Inhibitors of the Renin Angiotensin System

Pre-kallikrein

Angiotensinogen

Renin

Kininogen

Activated factor XII

Kallikrenin

Angiotensin I

Angiotensin II Angiotensin II

Angiotensin I

Angiotensin II Angiotensin II

Angiotensin converting enzyme Kininase II

Bradykinin

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7

Inactive peptide

Increased aldosterone release

Increased aldosterone release

Potentiation of sympathetic activity

Increased Ca2+ current

Vasoconstriction

Potentiation of sympathetic activity

Vasodilation

FIGURE 11-16

Soon after the release of this useful class of antihypertensive drugs, the syndrome of functional acute renal insufficiency was described as a class effect. This phenomenon was first observed in patients with renal artery stenosis, particularly when the entire renal mass was affected, as in bilateral renal artery stenosis or in renal transplants with stenosis to a solitary kidney [26]. Acute renal dysfunction appears to be related to loss of postglomerular efferent arteriolar vascular tone and in general is reversible after withdrawing the angiotensin-converting enzyme (ACE) inhibitor [27].

Inhibition of the ACE kinase II results in at least two important effects: depletion of angiotensin II and accumulation of bradykinin [28]. The role of the latter effect on renal perfusion pressure is not clear, A.

To understand the angiotensin I converting enzyme inhibitor-induced drop in glomerular filtration rate, it is important to understand the physiologic role of the renin-angiotensin system in the regulation of renal hemodynamics, B. When renal perfusion drops, renin is released into the plasma and lymph by the juxtaglomerular cells of the kidneys. Renin cleaves angiotensino-gen to form angiotensin I, which is cleaved further by converting enzyme to form angiotensin II, the principal effector molecule in this system. Angiotensin II participates in glomerular filtration rate regulation in a least two ways. First, angiotensin II increases arterial pressure—directly and acutely by causing vasoconstriction and more "chronically" by increasing body fluid volumes through stimulation of renal sodium retention; directly through an effect on the tubules, as well as by stimulating thirst

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and indirectly via aldosterone. Second, angiotensin II preferentially constricts the efferent arteriole, thus helping to preserve glomerular capillary hydrostatic pressure and, consequently, glomerular filtration rate.

When arterial pressure or body fluid volumes are sensed as subnormal, the renin-angiotensin system is activated and plasma renin activity and angiotensin II levels increase. This may occur in the context of clinical settings such as renal artery stenosis, dietary sodium restriction or sodium depletion as during diuretic therapy, congestive heart failure, cirrhosis, and nephrotic syndrome. When activated, this reninangiotensin system plays an important role in the maintenance of glomerular pressure and filtration through preferential angiotensin ¡¡-mediated constriction of the efferent arteriole. Thus, under such conditions the kidney becomes sensitive to the effects of blockade of the renin-angiotensin system by angiotensin ¡-converting enzyme inhibitor or angiotensin ¡I receptor antagonist. The highest incidence of renal failure in patients treated with ACE inhibitors was associated with bilateral renovascular disease [27]. In patients with already compromised renal function and congestive heart failure, the incidence of serious changes in serum creatinine during ACE inhibition depends on the severity of the pretreatment heart failure and renal failure.

Volume management, dose reduction, use of relatively short-acting ACE inhibitors, diuretic holiday for some days before initiating treatment, and avoidance of concurrent use of nonsteroidal anti-inflammatory drug (hyperkalemia) are among the appropriate measures for patients at risk.

Acute interstitial nephritis associated with angiotensin ¡-converting enzyme inhibition has been described [29]. (Adapted from Opie [30]; with permission.)

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