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

• Angiotensinogen levels are increased with estrogens, thyroid hormones, corticosteroids, ANG II. Angiotensinogen is also increased during pregnancy and in women taking estrogen-containing oral contraceptives. The implications of an increased level of angiotensinogen are associated with 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 block ACE, will also cause the inhibition of bradykinin breakdown to a non-active metabolite. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction which cause the adverse side effect of an irritating, dry cough. Therefore, drugs that block angiotensin receptors will not cause the inhibition of the breakdown on bradykinin. Thus, no adverse effects will be seen as bradykinin doesn’t increase.

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

• ACE inhibitors block the conversion of angiotensin I to angiotensin II. Angiotensin II type I receptors are also blocked. This leads to vasodilation instead of vasoconstriction which causes a decrease in blood pressure and peripheral resistance. Aldosterone secretion decreases which cause less salt and water retention and more excretion of salt and water. This excretion lowers cardiac preload, cardiac output and blood pressure. Left ventricular hypertrophy is reversed. ACE inhibitors inhibits bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which decreases blood pressure, increase vasodilation and decreases peripheral resistance.

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?

• They act on Angiotensin II type 1 receptors. Losartan and other similar drugs have no effect on Angiotensin II type 2 receptors.

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

• Yes, the Kinins cause vasoconstriction of veins and  vasodilation of arteries. Yes ,there are many other autacoids that also cause vasodilation such as neurokinin A, neurokinin B, natriuretic peptides, substance P, vasoactive intestinal peptides, Calcitonin gene-related peptide.

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

• Bradykinin 2 receptor.

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

• Natriuretic peptides such as carperitide and urodilatin causes natriuresis and diuresis, decrease the effect of angiotensin and aldosterone. Thus the above mentioned will relieve the oedema associated with congestive heart failure. These natriuretic peptides cause vasodilation which decrease peripheral resistance and blood pressure that can be effective in treating hypertension.

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 metabolizes the natriuretic peptides which lead to a decrease in concentrations of the peptides. In lowering ANP and BNP, their therapeutic effects in congestive heart failure is also lowered. Therefore neprilysin should be inhibited so that the therapeutic positive effects of the natriuretic peptides can dominate.

Give examples of endothelium-derived vasodilators and vasoconstrictors.

• Endothelium derived vasodilators: nitric oxide,PGI2
• Endothelium derived vasoconstrictors: Endothelin