Primarily angiotensin converting enzyme inhibitors reduce the activity of the renin-angiotensin-aldosterone system.
The renin-angiotensin-aldosterone system (RAAS)
One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in the kidney (specifically: the juxtaglomerular apparatus).
This produces another protein called 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) as well as markers of problems with the salt-water balance of the body, such as decreased sodium concentration in a part of the kidney known as the distal tubule, decreased blood volume and stimulation of the kidney by the sympathetic nervous system.
In such a situation, 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 I is then converted to angiotensin II by angiotensin converting enzyme (ACE) which removes a further 2 residues and is found in the pulmonary circulation as well as in the endothelium of many blood vessels.
The system in general aims to increase 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).
ACE inhibitors block the conversion of angiotensin I to angiotensin II. They therefore lower arteriolar resistance and increase venous capacity; increase cardiac output and cardiac index, stroke work and volume, lower renovascular resistance, and lead to increased natriuresis (excretion of sodium in the urine).
Normally, angiotensin II will have the following effects:
- vasoconstriction (narrowing of blood vessels), which may lead to increased blood pressure and hypertension
- – constriction of the efferent arterioles of the kidney, leading to increased perfusion pressure in the glomeruli.
- ventricular remodeling of the heart, which may lead to ventricular hypertrophy and CHF
- stimulation of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, 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 (also known as anti-diuretic hormone (ADH)) which also acts on the kidneys to increase water retention.
- decrease renal protein kinase C
With ACE inhibitor use, the effects of angiotensin II are prevented, leading to decreased blood pressure.
Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is utilised in the prevention of diabetic renal failure.
ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure.
The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent 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.).
ACE inhibitors have also been shown to cause a central enhancement of parasympathetic activity in healthy volunteers and patients with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.
The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure.
ACE-inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.
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