Blog 2.2

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

Hypertension is the disease in which angiotensinogen levels are increased. Angiotensinogen levels are increased with estrogens, thyroid hormones, corticosteroids, ANG II. It is also increased during pregnancy.

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

Drugs which blocks ACE will also lead to the inhibition of bradykinin breakdown. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction which cause the negative side-effect of a dry, irritating cough. Drugs which act specifically on angiotensin receptors will not inhibit bradykinin breakdown and thus will not have this adverse effect because due to the fact that the bradykinin concentration will not be increased.

• 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 leads to a decrease in peripheral resistance and BP. Aldosterone secretion decreases which leads to less salt and water retention and more excretion in the urine which lowers cardiac preload, decrease cardiac output and decrease BP. Left ventricular hypertrophy is also reversed.

Secondly, ACE inhibitors inhibit bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which increase arterial vasodilation, decrease peripheral resistance and decrease BP. 

• 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. They have no affect on angiotensin II type 2 receptors , like Lorsartan and other similar drugs.

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

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

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

Bradykinin 2 receptors

• 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. It will cause a decrease in angiotensin as well as aldosterone. This will relieve the oedema which is associated with congestive heart failure. The natriuretic peptides cause vasodilation which decrease peripheral resistance and decrease BP 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 ANP and BNP which lead to a decrease in their concentrations. In reducing ANP and BNP, their positive therapeutic effects in congestive heart failure is also reduced. Thus neprilysin should be blocked so that the therapeutic positive effects of ANP and BNP can dominate.

Neprilysin inhibitor drug is Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Endothelium derived vasodilators: PGI2, NO (nitric oxide)

Endothelium derived vasoconstrictors: Endothelin: ET1, ET2, ET3, ETA, ETB

Endothelium antagonists that cause vasodilation: Bosentan, macitentan, ambrisentan, sitaxsentan etc.