MB BS BSc(Med) MD FRACD
Department of Physiology
University of Melbourne
Angiotensin II (Ang II) is an extremely important factor to maintain salt and water homeostasis and to regulate blood pressure (BP). However, an imbalance between its plasma level and the sodium balances of an individual leads to the development of high BP and premature death from cardio- and cerebrovascular disease. In situations where end-organ damage results (renal disease, cardiac failure or myocardial infarction), Ang II appears to be an important intermediary causing disease progression.(1,2)
Plasma production of Ang II
In the plasma, angiotensin is produced by renin (released from the kidney) acting on angiotensinogen (produced by the liver) to form angiotensin I. Still in the plasma (at the endothelium of blood vessels), Ang I is converted to Ang II by the angiotensin-converting enzyme (ACE). Ang II acts on the arterial system to cause vasoconstriction, on the adrenals to release aldosterone and on the proximal tubule of the kidney to cause increased sodium reabsorption. This plasma-produced hormone also acts on the endothelium of blood vessels to initiate a series of events that leads to cellular proliferation and eventually atherosclerosis.
Tissue production of Ang II
In addition to the traditional view, it is clear that
Ang II can also be produced locally in a number of tissues (kidney, heart or brain) and reaches higher concentrations than in the plasma. In certain tissues, renin (even though it is produced in the kidney) may reach concentrations higher than in the plasma due to renin-binding proteins, and, in a number of tissues, angiotensinogen is also produced.(3) The formation of angiotensin may take place without the involvement of the traditional steps indicated above.(4) Ang II binds to two major receptors: the angiotensin type I (AT(1)) receptor, which mediates most of the traditional effects of Ang II listed above; and the angiotensin type II (AT(2)) receptor, which has vasodilator and antiproliferative effects.
Prevention of Ang II effects
Theoretically, Ang II effects could be prevented in four ways:
- Reduction of angiotensinogen levels.
- Reduction of synthesis or inhibition of the action of renin.
- Inhibition of the enzymatic action of ACE.
- Blockade of the Ang II receptor.
The last two hypotheses have been tested clinically, and the following questions arose:
- Are the results due to ACE inhibition and AT(1)-receptor blocking similar?
- Is there an additive effect of ACE inhibition and of AT(1)-receptor blockade on BP control and on other adverse effects of Ang II?
Prevention of Ang II formation and blockage of binding of Ang II to the AT(1) receptor should both prevent the effects mediated via the AT(1) receptor, but there are some important differences. ACE, in addition to its effects on Ang I conversion to Ang II, is also important in the breakdown of bradykinin. Thus, with ACE inhibition, the effects of Ang II via the AT(1) and AT(2) receptor are prevented, but, in addition, bradykinin levels rise. Bradykinin has vasodilator and antiproliferative effects, and thus some components of the response to ACE inhibition may be due to bradykinin. The AT(1)-receptor blockade prevents the action via the AT(1) receptor, but there may be beneficial effects exhibited by the AT(2) receptor, which will be more switched on because Ang II levels are high. With both groups of drugs, renin levels are elevated due to blockade of the short-loop feedback response. In the case of ACE inhibition, this leads to high levels of Ang I, and in the case of AT(1) blockage, to high levels of Ang II.
Effectiveness of ACEI and ARB
When clinically compared, the effects of ACE inhibition and AT(1)-receptor blockage 24 hours after drug dosage are relatively similar.(5) However, this comparison is flawed, as many ACE inhibitors used in the comparison have relatively short half-lives, while ARBs have a more prolonged duration of action. When compared at times of peak effect, enalapril caused a greater lowering of BP than losartan.(5) Lisinopril caused a greater fall than candesartan,(6) and in rats with BP measured by telemetry, captopril lowered pressure at the time of peak response more than losartan.(7) This latter effect may be due to the increased levels of bradykinin caused by the use of an ACE inhibitor (ACEI).
Relatively few studies have compared the effects of the two classes of drugs on end-organ damage. However, both ACEIs and AT(1)-receptor blockers reverse LVH, improve the outcome in cardiac failure, reduce proteinuria in diabetic and nondiabetic patients and delay the progression of renal failure. A direct comparison of telmisartan (an AT(1) blocker) with enalapril (ACEI) showed a similar effect on progression of renal disease, with a better adverse event profile for telmisartan.(8)
Combination of an ACEI and an ARB
A number of studies claim to show an additional effect of the two drugs on BP control.(9,10) Most studies are parallel- designed studies that do not allow full evaluation. A combination of the two drugs could be more potent, as there would be an additional effect due to a more complete blockage of the renin– angiotensin–aldosterone system (RAS). However, some people respond to one drug class and not to the other, and thus while it may be appropriate to replace one class with the other, it is not justified to use the two together.
A study by Morgan et al compared, in a six-way crossover study, placebo, lisinopril (20 and 40mg), candesartan (16 and 32mg) and lisinopril 20mg + candesartan 16mg on BP control using 24-hour BP recording.(6) On the doses of lisinopril and candesartan used, a plateau effect was achieved. The response of systolic BP to the combination was 3.1mmHg greater than the response to lisinopril, and 5.1mmHg greater than the response to candesartan (p<0.01). Analysis of the data indicated that more than 50% of this greater fall was due to three patients. Two had no fall in BP and no rise in plasma renin with either dose of lisinopril but had a fall in BP and a rise in renin with both doses of candesartan and the combination. One person had no response to candesartan but responded to lisinopril and the combination. Four other patients appeared to respond better to one or other drug, but the differences were not so certain. If the drugs had had additive effects, the extra fall in BP would have been 12/5mmHg.
In studies with a similar crossover design, the response to the addition of a dihydropyridine calcium-blocking drug (felodipine) to either enalapril(11) or candesartan(12) is fully additive, and the fall in BP with the combination is larger than the better of the falls with the comparative agents. Likewise, the fall with a diuretic added to either an ACEI or an ARB is close to additive.(6,11,12)
For BP lowering, it is not justified to use high doses of the two drugs together. However, it is possible that low doses of an AT(1) blocker and an ACEI used in combination may lead to lowering of BP similar to that achievable with maximum doses of either drug. A study in rats supports this concept. The use of captopril and losartan in doses that, as monotherapies, had equivocal effect on BP (measured by telemetry) had a significant effect when used in combination. (7,13)
A question arises as to why some people may respond to one class of drug and not the other, both in hypertension and in the prevention of progression of end-organ damage. The reason a patient may respond to an AT(1) blocker and not to an ACE inhibitor could be due to increased activity of enzyme systems in the tissue that can form Ang II without using the converting enzyme.(4)
Why some people respond to an ACEI and not to an AT1 blocker is more difficult to explain. There may be a high local production of Ang II right next to the receptor (as both ACE and the receptor are on the membrane), and sufficient tissue levels of the ARB are not achieved to prevent the Ang II effect. Alternatively, there may be a high turnover and an increased number of AT(1) receptors. Another possibility is that bradykinin may play a significant role in BP fall.
In the treatment of resistant hypertension, the use of the combination of an ACEI and an ARB cannot be justified before trying combinations of either drug with a diuretic, a dihydropyridine calcium blocker or a beta-blocker.This statement may not apply to the prevention of progression of end-organ damage. Thus, in patients with proteinuria or with renal failure, the combination may be needed, as it is extremely difficult to block the RAS fully in the kidney.(14,15) The same may also apply to cardiac hypertrophy and cardiac failure.
- N Engl J Med 2000;342:142-53.
- JAMA 1995;273:1450-6.
- Circulation 1998;98:73-81.
- J Biol Chem 1990;265: 22348-57.
- Hypertension 1995;25:1345-50.
- J Renin Angiotensin Aldosterone Syst 2004;5:64-71.
- J Renin Angiotensin Aldosterone Syst 2002;3:16-8
- N Engl J Med 2004;351:1952-61.
- BMJ 2000;321:1440-4.
- Lancet 2003;362:767-71.
- Am J Hypertens 1992;5:238-43.
- Am J Hypertens 2002;15:544-9.
- Am J Hypertens 2002;15:1003-5.
- Diabetes Care 2003;26:2268-74.
- Nephrol Dial Transplant 2002;17:597-601.