• In which diseases are angiotensinogen levels increased?  What are the implications of this?

Production of angiotensinogen is increased in corticosteroids, estrogens, thyroid hormones, and ANG II. It is further elevated during pregnancy and in women taking estrogen containing oral contraceptives. As a result, the increased plasma angiotensinogen concentration can lead to hypertension.

• Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

Drugs that inhibit the angiotensinogen system have a more complete blockage of the angiotensin system than ACE inhibitors, thus there is no increase in bradykinin, which leads to fewer side effects. The angiotensin blockers are also more selective than the non-selective ACE inhibitors, thus it will have less effects since the non-selective ACE inhibitors.

• In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?
  • ACE inhibitors decreases systemic vascular resistance without an increase in heart rate
  • ACE inhibitors inhibits bradykinin metabolism which causes hypotensive action.
• At which type of angiotensin receptor do losartan and similar drugs act?  Do they have any effect, direct or indirect, at other angiotensin II receptors?
  • AT1 receptors
  • Yes, they do

• What are the physiological effects of kinins on arteries and veins?  Do other autacoids play a role in this action?  Explain.
  • Kinins produce arteriolar dilation and causes the veins to contract
  • Yes, other autacoids play a role. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle or may be mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE2 and PGI2. The veins contracting may e due to direct stimulation of venous smooth muscle or from the release of venoconstrictor prostaglandins.
• Which receptor is probably the most involved in the important clinical effects of kinins?

B2-receptor

• In which way are natriuretic peptides possibly effective in the treatment of hypertension, as well as congestive heart failure?

They produce vasodilation and natriuresis.

• What is neprylisine and what is the rationale for inhibiting its action in the treatment of heart failure? Can you name the drug being used as such? Refer to Study unit 1 where you have also come across this drug.

Neprilysin is the neutral endopeptidase NEP 24.11 that metabolizes natriuretic peptides in the kidneys, lungs, and liver. The inhibition of neprilysin results in an increase in ANP and BNP which causes natriuresis and vasodilation and an increase in renin secretion and plasma ANG II levels. The drug being used is sacubitril.

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

        Vasodilators: Nitric oxide and PGI2

         Vasoconstrictors: ET 1 and receptor subtypes ETA and ETB