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Almoutaz Alkhier Ahmed, MBBCh, Senior Resident, Gurayat General Hospital, Diabetic Center, Gurayat North, P.O.Box 672, Saudi Arabia Angiotensin converting enzyme inhibitors (ACEI) are one of the beneficial groups of drugs for diabetic patients. ACEI is antihypertensive and provides renoprotection for diabetic patients. Physicians involved in the management of diabetes should be familiar with this group and know most of its effect and side effects. This article concentrates on the history of these drugs. It also reviews the international use of this group and reviews some of the trials supporting the use of this group of drugs in diabetes management.
Introduction
Diabetes mellitus affects many different systems in the body, including the kidneys. The longer the duration of the disease, the greater the effects on the various organs. Diabetic nephropathy is the term used to indicate the changes that occur in the kidney as a result of diabetes; the earliest manifestation of diabetic nephropathy is usually microalbuminuria.
Angiotensin-converting enzyme (ACE) inhibitors were the first class of antihypertensive drugs shown to reduce the vascular complications in those with diabetes independent of a reduction in blood pressure.1 The reno-protective effects of ACE inhibitors were not only seen in those with overt nephropathy (macroalbuminuria), but also extend to those with incipient nephropathy (microalbuminuria), even in the absence of hypertension.2
A slow deterioration in renal function is not a contraindication to the use of ACE inhibitors in patients with renal insufficiency, but a rapid progressive rise in serum creatinine following initiation of ACE inhibitors should trigger immediate discontinuation of the agent and further evaluation of the patient for advanced renovascular disease.3
Several of the reno-protective effects of ACE inhibitors have been related to the increase in kinins that occurs with these agents, which is also responsible for some of the side-effects associated with ACE inhibitor therapy such as a dry cough.4 Renal protection is related to the antihypertensive effects of ACE inhibitors in both normal and hypertensive patients: renal vasodilatation results in increased renal blood flow and dilatation of the efferent arterioles.
The history of ACE inhibitors
In 1954, Skeggs and coworkers5 started to recognize substrates participating in the renin–angiotensin system. In 1956, they purified the enzyme responsible for the conversion of inactive angiotensin I to the active vasoconstrictor angiotensin II in the presence of chloride ions from horse plasma.6
In 1965, Ferreira7 showed that a non-toxic ethanol extract of the venom of the Brazilian viper Bothrops jararaca potentiated the smooth muscle contraction, hypotension and increased capillary permeability induced by bradykinin. However, some years passed before it became clear that ACE was the same as bradykininase and was inhibited by bradykinin-potentiating factor (BPF). In 1968, Bakhle8 reported that BPF was a potent inhibitor of ACE from dog lung homogenate, and the long delayed purification of the active components of BPF was initiated by two groups – the first led by Ferreira in 19709 and the second led by Ondetti in 1971.10 Structure–activity correlation amongst the analogues of BPF suggested that these snake venom peptide inhibitors compete with substrates for binding to the active site of ACE.
By early 1974, the efficacy of ACE inhibitors as antihypertensive drugs had been demonstrated, but they were not yet available in an oral form for use in chronic hypertension. In the early 1980s, Squibb succeeded in developing an oral form known as captopril (Capoten) and received approval from the USA Food and Drug Administration for this drug.11 Since that time a number of other ACE inhibitors have been developed with differing pharmacokinetic qualities. More recently, the development of the orally active angiotensin-receptor blockers (ARBs) has added an alternative way to inhibit the effects of angiotensin II.
The superiority of ACE inhibitors in preventing the aggregate of major cardiovascular events has been demonstrated in two trials:12-13 one in which these agents were compared with diuretics/beta blockers and the other against a calcium antagonist.
The renin–angiotensin system
The renin–angiotensin system is located mostly in the kidney and plays a major role in the homeostatic regulation of blood pressure, fluid and electrolytes.14,15 It is composed of both functional and anatomical aspects (Table 1).
Functional aspects
The functions of the renin-angiotensin system are mediated by a number of hormones and enzymes.
Renin
Renin is a glycoprotein synthesized as a long preprohormone composed of 406 amino acid residues. Active renin contains 340 amino acid residues and is exclusively produced by the kidneys, being formed in the secretory granules of the juxtaglomerular cells. It converts the plasma protein angiotensinogen to angiotensin I.16
Angiotensinogen
Angiotensinogen is a protein synthesized in the liver. It is composed of 453 amino acid residues with a characteristic 32 amino acid signal sequence that is removed in the endoplasmic reticulum.17
ACE
ACE (also known as kininase II) is a dipeptidyl carboxpeptidase that converts angiotensin I to angiotensin II.17 It is located mainly in endothelial cells.18 Bradykinin, one of the vasodilator hormones, is inactivated by the same enzyme. Most of the conversion of angiotensin I to angiotensin II occurs as the blood passes through the lungs, though it also takes place in many other parts of the body.
Angiotensin I, II and III
Angiotensin I is a physiologically inactive decapeptide that is produced by the action of renin on angiotensinogen.17 Angiotensin II is a physiologically active octapeptide known previously as hypertensin or angiotonin. It is rapidly metabolized in the circulation, having a half-life of 1-2 min.17 Angiotensin III is a physiologically active heptapeptide resulting from the metabolism of angiotensin II.17
The different angiotensins have varying functions within the body (Table 2).
Anatomical aspects
Angiotensin II receptors19
There are at least two classes of angiotensin II receptors (AT). The main type is angiotensin receptor-1 (AT1). The gene for this receptor is located on chromosome 3. AT2 is less important than AT1; its gene is located on chromosome X.
The effect of these receptors differs from tissue to tissue. For example, the AT1 receptors in arterioles and those in the adrenal cortex are regulated in opposite directions: an excess of angiotensin II will downregulate the vascular receptors but upregulate the adrenal cortical receptors, making the gland more sensitive to aldosterone-stimulating hormone.
The AT1 receptor is classified into two subtypes. AT1A is located mainly in the blood vessel walls, the brain and other organs and mediates most of the known effects of angiotensin.20 AT1B is found in the anterior pituitary and adrenal cortex. AT2 receptors are more plentiful in fetal and neonatal life, but they persist in the 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 the renal conversion of prostaglandin E2 to prostaglandin F2a.21 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, which are epitheloid cells located in the media of the afferent arterioles as they enter the glomeruli. Renin is also found in the granular Lacis cells located at the junction between the afferent and efferent arterioles.
The macula densa is a modified region of tubular epithelium located at the beginning of the distal convoluted tubule close to the juxtaglomerular cells. The juxtaglomerular cells together with the macula densa cells are known as the juxtaglomerular apparatus.
The renin–angiotensin system in diabetes mellitus
There is increased stimulation of the sympathetic nervous system in diabetics compared with non-diabetics due to their need to increase the secretion of insulin from beta cells through stimulation of b2 receptors and to dilate the renal arterioles through stimulation of b1 and b2 receptors.
Dilatation of the renal arterioles occurs as a response to the pathological changes that develop in the kidney in diabetes. These vascular and interstitial changes (Table 3) eventually lead to deteriorating renal function. The development of diabetic nephropathy stimulates the renin–angiotensin system. Poor diabetic control will further increase this stimulation.
It has also been shown that angiotensin may be present in abundance in some other tissues, including adipose tissue. In 1987, angiotensin mRNA was found in periaortal brown adipose tissue and in cells found within the rat aorta wall.22 Other studies23-25 have demonstrated evidence for the existence of an intrinsic angiotensin-generating system in the pancreas. Recent epidemiological data have shown that administration of ACE inhibitors in hypertensive patients may have a protective role in preventing the occurrence of diabetes.26 This epidemiological data may explain why some antidiabetic drugs such as thiazoladinedione can decrease blood pressure in obese diabetics.
Clinical recommendations concerning ACE inhibitors
The clinical recommendations and guidelines of many medical and diabetic societies and associations include the use of ACE inhibitors in diabetes.
The European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension states that ACE inhibitors are indicated in the following conditions: congestive heart failure/left ventricular dysfunction post-myocardial infarction non-diabetic nephropathy type 1 diabetic nephropathy/proteinuria.
However, they recommend the use of an ARB in the following conditions: type 2 diabetic nephropathy diabetic microalbuminuria proteinuria left ventricular hypertrophy ACE inhibitor-induced cough.
In the Canadian Hypertension Education Program recommendations, ACE inhibitors are recommended as part of the initial therapy for the following conditions:
diabetes mellitus with nephropathy diabetes mellitus without nephropathy angina post-myocardial infarction heart failure post-cerebrovascular accident or transient ischaemic attack renal disease left ventricular hypertrophy.
The American Diabetes Association recommends that the use of an ACE inhibitor should be considered in all diabetic patients older than 55 years with or without hypertension, but with another cardiovascular risk factor (a history of cardiovascular disease, dyslipidaemia, microalbuminuria or smoking). A combination of an ACE inhibitor and an ARB can be used in the treatment of albuminuria and diabetic nephropathy.
The seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommends the use of ACE inhibitors in the following conditions: hypertension with acute coronary syndromes such as unstable angina or myocardial infarction post-myocardial infarction heart failure diabetic hypertension chronic kidney disease (a limited increase in serum creatinine of as much as 35% above the baseline with ACE inhibitors or ARBs is acceptable unless hyperkalaemia develops) cerebrovascular disease.
Clinical trials assessing the use of ACE inhibitors in diabetes
In the following trials, patients with type 2 diabetes mellitus were randomized to receive ACE inhibitors as initial therapy and the outcome compared with that in patients receiving other antihypertensive drugs: the UK Prospective Diabetes Study,27 which compared the effect of captopril versus atenolol the MICRO-HOPE Diabetic substudy,28 part of the larger Heart Outcome Prevention Evaluation (HOPE) study, which compared the use of ramipril versus placebo the Appropriate Blood Pressure Control in Diabetes (ABCD) trial,29 which compared the use of enalapril versus nisoldipine the Captopril Prevention Project (CAPPP),30 which compared the use of captopril versus diuretic or b-blockers the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET),31 which compared the use of fosinopril versus amlodipine.
Management of hypertension 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 avoiding certain classes of agents on the grounds of race. However, when prescribing ACE inhibitors the clinician should bear in mind that African Americans appear to be at increased risk for ACE inhibitor-associated angio-oedema and cough compared with Caucasians.
Conclusion
ACE inhibitors should be recommended for use in all diabetic patients, especially those with type 2 diabetes mellitus. They are useful not only as antihypertensive drugs but also provide renal protection. |
