MUSCARINIC AND NICOTINIC CHOLINOCEPTORS AGONISTS AND ANTAGONISTS Drugs on cardiovascular sys !

" in vivo
Pr!#ar!d $y Mar %n&ov' () C*l'd!& () +al*ousov' H, using PC #rogra": I,E,Hug*!s H!ar ra ! and $lood #r!ssur! -Univ!rsi y o. L!!ds) England/

In roduc ion
Demonstrations of the properties of drugs which affect the autonomic nervous system, heart and blood vessels can be performed on conscious or anaesthetised animals. Recordings of heart rate and blood pressure of animals (usually a dog, cat or rat) can easily be made and students gain immensely from working with such in vivo preparations. Unfortunately, such e periments are e pensive, are very time consuming and use many animals. !herefore, this simulation of these e periments may enable some of the teeching ob"ectives for which such preparations are used to be achieved without the use of animals and may also be usefull to suppliment #hands$on# e periments.

0, Progra" o#!ra ion

!he program is basically self$e planatory and menu driven. !he user must select a particular drug or procedure from menu% the re&uired dose (entirely in the hand of the user) is then entered. 'ppropriate blood pressure and heart rate records are then displayed on screen. !he menu in then redisplayed and the ne t drug or procedure can be selected. !he user can leave the program completely from the menu at any time. (ow to start: )ardiovascular pharmacology *ress: + for colour displey + for dose in ,g-kg + for blood pressure in mm(g . for output on .)R//0 1 for no pretreatment 02R3'4 *R/*'R'!520, 4ist of available drugs appears$ basic menu

1, P*ar"acological su""ary
2utlined below are the ma"or actions shown by the drugs available. !he presence of refle es may modify the effects observed. 0ote that at high dose levels additional effects will become apparent. 6ollow the instructions generated by the program:

2, Drugs in us!
Ta$,0, Agonis s on c*olinoc!# ors 'cetylcholine stimulates muscarinic cholinoceptors and evokes a depressor response along with negative chronotropic and inotropic effects. A *ig*!r dos!s stimulant effects at nicotinic cholinoceptors may be seen with conse&uential release of catecholamines 0eostigmine 'n anticholinesterase (')(/) agent Ta$,1, An agonis s on c*olinoc!# ors 'tropine ' competitive blocker on muscarinic cholinoceptors )ompare effects of atropine +7 a +777 ,g-kg on ')( dose$response curve

E3!rcis!s
E3#!ri"!n 04 E..!c s o. ac! ylc*olin! -ACH/ on $lood #r!ssur! and *!ar ra ! 5n"ect intermittent doses of ACH (press 8) in ,g-kg $ tab.1 and register systolic-diastolic blood pressure (.9*-D9*) and heart rate.
Ta$, 2, Sys olic5dias olic $lood #r!ssur! 5nitial values ACH 6g5&g 7.77+ 7.7+ 7.+ + +7 +77 +777 H!ar ra !

(ave you registered both muscarinic and nicotinic effects: !erminate the preparation (press 17). )ontinue ;. )onstruct the dose$response curve of acetylcholine (DR)')() < using .9* (tab. 1, 6ig. +). E3#!ri"!n 14 E..!c s o. n!os ig"in! and ACH on $lood #r!ssur! and *!ar ra ! 'dminister n!os ig"in! (press =>), =77 ,g-kg then ACH (press 8) at increasing doses $ tab.>.
Ta$, 7, Sys olic5dias olic $lood #r!ssur! 5nitial values N!os ig"in! 188 6g5&g /ffects of neostigmine 9 ACH 6g5&g 7.77+ 7.7+ 7.+ + +7 +77 H!ar ra !

(ave you registered both muscarinic and nicotinic effects: !erminate the preparation (17). )ontinue ;. )onstruct dose$response curve (.9*) of acetylcholine (DR)')() in presence of neostigmine.

E3#!ri"!n 24 E..!c s o. a ro#in! and ACH on $lood #r!ssur! and *!ar ra ! 'dminister a ro#in! (press +?), 08 6g5&g then use ACH (press 8) at increasing doses $ tab.@.
Ta$, :, Sys olic 5dias olic $lood #r!ssur! 5nitial value A ro#in! 08 6g5&g /ffects of atropine 9ACH 6g5&g +.7 +7 +77 +777 +7777 (ave you registered both muscarinic and nicotinic effects: !erminate the preparation. )ontinue ;. )onstruct DR)')( (.9*) in presence of atropine (6ig.+). )ompare DR)')( with that in e periment +. H!ar ra !

E3#!ri"!n 74 E..!c s o. a ro#in! and ACH on $lood #r!ssur! and *!ar ra ! 'dminister a ro#in! (press +?) 0888 6g5&g then use ACH (press 8) at increasing doses (tab.?).
Ta$, ;, Sys olic 5dias olic $lood #r!ssur! 5nitial value A ro#in! 0888 6g5&g /ffects of atropine 9 ACH 6g5&g +7 +77 +777 +7777 (ave you registered both muscarinic and nicotinic effects: !erminate the preparation. )ontinue ;. )onstruct DR)')( (.9*) in presence of atropine (6ig.+). )ompare DR)')( with that in e periment + (6ig.+). H!ar ra !

<ig, 0, R!la ions*i# a"ong *! .ull agonis s and an agonis s on c*olinoc!# ors
Fig. 1 Dose-response curve of acetylcholine 150
Systolic blood pressure (mm g)

100

50

0 0.001 0.01 0.1 1 10 100 1000 10000

Dose ( g/kg) 'cetylcholine doses are e pressed in a logarithmic scale.

Conclusion4
DR) of full agonists in the presence of antagonists:

S!l!c "ul i#l! r!c!# or su$ y#!s

0eurotransmitters have multiple receptor subtypes with which to interact. 5t is as though the neurotransmitter $ a master key capable of unlocking each of the multiple locks of receptors subtypes. Drugs can be made that mimic the neurotransmitter, but many are more selective than the natural neurotransmitter, thus defining a pharmacological subtype at which they specifically interact. !his figure shows a neurotransmitter capable of binding to several different receptor subtypes (i.e.master key). 'lso shown are several different drugs on a key chain. /ach of these drugs is selective for a single subtype of the neurotransmitter receptors. 5ndicate the cholinoceptor subtype stimulated (s) or blocked (b) if some drug is administered i.v. (intravenously).

3+$31 muscarinic cholinoceptors, 03 nicotinic cholinoceptors in skeletal muscle

00 in the ganglia

0)0. in the central nevrous system

)ompare the neurotransmitter with drugs influencing particular receptors subtypes and indicate which determines pharmacodynamic property: Conclusion
s$simulation b$blockade d$direct i$indirect

3+ ' 9 ) D / neostigmine pilocarpine atropine tolterodine nicotine

3=

31

03

00

0)0.