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PHAR3414 Tutorial 6 Q2

By Kan Chun Him (1155076777)


25-Oct-2017
Tutorial question 02
Explain the contractile mechanism of K+ & noradrenaline
Identify each of the agent P, Q & R
Suggest a drug with
Different mechanism of action as Q

PHAR3413 Tutorial 5 (n.d.) SOP, CUHK, HK; pp3


Vascular smooth muscle

Miller AL (2013) Muscle and Movement Lecture 3: Part A [Presentation slide]. Department of Life Science, HKUST, HK. pp 1-92
Contractile response by K+
1. Negative membrane potential
Low K+
High Ca2+ & Na+
2. K+ injection: Increase in [K+]ECF
Depolarization (?)
3. L-type Ca2+ channel activation
1. Ca2+ influx from ECF
2. Cascade with calmodulin & MLCK
4. Excitation-contraction coupling
End Result

Borda L, Shuchleib & Henry PD. (1977) Effects of Potassium on Isolated canine Coronary Arteries- Modulation of Adrenergic responsiveness and Release of Norepinephrine. Circulration research; 41(6): pp 778-788. DOI: 10.1161/01.RES.41.6.778
Contractile response by Noradrenaline
1. NA activation of 1 adrenoceptor
1. Gq activated
2. PLC activation
2. IP3 as 2nd messenger
1. Activates IP3-gated Ca2+ channel
2. Ca2+ efflux from sarcoplasmic reticulum
3. Ca2+(ICF)-induced depolarization
Activates voltage-gated Ca2+ channel
Calcium-induced-Calcium-release (CICR)
End Result

Borda L, Shuchleib & Henry PD. (1977) Effects of Potassium on Isolated canine Coronary Arteries- Modulation of Adrenergic responsiveness and Release of Norepinephrine. Circulration research; 41(6): pp 778-788. DOI: 10.1161/01.RES.41.6.778
Cromakalim: Q
1. KATP channel activation
K+ efflux & hyperpolarization
2. L-type Ca channel activation
Ca2+ influx
Scenario 1 (High [K+]ECF):
Little hyperpolarization / relaxation: Q
Scenario 2 (NA):
Relaxation with different mechanism as NA

End Result

Benton, D.C. & Haylett, D.C. (1992) Effects of cromakalim on the membrane potassium permeability of frog skeletal muscle in vitro. Br. J. Pharmacol. Macmillan Press Ltd, UK; 107: pp152-155 Retrieved on 13 October 2017 from
http://pubmedcentralcanada.ca/pmcc/articles/PMC1907595/pdf/brjpharm00212-0156.pdf
Nifedipine: R
1. L-type Ca2+ channel blocking
Blocks Ca2+ influx
Scenario 1 (K+):
High K+ in ECF
Ca2+ influx blocked
Vascular muscle relaxation
Scenario 2 (NA):
Cannot block Ca2+ release from SR
Can stop voltage-gated Ca2+ channel (CICR)
Much weaker response than scenario 1
End Result

Miller AL (2013) Muscle and Movement Lecture 3: Part A [Presentation slide]. Department of Life Science, HKUST, HK. pp1-92
Huang P. (2014) Signalling through G-protein coupled Receptors [Presentation slide]. Department of Life Science, HKUST, HK. pp1-37
Isoprenaline: P
Non-selective -adrenoceptor agonist
Dual mechanism
I. Vascular smooth muscle
1. Activates 2 adrenoceptor
2. Gs subunit activates AC
3. More cAMP to activate PKA
4. PKA phosphorylates MLCK
Inactivation
5. Muscle relaxation

Pelat M et.al. (2003) High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs. J Pharmacol Exp Ther; 304(1):pp246-53 DOI: 10.1124/jpet.102.040691
Valeria C. et.al. (2013) Adrenoreceptors and nitric oxide in the cardiovascular system. Front. Physiol., 4:321 DOI: 10.3389/fphys.2013.00321
Isoprenaline: P
II. Vascular endothelium
1. Activates 3 adrenoceptor
2. Gs subunit activate AC
3. More cAMP to activate PKA
4. PKA phosphorylates eNOS
Activation
NO releases & diffusion
NO activates GC in SMC
More cGMP
5. SMC relaxation

Pelat M et.al. (2003) High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs. J Pharmacol Exp Ther; 304(1):pp246-53 DOI: 10.1124/jpet.102.040691
Valeria C. et.al. (2013) Adrenoreceptors and nitric oxide in the cardiovascular system. Front. Physiol., 4:321 DOI: 10.3389/fphys.2013.00321
Alternatives of Q
1. Prazosin
1 adrenoceptor antagonist
Competes with Noradrenaline
Reversal of action
2. TNG
NO donor
Activates GC in SMC
More cGMP
SMC relaxation

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