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Old 11-13-2010
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Drug UW question - Pharmacology

Q : Milrinone is a strong inotropic agent. Its mechanism of action involves inhibition of phosphodiesterase isoenzyme 3. Which of the following additional responses is most likely an extension of its pharmacologic effect?


A. Angioedema
B. Antiarrhythmic action
C. Vasodilation
D. Increased right atrial pressure
E. Sodium and water retention
F. AV conduction block
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C. Vasodilation
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Very good. That's the correct answer.

But how does it work? I read the UW explanation but don't understand the way they explain. Inhibition of phosphodiesterase isoenzyme 3 can cause increase in cAMP which can vesoconstrict, Only cGMP can vesodilate rite?

Please explain to me in simple way... thank you.
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milrinone is phosphodiestrase inhibitor

phosphodiestrase metabolizes cyclic AMP [cAMP]

what is cAMP - second messenger in excitation-contraction coupling

what does cAMP do - it increases the conductance of calcium channels in sarcoplasmic reticulum, resulting in more calcium entering the cardiac myocyte and strengthening the force of contraction

in vascular smooth muscle, increase in cAMP causes vasodilation which can limit milrinone's use in hypotensive patients
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Quote:
Originally Posted by aktorque View Post
Very good. That's the correct answer.

But how does it work? I read the UW explanation but don't understand the way they explain. Inhibition of phosphodiesterase isoenzyme 3 can cause increase in cAMP which can vesoconstrict, Only cGMP can vesodilate rite?

Please explain to me in simple way... thank you.
How does smooth muscle contraction occur?

Smooth muscle contractile mechanism is slightly different form the cardiac and skeletal muscle. They all need the interaction between myosin and actin but one important difference is, smooth muscle does not have troponin and tropomyosin. So in smooth muscle for myosin to interact with actin, myosin must be phosphorylated.

Now who phosphorylate the myosin?

We all know phosphorylation is done by an enzyme called kinase, so here the enzyme is called myosin light chain kinase. That means if the myosin light chain kinase is inhibited then it won’t be able to phosphorylate myosin and then there is no interaction between the myosin and actin, hence we have relaxation of smooth muscle.

Now the question is how do we inhibit myosin light chain kinase?

As we all know, phosphorylation of an enzyme will either activated or inhibit the enzyme, so here phosphorylation of myosin light chain kinase will result in inactivation.

So how do we phosphorylate myosin light chain kinase?

There are several mechanisms. Increasing cAMP will result in increased level of Protein kinase A. the kinase will phosphorylate the myosin light chain kinase. This is how beta-2 adrenergic causes relaxation of bronchial smooth muscle and blood vessels.

How does nitric oxide dilate blood vessels?

Nitric oxide dilate blood vessels by binding to intra cytoplasmic Guanylate cyclase, which will convert GTP to cGMP and it in turn activates Protein Kinase G. the PKG will phosphorylate the Myosine light chain kinase and inactivate it.

Now how does milrinone cause blood vessels to dilate?

Milrinone is phosphodiestrase inhibitor. Phosphodiesterase inhibit cAMP. so if you inhibit Phosphodiesterase then cAMP is free to activate PKA. PKA will phosphorylate myosine light chain kinase and inactivate it. If myosin is not phosphorylated it cannot interact with actin, which means relaxation of smooth muscle.

I hope this will clear your concept on smooth muscle contraction.

Good luck for USMLE. “Let’s help each other “ …….“we all can ace the USMLE”


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Quote:
Originally Posted by aktorque View Post
Very good. That's the correct answer.

But how does it work? I read the UW explanation but don't understand the way they explain. Inhibition of phosphodiesterase isoenzyme 3 can cause increase in cAMP which can vesoconstrict, Only cGMP can vesodilate rite?

Please explain to me in simple way... thank you.
increase CAMP LEVELS: causes vasodilation
(increase cAMP levels which in turn relax the smooth muscles eg.vasodilation)
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