investigation of Angiotensin in adipose tissue began in 1987 when Angiotensin-mRNA was found in peri-aortal brown adipose tissue and in cells found within the rat aorta wall ⁽²⁰⁾. Also recent studies showed solid evidence for the existence of an intrinsic Angiotensin generating system in the pancreas s.Recent epidemiological data showed that administration of ACEI in hypertensive patients may exert a 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 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
- Proteinuria
-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 antagonists.

Canadian Hypertension Education Program recommendations.

ACEI is recommended as initial therapy for the following conditions:
- Diabetes mellitus with nephropathy
- Diabetes mellitus without nephropathy
- Angina
- Prior myocardial infarction
- Heart failure
- Post cerebro-vascular accident or transient ischaemic attack
- Renal disease
- Left ventricular hypertrophy

The American Diabetes Association (ADA) clinical recommendations.
The ADA state that all diabetic patients older than 55 years with or without hypertension, but with another cardiovascular risk factor (history of cardio-vascular diseases, dyslipidaemia, microalbuminuria or smoking) an ACEI should be considered.

Combination of ACEI and ARBs can be used 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 used by African Americans to lower their blood pressure. in terms of efficacy, there is no rationale for using race as a reason to avoid certain classes of agents in African American patients with high blood pressure. When prescribing ACEI for blacks, clinicans should note that compared with whites, African Americans 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 to compare the outcome of these patients with the other group receiving 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 with Amlodipine ⁽²⁶⁾.
   

Angiotensin Converting Enzyme inhibitors are a class of antihypertensinve drugs which should be recommended for use by all diabetic patients, especially those with type 2 diabetes mellitus .It can also be used as a renal protective drug.

<< back to text

<< back to text

<< back to text