ACE inhibitor

From Wikipedia, the free encyclopedia
Jump to: navigation, search
ACE inhibitor
(angiotensin-converting enzyme inhibitor)
Drug class
Captopril skeletal.svg
Captopril, the first synthetic ACE inhibitor
Use Hypertension
Biological target angiotensin-converting enzyme
ATC code C09
External links
MeSH D000806
AHFS/Drugs.com Drug Classes
Consumer Reports Best Buy Drugs
WebMD medicinenet  rxlist

An ACE inhibitor (or angiotensin-converting-enzyme inhibitor) is a medication used primarily for the treatment of hypertension (elevated blood pressure) and congestive heart failure (CHF). This group of medications causes blood vessels to dilate, which results in lower blood pressure. ACE inhibitors are often paired with other medications when used to treat heart disease.

ACE inhibitors inhibit the angiotensin-converting enzyme (a component of the blood pressure-regulating renin-angiotensin-aldosterone system), thereby decreasing the tension of blood vessels and the blood volume, thus lowering blood pressure.

Frequently prescribed ACE inhibitors include perindopril, captopril, enalapril, lisinopril, and ramipril.

Medical use[edit]

ACE inhibitors were initially approved for the treatment of hypertension (high blood pressure), and can be used alone or in combination with other anti-hypertensive medications.

Later, ACE inhibitors were found to be useful in other cardiovascular and kidney conditions[1] including the following:

ACE inhibitors have also been used in chronic renal failure and kidney involvement in systemic sclerosis.

Efficacy[edit]

Hypertension[edit]

ACE inhibitors are approved for the treatment of hypertension (high blood pressure), and can be used alone or in combination with other anti-hypertensive medications. Efficiency is better with association of diuretics. There is no clinically meaningful BP lowering difference between different ACE inhibitors. The BP lowering effect of ACE inhibitors is modest; the magnitude of trough BP lowering at one-half the manufacturers' maximum recommended dose and above is -8/-5 mm Hg. Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses.[2] In people with hypertension, ACE inhibitors lower the risk of death and risk of stroke, coronary heart disease, and cardiovascular events. ACE inhibitors and calcium channel blockers may be similarly effective as low dose diuretics, but the evidence is not as strong. Low-dose thiazides are often considered to be the first choice drug in most patients with elevated blood pressure.[3] In hypertension there was mortality reduction with ACE inhibitor treatment, contrary to angiotensin receptor blockers (ARB).[4]

Acute myocardial infarction[edit]

In acute myocardial infarction (AMI, heart attack) treatment with ACE inhibitor is started within 24 hours in prevention of remodeling of the heart's left ventricle.[1] ACE inhibitors decrease mortality when continued for 10 days (3 to 5 deaths prevented per 1000).[citation needed] No other class of drug, apart from nitrates showed a reduction in mortality.[5]

Heart failure[edit]

In heart failure, ACE inhibitors associated with diuretics lower the risk of death and cardiovascular events.[6] ACE inhibitors are used together with diuretics, beta blockers and sometimes aldosterone antagonists.

Diabetic nephropathy[edit]

In diabetics with protein in the urine, ACE inhibitors prevent progression of renal impairment. The effects of ACE inhibitors on kidney disease outcomes such as progression to end-stage kidney disease, increases in the serum creatinine level, prevention of progression of microalbuminuria to macroalbuminuria, and remission of microalbuminuria to normoalbuminuria, were similarly beneficial for ACE inhibitors and for angiotensin receptor blockers.[7][8] In placebo-controlled studies, only ACE inhibitors at the maximum tolerable dose, were found to significantly reduce the risk of all-cause mortality. ACE inhibitors in lower dose and angiotensin receptor blockers didn't reduce the risk of all cause mortality.[7][9]

Nephropathy[edit]

ACE inhibitors have also been used in chronic renal failure and kidney involvement in other diseases. ACE inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage non-diabetic kidney disease.[10] However, there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 chronic kidney disease who do not have diabetes mellitus.[11]

Dual blockade[edit]

Dual blockade of the renin-angiotensin system include the combination of an ACE inhibitor and an angiotensin-receptor blocker (ARBs), or a direct renin inhibitor (aliskiren Tekturna, Novartis). A meta-analysis of 33 randomized controlled trials on dual blockade of the renin-angiotensin system (RAS) found although it might have seemingly beneficial effects on certain markers of kidney disease such as the presence of albumin in the urine and protein in the urine, it failed to reduce mortality and was associated with an excessive risk of adverse events such as high blood levels of potassium, low blood pressure, and kidney failure compared with therapy with one medication. The risk to benefit ratio argues against the use of dual therapy.[12] In 2009 Lancet retracted the 2003 COOPERATE trial of dual renin-angiotensin system inhibition which concluded that combination therapy of an ACE inhibitor and an ARB was superior to an ACE inhibitor alone, and spanked the lead author for serious misconduct.[13][14] By 2008, about 140,000 patients in the U.S. took combined therapy.[15]

On April 4, 2014 EMA recommends against combined use of medicines affecting the renin-angiotensin (RAS) system, and in particular that patients with diabetes-related kidney problems (diabetic nephropathy) should not be given an ARB with an ACE-inhibitor.[16]

With regard to blood pressure, a small additional fall with dual RAS blockade was observed when compared with that seen in monotherapy. However the 2008 ONTARGET study showed no benefit of combining the agents and more adverse events as hypotension, hyperkalaemia and renal impairment.[17]

Earlier studies have found that people with heart failure might benefit from the combination in terms of reducing morbidity and ventricular remodeling.[18][19] But a 2013 meta analysis found combination therapy with ARBs and ACE inhibitors reduced admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but didn't reduce overall mortality or all-cause hospitalization and was associated with more adverse events. The combination therapy had a higher risk of worsening renal function, worsening symptomatic hypotension and a higher rate of permanent discontinuation of trial medications.[20] and a higher risk of hyperkalaemia.[12]

In the treatment of nephropathy early surrogate evidence found the combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy,[21] and pediatric IgA nephropathy.[22] A 2011 systematic review of 58 trials in patients with micro- and macroalbuminuria found there was no significant reduction in the risk of all-cause mortality or cardiac–cerebrovascular mortality with combined therapy with ACEI + ARB versus monotherapy. The risk of non fatal cardiovascular events was lower with combined therapy with ACEI + ARB versus monotherapy. Development of end-stage kidney disease and progression of microalbuminuria to macroalbuminuria were not reduced with combined therapy with ACEI + ARB versus monotherapy.[23]

Mechanism of action[edit]

Angiotensin-converting enzyme inhibitors reduce the activity of the 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 (outward indication) of renal disease.[24]

Renin-angiotensin-aldosterone system[edit]

One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in the kidney (to be specific, the juxtaglomerular apparatus). This produces another protein, angiotensin, which signals the adrenal gland to produce a hormone called aldosterone. This system is activated in response to a fall in blood pressure (hypotension) and markers of problems with the salt-water balance of the body, such as decreased sodium concentration in the distal tubule of the kidney, decreased blood volume, and stimulation of the kidney by the sympathetic nervous system. In such situations, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10 amino acid residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin converting enzyme (ACE) then removes a further two residues, converting angiotensin I into angiotensin II. Angiotensin II is found in the pulmonary circulation and in the endothelium of many blood vessels.[25] The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin is also very good at causing the blood vessels to tighten (a potent vasoconstrictor).

Effect on blood pressure[edit]

ACE inhibitors block the conversion of angiotensin I to angiotensin II.[26] They thereby: lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin will increase in concentration in the blood as a result of negative feedback of conversion of AI to AII. Angiotensin I will increase for the same reason. Angiotensin II and Aldosterone will decrease. Bradykinin will increase because of less inactivation that is done by ACE.

Under normal conditions, angiotensin II will have the following effects:

  • Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by AII may lead to increased blood pressure and hypertension. Further, constriction of the efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli.
  • It contributes to ventricular remodeling and ventricular hypertrophy of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death). Stimulation by AII 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+ 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.

With ACE inhibitor use, the production of angiotensin II is decreased, leading to decreased blood pressure.

Adverse effects[edit]

Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and renal impairment.[27] Fein also suggests ACE inhibitors might increase inflammation-related pain, perhaps mediated by the buildup of bradykinin that accompanies ACE inhibition.[28]

A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed.[29]

Patients who experience this cough are often switched to angiotensin II receptor antagonists.

Rash and taste disturbances, infrequent with most ACE inhibitors, are more prevalent in captopril, and this is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting, although it is still used in scintigraphy of the kidney.

Renal impairment is a significant potential adverse effect of all ACE inhibitors, but the reason is still unknown. It may be associated with their effect on angiotensin II-mediated homeostatic functions, such as renal blood flow.[citation needed] Renal blood flow may be affected by angiotensin II because it vasoconstricts the efferent arterioles of the glomeruli of the kidney, thereby increasing glomerular filtration rate (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of renal function. To be specific, they can induce or exacerbate renal impairment in patients with renal artery stenosis. This is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, there is a significantly increased risk of developing renal failure.[30]

ACE inhibitors may cause hyperkalemia. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor.[31]

A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.[citation needed]

Some patients develop angioedema due to increased bradykinin levels. There appears to be a genetic predisposition toward this adverse effect in patients who degrade bradykinin more slowly than average.[32] One gene region (XPNPEP2) was associated with ACEI-induced angioedema in three studies.[33]

In pregnant women, ACE inhibitors taken during the first trimester have been reported to cause major congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull.[34] Overall, about half of newborns exposed to ACE inhibitors are adversely affected.[35]

Contraindications and precautions[edit]

The ACE inhibitors are contraindicated in patients with:

  • Previous angioedema associated with ACE inhibitor therapy
  • Renal artery stenosis (bilateral or unilateral with a solitary functioning kidney)[36]
  • Hypersensitivity to ACE inhibitors

ACE inhibitors should be used with caution in patients with:

ACE inhibitors are ADEC pregnancy category D, and should be avoided in women who are likely to become pregnant.[27] In the U.S., ACE inhibitors must be labeled with a "black box" warning concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.[37]

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.[38]

Examples[edit]

ACE inhibitors can be divided into three groups based on their molecular structure:

Sulfhydryl-containing agents[edit]

Dicarboxylate-containing agents[edit]

This is the largest group, including:

Phosphinate-containing agents[edit]

  • Fosinopril (Fositen/Monopril) is the only member of this group

Naturally occurring[edit]

Comparative information[edit]

All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with captopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. Captopril is also the only ACE inhibitor that is capable of passing through the blood–brain barrier, although the significance of this characteristic has not been shown to have any positive clinical effects.

Research[edit]

ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.[42]

History[edit]

The first step in the development of ACE inhibitors was the discovery of ACE in plasma by Leonard T. Skeggs and his colleagues in 1956. Brazilian scientist Sergio Ferreira reported a bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca, a South American pit viper, in 1965.[43] Ferreira then went to John Vane's laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II in vivo. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.[44]

Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme.[45] In 1970, Ng and Vane, using BPF provided by Sérgio Henrique Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[46]

BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF teprotide (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect in vivo. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.

Captopril was approved by the United States Food and Drug Administration in 1981. The first nonsulfhydryl-containing ACE inhibitor, enalapril, was marketed two years later. At least twelve other ACE inhibitors have since been marketed.

In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the tripeptide isoleucine-proline-proline (IPP) from the dairy protein. Valine-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as lactotripeptides. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.[47] Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect.[48] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[41]

See also[edit]

References[edit]

  1. ^ a b Laurence L. Brunton, ed. (2006). "Chapter 30. Renin and Angiotensin - Edwin K. Jackson". Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11 ed.). McGraw-Hill. ISBN 0-07-142280-3. 
  2. ^ Heran BS, Wong MM, Heran IK, Wright JM (Oct 8, 2008). "Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension.". The Cochrane database of systematic reviews (4): CD003823. PMID 18843651. 
  3. ^ Wright JM, Musini VM (2009). "First-line drugs for hypertension". Cochrane Database Syst Rev (3): CD001841. doi:10.1002/14651858.CD001841.pub2. PMID 19588327. 
  4. ^ van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, Boersma E (2012). "Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients". Eur. Heart J. 33 (16): 2088–97. doi:10.1093/eurheartj/ehs075. PMC 3418510. PMID 22511654. 
  5. ^ Perez MI, Musini VM, Wright JM (2009). "Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event". Cochrane Database Syst Rev (4): CD006743. doi:10.1002/14651858.CD006743.pub2. PMID 19821384. 
  6. ^ "Angiotensin II receptor antagonists and heart failure: angiotensin-converting-enzyme inhibitors remain the first-line option.". préscrire international. Oct 2005. PMID 16285075. 
  7. ^ a b Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC (Oct 18, 2006). "Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease.". The Cochrane database of systematic reviews (4): CD006257. PMID 17054288. 
  8. ^ Sarafidis PA, Stafylas PC, Kanaki AI, Lasaridis AN (Aug 2008). "Effects of renin-angiotensin system blockers on renal outcomes and all-cause mortality in patients with diabetic nephropathy: an updated meta-analysis.". American journal of hypertension 21 (8): 922–9. PMID 18535536. 
  9. ^ Sarafidis PA, Stafylas PC, Kanaki AI, Lasaridis AN (Aug 2008). "Effects of renin-angiotensin system blockers on renal outcomes and all-cause mortality in patients with diabetic nephropathy: an updated meta-analysis.". American journal of hypertension 21 (8): 922–9. PMID 18535536. 
  10. ^ Giatras I, Lau J, Levey AS (1997). "Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group". Ann. Intern. Med. 127 (5): 337–45. doi:10.7326/0003-4819-127-5-199709010-00001. PMID 9273824. 
  11. ^ Sharma P, Blackburn RC, Parke CL, McCullough K, Marks A, Black C (Oct 5, 2011). "Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease.". The Cochrane database of systematic reviews (10): CD007751. PMID 21975774. 
  12. ^ a b Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH (2013). "Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials". BMJ 346: f360. doi:10.1136/bmj.f360. PMC 3556933. PMID 23358488. 
  13. ^ Husten, Larry (October 8, 2009). "Lancet retracts COOPERATE trial of dual RAS inhibition and spanks lead author for serious misconduct". CardioBrief. 
  14. ^ Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T (2003). "RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial". Lancet 361 (9352): 117–24. doi:10.1016/S0140-6736(03)12229-5. PMID 12531578. 
  15. ^ Naik, Gautam (August 10, 2011). "Mistakes in Scientific Studies Surge". The Wall street journal. Retrieved 13 April 2014. 
  16. ^ "PRAC recommends against combined use of medicines affecting the renin-angiotensin (RAS) system". Retrieved 12 April 2014. 
  17. ^ Messerli FH (2009). "The sudden demise of dual renin-angiotensin system blockade or the soft science of the surrogate end point". J. Am. Coll. Cardiol. 53 (6): 468–70. doi:10.1016/j.jacc.2008.10.036. PMID 19195602. 
  18. ^ Krum H, Carson P, Farsang C, Maggioni AP, Glazer RD, Aknay N, Chiang YT, Cohn JN (2004). "Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT". Eur. J. Heart Fail. 6 (7): 937–45. doi:10.1016/j.ejheart.2004.09.005. PMID 15556056. 
  19. ^ Solomon SD, Skali H, Anavekar NS, Bourgoun M, Barvik S, Ghali JK, Warnica JW, Khrakovskaya M, Arnold JM, Schwartz Y, Velazquez EJ, Califf RM, McMurray JV, Pfeffer MA (2005). "Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction". Circulation 111 (25): 3411–9. doi:10.1161/CIRCULATIONAHA.104.508093. PMID 15967846. 
  20. ^ Kuenzli A, Bucher HC, Anand I, Arutiunov G, Kum LC, McKelvie R, Afzal R, White M, Nordmann AJ (2010). "Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure". PLoS ONE 5 (4): e9946. doi:10.1371/journal.pone.0009946. PMC 2848587. PMID 20376345. 
  21. ^ Luno J, Praga M, de Vinuesa SG (2005). "The reno-protective effect of the dual blockade of the renin angiotensin system (RAS)". Curr. Pharm. Des. 11 (10): 1291–300. doi:10.2174/1381612053507413. PMID 15853685. 
  22. ^ Yang Y, Ohta K, Shimizu M, Nakai A, Kasahara Y, Yachie A, Koizumi S (2005). "Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy". Clin. Nephrol. 64 (1): 35–40. doi:10.5414/CNP64035. PMID 16047643. 
  23. ^ Maione A, Navaneethan SD, Graziano G, Mitchell R, Johnson D, Mann JF, Gao P, Craig JC, Tognoni G, Perkovic V, Nicolucci A, De Cosmo S, Sasso A, Lamacchia O, Cignarelli M, Manfreda VM, Gentile G, Strippoli GF (2011). "Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors: a systematic review of randomized controlled trials". Nephrol. Dial. Transplant. 26 (9): 2827–47. doi:10.1093/ndt/gfq792. PMID 21372254. 
  24. ^ Jandeleit-Dahm K, Cooper ME (2006). "Hypertension and diabetes: role of the renin-angiotensin system". Endocrinol. Metab. Clin. North Am. 35 (3): 469–90, vii. doi:10.1016/j.ecl.2006.06.007. PMID 16959581. 
  25. ^ Human Physiology, Silverthorn (Pearson Benjamin Cummings 2004)[page needed]
  26. ^ Ogbru O. "ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors)". MedicineNet.com. MedicineNet, Inc. Archived from the original on 26 March 2010. Retrieved 2010-03-20. 
  27. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3.[page needed]
  28. ^ Fein A (2009). "ACE inhibitors worsen inflammatory pain". Medical Hypotheses 72 (6): 757. doi:10.1016/j.mehy.2009.01.012. 
  29. ^ Okumura H, Nishimura E, Kariya S, Ohtani M, Uchino K, Fukatsu T, Odanaka J, Takahashi T, Watanabe K, Itoh T, Hashiguchi M, Echizen H, Rikihisa T (2001). "Angiotensin-converting enzyme (ACE)阻害薬誘発性の咳嗽発現とACE 遺伝子型,血漿中ブラジキニン,サブスタンスP 及びACE 阻害薬濃度との関連性" [No Relation between Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Cough and ACE Gene Polymorphism, Plasma Bradykinin, Substance P and ACE Inhibitor Concentration in Japanese Patients]. Yakugaku Zasshi (in Japanese) 121 (3): 253–7. doi:10.1248/yakushi.121.253. PMID 11265121. 
  30. ^ Thomas (2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". The Medical journal of Australia 172 (4): 184–5. PMID 10772593. 
  31. ^ Cohn JN, Kowey PR, Whelton PK, Prisant LM (2000). "New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice". Arch. Intern. Med. 160 (16): 2429–36. doi:10.1001/archinte.160.16.2429. PMID 10979053. 
  32. ^ Molinaro G, Cugno M, Perez M, Lepage Y, Gervais N, Agostoni A, Adam A (2002). "Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin". J. Pharmacol. Exp. Ther. 303 (1): 232–7. doi:10.1124/jpet.102.038067. PMID 12235256. 
  33. ^ Mahmoudpour SH, Leusink M, van der Putten L, Terreehorst I, Asselbergs FW, de Boer A, Maitland-van der Zee AH (Feb 2013). "Pharmacogenetics of ACE inhibitor-induced angioedema and cough: a systematic review and meta-analysis.". Pharmacogenomics 14 (3): 249–60. PMID 23394388. 
  34. ^ Sørensen AM, Christensen S, Jonassen TE, Andersen D, Petersen JS (March 1998). "[Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists]". Ugeskrift for Laeger (in Danish) 160 (10): 1460–4. PMID 9520613. 
  35. ^ Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD (2012). "Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review". Hypertension 60 (2): 444–50. doi:10.1161/HYPERTENSIONAHA.112.196352. PMID 22753220. 
  36. ^ Hricik DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ (1983). "Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney". N. Engl. J. Med. 308 (7): 373–6. doi:10.1056/NEJM198302173080706. PMID 6337327. 
  37. ^ Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA (2006). "Major congenital malformations after first-trimester exposure to ACE inhibitors". N. Engl. J. Med. 354 (23): 2443–51. doi:10.1056/NEJMoa055202. PMID 16760444. 
  38. ^ Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert L, Agarwal R, Catanzaro D (2000). "ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group". Kidney Int. 58 (5): 2084–92. doi:10.1111/j.1523-1755.2000.00381.x. PMID 11044229. 
  39. ^ FitzGerald RJ, Murray BA, Walsh DJ (2004). "Hypotensive peptides from milk proteins". J. Nutr. 134 (4): 980S–8S. PMID 15051858. 
  40. ^ Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y (2005). "Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension". J Am Coll Nutr 24 (4): 257–65. doi:10.1080/07315724.2005.10719473. PMID 16093403. 
  41. ^ a b Boelsma E, Kloek J (2009). "Lactotripeptides and antihypertensive effects: a critical review". Br. J. Nutr. 101 (6): 776–86. doi:10.1017/S0007114508137722. PMID 19061526. 
  42. ^ von Haehling S, Morley JE, Anker SD (2010). "An overview of sarcopenia: facts and numbers on prevalence and clinical impact". J Cachexia Sarcopenia Muscle 1 (2): 129–133. doi:10.1007/s13539-010-0014-2. PMC 3060646. PMID 21475695. 
  43. ^ FERREIRA SH (February 1965). "A bradykinin-potentiating factor (bpf) present in the venom of bothrops jararaca". Br J Pharmacol Chemother 24 (1): 163–9. doi:10.1111/j.1476-5381.1965.tb02091.x. PMC 1704050. PMID 14302350. 
  44. ^ Ng KK, Vane JR (1967). "Conversion of angiotensin I to angiotensin II". Nature 216 (5117): 762–6. doi:10.1038/216762a0. PMID 4294626. 
  45. ^ Ng KK, Vane JR (1968). "Fate of angiotensin I in the circulation". Nature 218 (5137): 144–50. doi:10.1038/218144a0. PMID 4296306. 
  46. ^ Ng KK, Vane JR (1970). "Some properties of angiotensin converting enzyme in the lung in vivo". Nature 225 (5238): 1142–4. doi:10.1038/2251142b0. PMID 4313869. 
  47. ^ Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T (1996). "A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects". Am. J. Clin. Nutr. 64 (5): 767–71. PMID 8901799. 
  48. ^ Nakamura Y, Yamamoto N, Sakai K, Takano T (1995). "Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme". J. Dairy Sci. 78 (6): 1253–7. doi:10.3168/jds.S0022-0302(95)76745-5. PMID 7673515. 

External links[edit]