Renin-angiotensin system

The renin-angiotensin system is a "blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin I; angiotensin II; and angiotensinase."

Components and physiology

For links to more information, see: Renin-angiotensin system: Subtopics

"Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system."

Angiotensin-converting enzyme 2 is a newly recognized component of the renin-angiotensin system.

Clinical significance

Several classes of medications affect the renin-angiotensin system.

Direct renin inhibitors

Aliskiren is an oral direct renin inhibitor that according to a randomized controlled trial may have "renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy."

Angiotensin-converting enzyme inhibitors

Angiotensin-converting enzyme inhibitors are medications used for the treatment of hypertension and heart failure.

Angiotensin II receptor antagonists

Angiotensin II receptor antagonists are medications that antagonize the angiotensin II type 1 receptor and are used for the treatment of hypertension and heart failure.

Combination therapy

Regarding combining these medications for a synergistic effect:

• An initial randomized controlled trial of patients with hypertension and diabetes mellitus type 2 with nephropathy found reduced albuminuria by combining aliskiren (an oral direct renin inhibitor) with losartan (an angiotensin II receptor antagonist).
• Randomized controlled trials have investigated the use of the latter two classes together for a synergistic effect, but have usually found increased adverse effects with no added benefit from their combination (see summary Table).

Trials of combining angiotensin-converting enzyme inhibitors with angiotensin II receptor antagonists

Trial	Year	Setting	Findings
Valsartan Heart Failure Trial	2001	New York Heart Association class II-IV heart failure	"Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, an ACE inhibitor, and a beta-blocker raises concern about the potential safety of this specific combination"
CHARM-Added	2003	New York Heart Association class II-IV heart failure and left-ventricular ejection fraction 40% or lower"	"The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients."
VALIANT	2003	myocardial infarction with left ventricular systolic dysfunction or heart failure	"Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival."
ONTARGET	2008	vascular disease or high-risk diabetes	"Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit."