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

Angiotensinogen levels increase when low blood pressure is detected. High levels of angiotensinogen 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 ACE allow a surplus of bradykinin in the body which is a potent vasodilator and can accumulate in the respiratory tract causing dry cough from the irritation (CI in patients with asthma). Angiotensin receptor blockers still allow the activity of ACE and so bradykinin can still be broken down into inactive metabolites by this enzyme, preventing any unnecessary side effects cause by the vasodilation.

• In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?

ACE inhibitors such as Captopril, Enalapril and benazepril inhibit the conversion of angiotensin 1 to angiotensin 2. ACE also cannot break down bradykinin into inactive metabolites and so the bradykinin causes major vasodilation.

• 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?

Angiotensin ii receptors. These drugs inhibit AT receptors at the heart, blood vessels kidneys and brain, decrease aldosterone release and thus the RAAS system.

• What are the physiological effects of kinins on arteries and veins? Do other autacoids play a role in this action? Explain.

Kinins cause vasodilatory effects.

• Which receptor is probably the most involved in the important clinical effects of kinins?

B2 receptors

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

Natriuretic peptides cause vasodilation and so reduces blood pressure. A high concentration of ANP and BNP allows for the diagnosis of congestive heart failure.

• 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 metabolises ANP and BNP, a drug that inhibits this is sacubitril. By inhibiting its action the increased amount of ANP and BNP allows the increase of glomerular filtration and so an increase in sodium excretion. This causes a decrease in intervascular blood volume and so a decrease in blood pressure.

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Bosentan.