RAAS inhibitors, mechanisms and effects
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RAAS inhibitors, mechanisms and effects
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[post_date] => 2024-12-23 18:40:49
[post_date_gmt] => 2024-12-23 23:40:49
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
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.
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[question] => What activates the renin–angiotensin–aldosterone system?
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[answer] => 4
[description] => Reason for Correct Answer:
In the RAAS, renin acts on angiotensinogen to form angiotensin I, which is then converted to the biologically active angiotensin II by ACE.
Angiotensin II exerts its effects, including vasoconstriction and stimulation of aldosterone and ADH release, to increase blood volume, increase blood pressure and conserve water.
‘Increased blood volume’ is almost always synonymous with ‘increased blood pressure’.
The RAAS is tightly regulated through a complex feedback mechanism to maintain blood pressure and fluid balance. When blood pressure drops or there is a decrease in blood volume, specialized cells called juxtaglomerular cells in the kidneys release the enzyme renin into the bloodstream.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Increased early distal tubule osmolarity
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[1] => Array
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[each_answer] => B. Increased blood volume
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[2] => Array
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[each_answer] => C. Decreased renal sympathetic activity
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[3] => Array
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[each_answer] => D. Decreased blood pressure
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => Both ACE inhibitors and ARBs result in:
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Here is an overview of the RAAS, which includes the effects of angiotensin II on aldosterone release:
https://commons.wikimedia.org/wiki/File:Renin-angiotensin-aldosterone_system.png
As shown, angiotensin II stimulates the release of aldosterone from the adrenal gland.
Aldosterone acts to increase the reabsorption of sodium in the distal convoluted tubule and collecting duct. This contributes to higher blood pressure, as water follows sodium back into the blood.
According to the passage, both ACE inhibitors and ARBs would decrease the secretion of aldosterone by decreasing the levels of angiotensin II (ACE inhibitors) or blocking its effects (ARBs). This would have the effect of decreasing reabsorption of sodium in the distal nephron.
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[answers] => Array
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[0] => Array
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[each_answer] => A. increased sodium reabsorption in the distal nephron due to decreased release of aldosterone.
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[each_answer] => B. decreased sodium reabsorption in the distal nephron due to decreased release of aldosterone.
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[2] => Array
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[each_answer] => C. decreased sodium reabsorption in the proximal nephron due to increased release of aldosterone.
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[each_answer] => D. increased sodium reabsorption in the proximal nephron due to increased release of aldosterone.
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Which of the initial treatment groups would the new treatment group with “drug X” most likely resemble and why?
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[answer] => 3
[description] => Reason for Correct Answer:
The passage states that Drug X directly inhibits renin.
Inhibition of renin would decrease the formation of angiotensin I and other downstream products and effects, but it would not affect the levels of the enzyme ACE.
In the passage, captopril is an ACE inhibitor, and eprosartan is an ARB (angiotensin receptor blocker).
Inhibition of renin would more likely have the same effects as eprosartan, since it affects the RAAS but does not have the other effects of blocking the enzyme ACE.
Specifically, like eprosartan, it would not inhibit the breakdown of bradykinin, as ACE inhibitors do, according to Figure 1.
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[answers] => Array
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[each_answer] => A. The captopril group, because the actions of drug X and captopril would both inhibit ACE
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[1] => Array
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[each_answer] => B. The eprosartan group, because the inhibition of renin would mimic the blood pressure effect of blocking AT receptors
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[2] => Array
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[each_answer] => C. The eprosartan group, because neither drug X nor eprosartan would inhibit the degradation of bradykinin
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[each_answer] => D. The captopril group, because the actions of drug X and captopril both result in a net decrease in renin
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[3] => Array
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[quiz_unique_key] => 1403770772
[question] => According to the information presented in the passage, what is the effect of treatment with captopril on insulin- resistant muscles?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Figure 2 shows the amount of glucose uptake in muscle cells in the presence (+) or absence (−) of insulin. (The triangle shows the difference between the insulin and no insulin conditions.) Controls are also provided for points of comparison (shown as “vehicle-treated”, which means that they are treated with the same buffer/formulation as the drug-treated groups but without the active ingredient).
Observe how the captopril group compares with the vehicle group.
Compared with the vehicle, the captopril group shows similar glucose uptake in the absence of added insulin.
However, the captopril group shows a much higher uptake of glucose in response to insulin, compared with the control.
The only conclusion that can be drawn is that treatment with captopril increases the response of insulin-resistant muscles to insulin. It takes up more glucose in response to insulin (the hormone that promotes glucose uptake).
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[answers] => Array
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[0] => Array
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[each_answer] => A. Increase in the amount of available insulin in insulin-resistant muscles
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[1] => Array
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[each_answer] => B. Increase in response to insulin in insulin-resistant muscles
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[each_answer] => C. Decrease in the amount of available insulin in insulin-resistant muscles
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[each_answer] => D. Decrease in response to insulin in insulin-resistant muscles
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[4] => Array
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[quiz_unique_key] => 1403770772
[question] => With respect to stroke volume and cardiac output, what physiologic changes in the heart would be expected after treatment with captopril?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
Blocking the RAA system promotes a decrease in blood volume and therefore blood pressure. Decreased blood pressure is achieved by: 1) decreased salt and water reabsorption mediated by aldosterone and 2) decreased vasoconstriction by angiotensin II (a net vasodilation occurs).
Cardiac output = stroke volume x heart rate, where stroke volume = end diastolic volume − end systolic volume. Reduced stroke volume produces a decreased cardiac output.
Decreased blood volume leads to decreased venous return to the heart, which is congruent with a decrease in preload (end diastolic volume), thus a decrease in stroke volume.
Treatment with captopril would induce a decrease in cardiac output and a decrease in stroke volume caused by decreased blood volume overall and a decrease in venous return to the heart.
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[each_answer] => A. Decreased cardiac output, decreased stroke volume
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[each_answer] => B. Decreased cardiac output, increased stroke volume
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[each_answer] => C. Increased cardiac output, decreased stroke volume
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[each_answer] => D. Increased cardiac output, increased stroke volume
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[quiz_unique_key] => 1997864699
[question] => Which is more likely true considering the relative side effects of ACE inhibitors and ARBs?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
According to the passage and Figure 1, ACE inhibitors differ from ARBs in that they inhibit the enzyme ACE, which has other effects besides inhibiting the RAAS system.
Specifically, ACE inhibitors lead to an increase in bradykinin levels by inhibiting bradykinin breakdown.
Note that ARBs, on the other hand, should not affect the levels of bradykinin. (So, Choices C and D are wrong.)
The passage states that “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 also involved in the mechanism of pain.”
According to this information, increased levels of bradykinin from taking ACE inhibitors could result in angioedema/leg swelling from vasodilation and vascular permeability. (ACE inhibitors can also cause symptoms like dry cough and diarrhea from contraction of muscles in the bronchi and gut.)
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[answers] => Array
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[0] => Array
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[each_answer] => A. ACE inhibitors are more likely to result in constipation due to increased effects of bradykinin.
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[1] => Array
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[each_answer] => B. ACE inhibitors are more likely to result in leg swelling due to increased effects of bradykinin.
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[each_answer] => C. ARBs are more likely to result in dry cough due to decreased levels of bradykinin in circulation.
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[each_answer] => D. ARBs are more likely to result in pneumonia due to decreased levels of bradykinin in circulation.
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[554882|5] => A
[554882|6] => B
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Figure 1
Figure 2
