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."[1]
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."[1]
Angiotensin-converting enzyme 2 is a newly recognized component of the renin-angiotensin system.[2]
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."[3]
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).[3]
- 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).[4]
| Trial | Year | Setting | Findings |
|---|---|---|---|
| Valsartan Heart Failure Trial[5] | 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"[5] |
| CHARM-Added[6] | 2003 | New York Heart Association class II-IV heart failure and left-ventricular ejection fraction 40% or lower"[6] | "The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients."[6] |
| VALIANT[7] | 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[8] | 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."[8] |
References
- ↑ 1.0 1.1 Anonymous (2024), Renin-angiotensin system (English). Medical Subject Headings. U.S. National Library of Medicine.
- ↑ Boehm M, Nabel EG (November 2002). "Angiotensin-converting enzyme 2--a new cardiac regulator". N. Engl. J. Med. 347 (22): 1795–7. DOI:10.1056/NEJMcibr022472. PMID 12456857. Research Blogging.
- ↑ 3.0 3.1 Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK (June 2008). "Aliskiren combined with losartan in type 2 diabetes and nephropathy". N. Engl. J. Med. 358 (23): 2433–46. DOI:10.1056/NEJMoa0708379. PMID 18525041. Research Blogging.
Cite error: Invalid
<ref>tag; name "pmid18525041" defined multiple times with different content - ↑ McMurray JJ (April 2008). "ACE inhibitors in cardiovascular disease--unbeatable?". N. Engl. J. Med. 358 (15): 1615–6. DOI:10.1056/NEJMe0801925. PMID 18378521. Research Blogging.
- ↑ 5.0 5.1 5.2 Cohn JN, Tognoni G (December 2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". N. Engl. J. Med. 345 (23): 1667–75. PMID 11759645. [e]
- ↑ 6.0 6.1 6.2 6.3 McMurray JJ, Ostergren J, Swedberg K, et al (September 2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial". Lancet 362 (9386): 767–71. DOI:10.1016/S0140-6736(03)14283-3. PMID 13678869. Research Blogging.
- ↑ 7.0 7.1 Pfeffer MA, McMurray JJ, Velazquez EJ, et al (November 2003). "Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both". N. Engl. J. Med. 349 (20): 1893–906. DOI:10.1056/NEJMoa032292. PMID 14610160. Research Blogging. ACP Journal Club
- ↑ 8.0 8.1 8.2 Yusuf S, Teo KK, Pogue J, et al (April 2008). "Telmisartan, ramipril, or both in patients at high risk for vascular events". N. Engl. J. Med. 358 (15): 1547–59. DOI:10.1056/NEJMoa0801317. PMID 18378520. Research Blogging.