Question

6. Give three examples of pathologies in which there is an upregulation of RAAS. Next to each one explain your reasoning.

7. How would high levels of angiotensin II (Ang II) affect someone with hypertension?

Part II – Grandpa’s Medications

“Now, what about your grandfather’s medications? He’s taking lisinopril and furosemide. How do those interact with your RAAS system on this diagram that you’ve made?” asked Mom.

“My professor, Dr. Sven, did mention how certain medications disrupt the system and lower blood pressure, which is why grandpa is on these medications. But I’m not sure what drug classes those particular medications belong to.” Arie picked up her iPhone and said, “Hey Siri! What is lisinopril?”

An automated friendly voice boomed, “Lisinopril is a medication of the angiotensin-converting enzyme inhibitor class used to treat high blood pressure, heart failure and after heart attacks. For high blood pressure it is usually a first line treatment…” (Wikipedia, Lisinopril, 2020).

“Ah! Lisinopril is an ACE inhibitor, and furosemide is a diuretic. Ok, now I get it. Let me show you how these drugs disrupt the RAAS pathway and lower Grandpa’s blood pressure.”

Questions

1. Explain why ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) are prescribed to treat hypertension and heart failure.

2. A drug that amplifies the effect of bradykinin would have what effect? What diseases could it be prescribed to treat?

3. Would a patient taking an ARB have the same vasodilation effect via bradykinin as a patient taking an ACE inhibitor?

4. Spironolactone is a drug that blocks the aldosterone receptor in the renal collecting tubule. How would the sodium and potassium levels in the urine change after a patient is placed on spironolactone? Based on these changes, what are possible metabolic adverse effects of the drug?

Answer 1

6.

• Hypertension: RAAS upregulation causes increase Angiotensin II levels which causes vasoconstriction, Na+ and water retention and aldosterone secretion. All of these increases plasma blood volume and causes Hypertension.

• Heart Failure: When heart fails, RAAS gets activated as a compensatory mechanism for short time. This is done to restore adequate perfusion and blood pressure as the failing heart in unable to pump adequate blood.

• Hypovolemic Shock: When there is less blood volume, RAAS gets activated to restore blood volume as already described in previous points ie, by Vasoconstriction, Sodium and Water retention, and Aldosterone secretion.

7. High level of angiotensin produces-

• Direct vasoconstriction (Efferent Arterioles > Afferent Arterioles) causing Increasd GFR in Renovascular disease patients.
• Enhances Catecholamines release from adrenal medulla/adrenergic nerve endings -> more sympathetic activity.
• Increased sympathetic outflow -> Increase heart rate -> more Cardiac Output.
• Inhibits reuptake of Noradrenaline.
• Augments vascular smooth muscles responsiveness.
• Increase force of myocardial contraction by promoting calcium influx -> more cardiac output.
• Enhances synthesis and release of Aldosterone -> more sodium reabsorption from DCT.
• Induce ADH release -> more plasma volume.

All the above actions increase volume of blood and thus causes Hypertension.

1. ACE inhibitors :

Ang I is converted to Ang II by Angiotensin Converting Enzyme (ACE).

ACEi blocks this ACE. There is no conversion of Ang I to Ang II.

ARBs block the receptor of Ang II. This it inhibits the action of Ang II direcly.

Less Ang II effect means lessening of all it's actions which I described above which leads to less plasma blood volume and ultimately less blood pressure.

In a failing heart, RAAS is activated as a compensatory mechanism. This is actually not good the heart which is already failing. So ACEi/ARBs is prescribed to decrease sympathetic activity, plasma voume and blood pressure so that there is less stress on the failing heart.

2. ACE inhibitor amplifies the action of Bradykinin by preventing it's degeneration. This leads to Vasodilation causing cough and Angioedema. These are the side effects of ACEi.

3. No, patients on ARBs have no such effect. Therefore, it is given in patients who exhibit cough and angioedema with ACEi.

4. Spironolactone is the Aldosterone antagonist. It causes increased sodium excretion and decreased potassium secretion. So, in urine, sodium levels rise in urine and potassium level falls.

Consequently, the possible metabolic adverse effects of Spironolactone are:

• Hyponatremia (less sodium in blood)
• Hyperkalemia (more potassium in blood)