Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.
Renin, also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that increases the volume of extracellular fluid and causes arterial vasoconstriction. Thus, it increases the body's mean arterial blood pressure.
The renin-angiotensin system (RAS), or renin-angiotensin-aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid, and electrolyte balance, and systemic vascular resistance.
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.
Bradykinin (BK) (from Greek brady- 'slow' + -kinin, kīn(eîn) 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.
Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.
Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furosemide. It is given by mouth or by injection into a vein. Onset of effects are typically within an hour when taken by mouth and last for up to a day.
Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.
Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.
Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.
Angiotensin-converting enzyme 2 (ACE2) is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2). Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 in a process regulated by substrate presentation. ADAM17 cleavage releases the extracellular domain creating soluble ACE2 (sACE2). ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing the hydrolysis of angiotensin II into angiotensin (1–7). Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. This decrease in blood pressure makes the entire process a promising drug target for treating cardiovascular diseases.
Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease. As a long-acting ACE inhibitor, it works by relaxing blood vessels and decreasing blood volume. As a prodrug, perindopril is hydrolyzed in the liver to its active metabolite, perindoprilat. It was patented in 1980 and approved for medical use in 1988.
Aliskiren is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.
The discovery of an orally inactive peptide from snake venom established the important role of angiotensin converting enzyme (ACE) inhibitors in regulating blood pressure. This led to the development of captopril, the first ACE inhibitor. When the adverse effects of captopril became apparent new derivates were designed. Then after the discovery of two active sites of ACE: N-domain and C-domain, the development of domain-specific ACE inhibitors began.
Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure.
Moexipril was an angiotensin converting enzyme inhibitor used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with other antihypertensives or diuretics.
Pathophysiology is a study which explains the function of the body as it relates to diseases and conditions. The pathophysiology of hypertension is an area which attempts to explain mechanistically the causes of hypertension, which is a chronic disease characterized by elevation of blood pressure. Hypertension can be classified by cause as either essential or secondary. About 90–95% of hypertension is essential hypertension. Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium. Secondary hypertension indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excess aldosterone, cortisol, or catecholamines. Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease.
Sacubitril/valsartan, sold under the brand name Entresto among others, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). In 2016, the American College of Cardiology/American Heart Association Task Force recommended it as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.
Peptidyl-dipeptidase Dcp (EC 3.4.15.5, dipeptidyl carboxypeptidase (Dcp), dipeptidyl carboxypeptidase) is a metalloenzyme found in the cytoplasm of bacterium E. Coli responsible for the C-terminal cleavage of a variety of dipeptides and unprotected larger peptide chains. The enzyme does not hydrolyze bonds in which P1' is Proline, or both P1 and P1' are Glycine. Dcp consists of 680 amino acid residues that form into a single active monomer which aids in the intracellular degradation of peptides. Dcp coordinates to divalent zinc which sits in the pocket of the active site and is composed of four subsites: S1’, S1, S2, and S3, each subsite attracts certain amino acids at a specific position on the substrate enhancing the selectivity of the enzyme. The four subsites detect and bind different amino acid types on the substrate peptide in the P1 and P2 positions. Some metallic divalent cations such as Ni+2, Cu+2, and Zn+2 inhibit the function of the enzyme around 90%, whereas other cations such as Mn+2, Ca+2, Mg+2, and Co+2 have slight catalyzing properties, and increase the function by around 20%. Basic amino acids such as Arginine bind preferably at the S1 site, the S2 site sits deeper in the enzyme therefore is restricted to bind hydrophobic amino acids with phenylalanine in the P2 position. Dcp is divided into two subdomains (I, and II), which are the two sides of the clam shell-like structure and has a deep inner cavity where a pair of histidine residues bind to the catalytic zinc ion in the active site. Peptidyl-Dipeptidase Dcp is classified like Angiotensin-I converting enzyme (ACE) which is also a carboxypeptidase involved in blood pressure regulation, but due to structural differences and peptidase activity between these two enzymes they had to be examined separately. ACE has endopeptidase activity, whereas Dcp strictly has exopeptidase activity based on its cytoplasmic location and therefore their mechanisms of action are differentiated. Another difference between these enzymes is that the activity of Peptidyl-Dipeptidase Dcp is not enhanced in the presence of chloride anions, whereas chloride enhances ACE activity.
Pierre Corvol is a French doctor and biology researcher. He was director of the Collège de France from 2006 to August 2012.
