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As shown on Plate 3-19, the renin-angiotensin system plays an essential role in the regulation of systemic blood pressure. In brief, renin is released from juxta-glomerular cells in response to decreased renal tubular flow, sympathetic input, or decreased stretch of afferent arterioles. Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is rapidly converted by angiotensin-converting enzyme (ACE) into angiotensin II (AII). AII increases blood pressure through direct vasoconstrictor effects on systemic vessels and through various other mechanisms, including increased sodium reabsorption from the renal tubules, potentiation of sympathetic tone, and stimulation of aldosterone and antidiuretic hormone release.

Several agents can inhibit this system, including ACE inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors. These agents are powerful anti-hypertensive medications, but they are also capable of slowing the progression of renal disease. The mechanism by which these agents protect the kidneys is not fully known, but it likely relates in part to their effects on glomerular hemodynamics. Whenever renal disease causes nephron loss, there is compensatory hyperfiltration of the remaining nephrons that is mediated, at least in part, by AII-dependent constriction of efferent arterioles. Although this response allows the kidneys to temporarily maintain high levels of filtration function, it is ultimately maladaptive because the high intraglomerular pressure causes capillary wall damage, leading to worsening proteinuria and glomerulosclerosis. By relieving constriction of the efferent arterioles, these drugs lower intraglomerular pressure, reducing proteinuria and protecting the glomerular capillary walls. Although this effect is renoprotective in the long term, it is associated with a reversible and expected 20% to 30% decline in glomerular filtration rate (GFR) at the onset of drug therapy, especially if other diuretics are also used. In most patients, however, this effect should not be a reason to stop treatment.


Plate 10-6


ACE inhibitors prevent the ACE-mediated conversion of angiotensin I to angiotensin II, thereby interfering with the latter’s prohypertensive effects. These agents also inhibit other ACE-mediated pathways, which may contribute to their clinical effect. For example, they also inhibit the metabolism of bradykinins, which promote vasodilation and upregulate prostaglandin synthesis.

ACE inhibitors can be broadly classified as sulfhydryl-containing, carboxyl-containing, or phosphinyl-containing. In addition, some of these agents directly block ACE, whereas others must first undergo transformation into active metabolites.

The major indications for ACE inhibitors are:

·  Hypertension, especially in patients with congestive heart failure, diabetes mellitus, and, or renal insufficiency

·   Systolic left ventricular dysfunction, since these agents reduce afterload and inhibit ventricular remodeling

·    Chronic kidney disease

The major adverse effects of ACE inhibitors include:

·     Cough, owing to increased levels of bradykinin and prostaglandins

·     Angioedema, also thought to be bradykinin-mediated

·     tension, generally at the onset of drug treatment

·     Hyperkalemia, owing to reduced aldosterone levels, especially when used in combination with a potassium-sparing diuretic

·  Acute kidney injury. Although some decline in GFR is expected, patients with renal artery stenosis (see Plate 4-36) may experience renal failure because they require efferent arteriolar constriction to maintain adequate hydrostatic pressure in the glomerular capillaries

·     Dysgeusia, especially with captopril

·     Maculopapular, sometimes pruritic rash

·     Neutropenia, especially in those with renal insufficiency or autoimmune disease



The ARBs are a class of competitive and noncompetitive antagonists of the AT1 angiotensin receptor. These agents are very similar to ACE inhibitors, but they do differ in several important respects. First, because they do not interfere with bradykinin metabolism, these agents are associated with a much smaller risk of cough and angioedema. Second, ARBs are theoretically more potent than ACE inhibitors because they can inhibit the small amount of AII produced through ACE-independent mechanisms. Third, ARBs block AT1 receptors but not AT2 receptors, although the significance of this difference is unclear.

The indications for ARBs are essentially the same as those for ACE inhibitors. In many instances, patients are started on ARBs if they are unable to tolerate the coughing associated with ACE inhibitors. The major adverse effects of ARBs include angioedema (although to a lesser extent than with ACE inhibitors), hyperkalemia, and acute kidney injury, all of which occur through the same mechanisms as with ACE inhibitors.



The direct renin inhibitors (DRIs) block the conversion of angiotensinogen, renin’s only known substrate, to angiotensin I. Thus, unlike ACE inhibitors, these agents can effectively block the non-ACE conversion of angiotensin I to angiotensin II, and they do not inter-fere with bradykinin metabolism. Unlike ARBs, they also prevent AT2 receptor-mediated signaling. These drugs have been associated with a reduction of proteinuria in combination with ACE inhibitors and ARBs. Their adverse effect profile appears to be similar to that of ARBs.