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Course: MCAT > Unit 2

Lesson 3: Foundation 3: Organ Systems

Renal: RAAS inhibitors, mechanisms and effects


Angiotensin-converting enzyme (ACE) inhibitors are a first-line pharmacological therapy in the management of hypertension and congestive heart failure. They lower blood pressure primarily by inhibiting the activity of ACE; this causes the inhibition of conversion of angiotensin I to angiotensin II. In addition, ACE Inhibitors have been shown to inhibit the degradation of bradykinin by ACE. Bradykinin is a potent vasodilatory peptide that also causes contraction of non-vascular smooth muscle in the bronchi and gut, increases vascular permeability, and is involved in the mechanism of pain. Figure 1 summarizes how ACE inhibitors affect the renin–angiotensin–aldosterone system (RAAS) pathway and the metabolism of bradykinin.
Figure 1 RAAS pathway and other processes inhibited by ACE inhibitors (ACEI)
In addition to ACE inhibitors, angiotensin receptor blockers (ARBs), as well as direct renin inhibitors, are routinely used to manage blood pressure. Although all of these drugs are effective, they each affect blood pressure by a different mechanism and are often accompanied by unique secondary effects.
Because a majority of hypertensive individuals demonstrate insulin resistance and hyperinsulinemia, researchers examined the effects of ACE inhibitors and ARBs on glucose transport in insulin-resistant, or insulin-desensitized, muscles. Obese rats were injected with water, captopril (an ACE inhibitor), bradykinin, or eprosartan (an ARB). After treatment, the rats were anesthetized, and both epitrochlearis muscles were removed and incubated in a solution of 8 mM glucose, 32 mM mannitol, and 0.1% bovine serum albumin (BSA). One muscle from each rat was incubated with the addition of 2 units/mL insulin. After twenty minutes of incubation, the muscles were examined to determine glucose transport activity. The results of the experiment are shown in Figure 2.
Figure 2 Effects of acute treatment with captopril, bradykinin, or eprosartan on glucose transport activity. Controls (vehicle-treated) are demonstrated for each treatment group. The glucose uptake in the absence (−) and presence (+) of insulin is reported, along with the net increase above basal (∆) caused by insulin. A “*” denotes data that is statistically significant.
To further elucidate causal relationships, the experiment was repeated with the inclusion of a treatment group that received a dose of “drug X”. Drug X is a well-documented agent that is known to produce significant anti-hypertensive effects in patients and experimental models. The mechanism by which this is achieved is the direct inhibition of renin.
Passage adapted from: Henriksen, E. J. et al. ACE inhibition and glucose transport in insulin-resistant muscle: roles of bradykinin and nitric oxide. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 277.
What activates the renin–angiotensin–aldosterone system?
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