Editing ACE inhibitor (section)

==Mechanism of action==
ACE inhibitors reduce the activity of the [[Renin–angiotensin system|renin–angiotensin–aldosterone system]] (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.<ref>{{cite journal | vauthors = Jandeleit-Dahm K, Cooper ME | title = Hypertension and diabetes: role of the renin-angiotensin system | journal = Endocrinology and Metabolism Clinics of North America | volume = 35 | issue = 3 | pages = 469–90, vii | date = September 2006 | pmid = 16959581 | doi = 10.1016/j.ecl.2006.06.007 }}</ref><ref>{{cite journal | vauthors = Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, Llorens-Cortes C, Hazra S, Murray AG, Vederas JC, Oudit GY | title = Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System | journal = Hypertension | volume = 68 | issue = 2 | pages = 365–377 | date = August 2016 | pmid = 27217402 | doi = 10.1161/HYPERTENSIONAHA.115.06892 | s2cid = 829514 | doi-access = free }}</ref>

===Renin–angiotensin–aldosterone system===
{{Main|Renin–angiotensin system}}
[[Image:Renin-angiotensin-aldosterone system.svg|thumb|475px|class=skin-invert-image|[[Renin–angiotensin system|Renin–angiotensin–aldosterone system]]]]
The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as [[hypotension]], low [[Distal convoluted tubule|distal tubule]] [[Sodium in biology|sodium]] concentration, decreased blood volume and high [[sympathetic nervous system|sympathetic]] tone trigger the release of the enzyme [[renin]] from the cells of [[juxtaglomerular apparatus]] in the kidney.{{citation needed|date=August 2024}}

Renin activates a circulating liver derived [[prohormone]] [[angiotensin]]ogen by proteolytic cleavage of all but its first ten [[amino acid]] residues known as [[angiotensin I]]. [[Angiotensin converting enzyme|ACE]] (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into [[angiotensin II]]. ACE is found in the [[pulmonary circulation]] and in the [[endothelium]] of many blood vessels.<ref>Human Physiology, Silverthorn (Pearson Benjamin Cummings 2004){{Page needed|date=September 2010}}</ref> The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin II is also a potent [[vasoconstrictor]].<ref name="Weir 1999 pp. 205–213">{{cite journal | vauthors = Weir MR, Dzau VJ | title = The renin-angiotensin-aldosterone system: a specific target for hypertension management | journal = American Journal of Hypertension | volume = 12 | issue = 12 Pt 3 | pages = 205S–213S | date = December 1999 | pmid = 10619573 | doi = 10.1016/s0895-7061(99)00103-x | publisher = Oxford University Press (OUP) }}</ref>

===Effects===
ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII).<ref name="Ogbru">{{cite web|url=http://www.medicinenet.com/ace_inhibitors/article.htm |title=ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors) |access-date=2010-03-20 |author =Ogbru O |work=MedicineNet.com |publisher=MedicineNet, Inc. | archive-url= https://web.archive.org/web/20100326095902/http://www.medicinenet.com/ace_inhibitors/article.htm| archive-date= 26 March 2010 | url-status= live}}</ref> They thereby lower [[arteriole|arteriolar]] resistance and increase venous capacity; decrease [[cardiac output]], [[cardiac index]], stroke work, and [[stroke volume|volume]]; lower resistance in blood vessels in the kidneys; and lead to increased [[natriuresis]] (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease. [[Bradykinin]] increases because of less inactivation by ACE.{{citation needed|date=August 2024}}

Under normal conditions, angiotensin II has these effects:{{cn|date=February 2025}}
* Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by ATII may lead to increased blood pressure and hypertension. Further, constriction of the [[efferent arteriole]]s of the kidney leads to increased perfusion pressure in the [[glomerulus (kidney)|glomeruli]].
* It contributes to [[ventricular remodeling]] and [[ventricular hypertrophy]] of the heart through stimulation of the [[proto-oncogene]]s [[c-fos]], [[c-jun]], [[c-myc]], [[transforming growth factor beta]] (TGF-B), through fibrogenesis and apoptosis (programmed cell death).
* Stimulation by ATII of the [[adrenal cortex]] to release [[aldosterone]], a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
* Stimulation of the posterior pituitary to release [[vasopressin]] (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na<sup>+</sup> level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients.
* A decrease renal protein kinase C

During the course of ACE inhibitor use, the production of ATII is decreased,{{noteTag|name=|1=ACE inhibitors don't appear to permanently reduce ATII plasma level after cessation of taking it. In short, ACE inhibitors don't cure high ATII plasma levels.<ref name="Gradman Traub 2007 pp. 985–1001"/> }}<ref name="Gradman Traub 2007 pp. 985–1001">{{cite book | vauthors = Gradman AH, Traub D | title=Comprehensive Hypertension | chapter=Angiotensin-Converting Enzyme Inhibitors | publisher=Elsevier | year=2007 | isbn=978-0-323-03961-1 | doi=10.1016/b978-0-323-03961-1.50083-0 | pages=985–1001 | quote=Despite the lack of long-term suppression in plasma angiotensin II levels, they maintain their BP-lowering effect without the development of tolerance. Importantly, ACE inhibitors do not interfere with cognitive function or cardiovascular reflexes.}}</ref> which prevents aldosterone release from the adrenal cortex.<ref name="Gradman Traub 2007 pp. 985–1001"/> This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.<ref name="Gradman Traub 2007 pp. 985–1001"/>

[[Epidemiology|Epidemiological]] and clinical studies have shown ACE inhibitors reduce the progress of [[diabetic nephropathy]] independently from their blood pressure-lowering effect.<ref name="pmid10780101">{{cite journal | vauthors = Hoogwerf BJ, Young JB | title = The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not | journal = Cleveland Clinic Journal of Medicine | volume = 67 | issue = 4 | pages = 287–293 | date = April 2000 | pmid = 10780101 | doi = 10.3949/ccjm.67.4.287 }}</ref> This action of ACE inhibitors is used in the prevention of diabetic [[renal failure]].{{citation needed|date=August 2024}}

ACE inhibitors have been shown to be effective for indications other than hypertension<ref>{{cite journal | vauthors = Bicket DP | title = Using ACE inhibitors appropriately | journal = American Family Physician | volume = 66 | issue = 3 | pages = 461–468 | date = August 2002 | pmid = 12182524 | url = https://www.aafp.org/afp/2002/0801/p461.html | access-date = 20 February 2019 }}</ref> even in patients with normal blood pressure.<ref>{{cite journal | vauthors = Jerums G, Allen TJ, Campbell DJ, Cooper ME, Gilbert RE, Hammond JJ, O'Brien RC, Raffaele J, Tsalamandris C | title = Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with Type 2 diabetes and microalbuminuria | journal = Diabetic Medicine | volume = 21 | issue = 11 | pages = 1192–1199 | date = November 2004 | pmid = 15498085 | doi = 10.1111/j.1464-5491.2004.01316.x | s2cid = 12855742 }}</ref> The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified,<ref>{{cite journal | vauthors = Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC | title = Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review | journal = BMJ | volume = 329 | issue = 7470 | pages = 828 | date = October 2004 | pmid = 15459003 | pmc = 521570 | doi = 10.1136/bmj.38237.585000.7C }}</ref> because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).{{citation needed|date=August 2024}}

ACE inhibitors have also been shown to cause a central enhancement of [[parasympathetic nervous system]] activity in healthy volunteers and patients with heart failure.<ref>{{cite journal | vauthors = Ajayi AA, Campbell BC, Howie CA, Reid JL | title = Acute and chronic effects of the converting enzyme inhibitors enalapril and lisinopril on reflex control of heart rate in normotensive man | journal = Journal of Hypertension | volume = 3 | issue = 1 | pages = 47–53 | date = February 1985 | pmid = 2987341 | doi = 10.1097/00004872-198502000-00008 }}</ref><ref>{{cite journal | vauthors = Adigun AQ, Asiyanbola B, Ajayi AA | title = Cardiac autonomic function in Blacks with congestive heart failure: vagomimetic action, alteration in sympathovagal balance, and the effect of ACE inhibition on central and peripheral vagal tone | journal = Cellular and Molecular Biology | volume = 47 | issue = 6 | pages = 1063–1067 | date = September 2001 | pmid = 11785658 }}{{Verify source|title?|date=October 2009}}</ref> This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.<ref>{{cite journal | vauthors = Binkley PF, Haas GJ, Starling RC, Nunziata E, Hatton PA, Leier CV, Cody RJ | title = Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure | journal = Journal of the American College of Cardiology | volume = 21 | issue = 3 | pages = 655–661 | date = March 1993 | pmid = 8436747 | doi = 10.1016/0735-1097(93)90098-L | doi-access = free }}</ref>
ACE Inhibitors also reduce plasma [[norepinephrine]] levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of [[sympathetic nervous system|sympathetic]] and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure{{citation needed|date=August 2024}}

The ACE inhibitor [[enalapril]] has also been shown to reduce cardiac [[cachexia]] in patients with chronic heart failure.<ref>{{cite journal | vauthors = Adigun AQ, Ajayi AA | title = The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia | journal = European Journal of Heart Failure | volume = 3 | issue = 3 | pages = 359–363 | date = June 2001 | pmid = 11378008 | doi = 10.1016/S1388-9842(00)00146-X | s2cid = 31118266 | doi-access = free }}</ref> Cachexia is a poor prognostic sign in patients with chronic heart failure.<ref>{{cite journal | vauthors = Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA, Coats AJ | title = Wasting as independent risk factor for mortality in chronic heart failure | journal = Lancet | volume = 349 | issue = 9058 | pages = 1050–1053 | date = April 1997 | pmid = 9107242 | doi = 10.1016/S0140-6736(96)07015-8 | s2cid = 27285694 }}</ref>
ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.<ref>{{cite journal | vauthors = von Haehling S, Morley JE, Anker SD | title = An overview of sarcopenia: facts and numbers on prevalence and clinical impact | journal = Journal of Cachexia, Sarcopenia and Muscle | volume = 1 | issue = 2 | pages = 129–133 | date = December 2010 | pmid = 21475695 | pmc = 3060646 | doi = 10.1007/s13539-010-0014-2 }}</ref>