History of RAS Discovery and Therapeutic Development Against Hypertension for Medical Students

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Instructions

Read the information and complete the exercises below to explore the history of the Renin-Angiotensin System (RAS) and the development of drugs to treat hypertension.

Part 1: Key Discoveries in RAS History

Match the scientist(s) or event in Column A with the corresponding discovery or contribution in Column B. Write the correct letter in the blank provided.

Column A
  1. _____ Cushman & Ondetti
  2. _____ Harry Goldblatt
  3. _____ Robert Tigerstedt & Per Bergman
  4. _____ Leonard Skeggs
  5. _____ Sérgio Ferreira
  6. _____ Development of Losartan
 Column B
  1. Demonstrated that constricting the renal artery in dogs led to persistent high blood pressure, linking kidney ischemia to hypertension.
  2. Sequenced angiotensin I and II and discovered the enzyme that converts one to the other (ACE).
  3. Represents the first-in-class Angiotensin II Receptor Blocker (ARB), offering a new way to target the RAS.
  4. Using a compound from snake venom as a model, they developed captopril, the first orally active ACE inhibitor.
  5. In 1898, discovered a substance in rabbit kidney extracts that raised blood pressure, which they named "renin".
  6. Discovered a "bradykinin-potentiating factor" in pit viper venom that was later found to be a potent inhibitor of ACE.

Part 2: The RAS Cascade

Fill in the blanks to correctly describe the sequence of the Renin-Angiotensin System.

The RAS cascade begins in response to low blood pressure or low sodium levels. The liver produces a precursor protein called (1)____________________. The kidneys then release an enzyme called (2)____________________, which cleaves the precursor to form the inactive peptide, (3)____________________. This peptide travels through the bloodstream to the lungs, where an enzyme embedded in the blood vessel walls, called (4)______________________________ (ACE), converts it into the potent, active hormone (5)____________________. This final hormone has several effects: it causes powerful (6)____________________ (narrowing of blood vessels) and stimulates the adrenal gland to release (7)____________________, which promotes sodium and water retention. Both of these actions work to increase blood pressure.

Part 3: Targeting the Cascade for Therapy

Complete the table below to describe the three main classes of drugs that target the Renin-Angiotensin System to treat hypertension.

Drug Class Mechanism of Action Side Effect Profile Note
ACE Inhibitors
(e.g., Lisinopril, Captopril)		   Can cause a persistent dry cough.
Angiotensin II Receptor Blockers (ARBs)
(e.g., Losartan, Valsartan)		   Cough is much less common than with ACE inhibitors.
Direct Renin Inhibitors (DRIs)
(e.g., Aliskiren)		   Blocks the very first step of the cascade.

Part 4: Critical Thinking

Answer the following questions in the space provided.

1. The development of captopril from a snake venom compound is a classic example of "rational drug design." What does this mean in this specific context?

 

 

2. ACE inhibitors are known to cause a dry cough in some patients, while ARBs are not. ACE is responsible for breaking down another substance called bradykinin. How might this secondary function of ACE explain the difference in this side effect?

 

 





Answer Key

Part 1: Key Discoveries in RAS History

  1. D - Cushman & Ondetti
  2. A - Harry Goldblatt
  3. E - Robert Tigerstedt & Per Bergman
  4. B - Leonard Skeggs
  5. F - Sérgio Ferreira
  6. C - Development of Losartan

Part 2: The RAS Cascade

  1. Angiotensinogen
  2. Renin
  3. Angiotensin I
  4. Angiotensin-Converting Enzyme
  5. Angiotensin II
  6. Vasoconstriction
  7. Aldosterone

Part 3: Targeting the Cascade for Therapy

Drug Class Mechanism of Action Side Effect Profile Note
ACE Inhibitors
(e.g., Lisinopril, Captopril)		 Blocks the Angiotensin-Converting Enzyme (ACE), preventing the conversion of angiotensin I to the active angiotensin II. Can cause a persistent dry cough.
Angiotensin II Receptor Blockers (ARBs)
(e.g., Losartan, Valsartan)		 Blocks angiotensin II from binding to its primary receptor (the AT1 receptor), thus preventing its effects like vasoconstriction. Cough is much less common than with ACE inhibitors.
Direct Renin Inhibitors (DRIs)
(e.g., Aliskiren)		 Binds directly to renin and inhibits its enzymatic activity, preventing it from converting angiotensinogen to angiotensin I. Blocks the very first step of the cascade.

Part 4: Critical Thinking

1. The development of captopril from a snake venom compound is a classic example of "rational drug design." What does this mean in this specific context?
It means that instead of randomly screening thousands of compounds, scientists used a known biological mechanism. They knew that a peptide in snake venom inhibited ACE. They studied the structure of that peptide to understand how it worked and then designed a smaller, simpler, orally active molecule (captopril) to specifically target and inhibit the same enzyme.

2. ACE inhibitors are known to cause a dry cough in some patients, while ARBs are not. ACE is responsible for breaking down another substance called bradykinin. How might this secondary function of ACE explain the difference in this side effect?
When ACE is inhibited by an ACE inhibitor, it can no longer break down bradykinin effectively. The resulting accumulation of bradykinin in the lungs is thought to be an irritant that causes the characteristic dry cough. ARBs do not inhibit the ACE enzyme itself, so bradykinin metabolism is unaffected, and this side effect is avoided.

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