08 Smooth Muscle Flashcards
Electromechanical Coupling
- operates thru changes in cell membrane potential
- - - 40 to - 70mV
Pharmacomechanical Coupling
- operates independent of cell membrane potential
- - Receptors / Intracellular Signaling
Mechanism of Smooth Muscle Contraction
- PLC => DG + IP3 (IP3 on SR releases Ca2+)
- VG Ca2+ channel
- Myosin Light Chain (MLC) Kinase: when phosphorylated, leads to contraction in actin
- Rho Kinase: inactivates myosin phosphatase which dephosphorylates MLC
Contraction = actin + MLC(P)
Mechanisms of Smooth Muscle Relaxation
Block:
- VG Ca2+ channel
- Rho kinase
- Agonist binding Receptor
Paracrine Factors:
- NO
- Dopamine
- Prostacyclin
Pre-Load
Volume of blood in ventricles at end of diastole
Increased in:
- Hypervolemia
- Regurgitation of cardiac valves
Afterload
Resistance left ventricle must overcome to circulate blood
Increased in:
- Hypertension
- Vasoconstriction
An increase in afterload increases cardiac workload
What is decreased with Nitrates?
Pre-load
What is the mechanism of action of Nitric Oxide (NO)?
NO binds to guanylate cyclase which converts GTP to cGMP
cGMP leads relaxation
Arterial and venous circulation (venous dominant)
Nitroglycerin
Organic Nitrate
- Venous (dominant)
Tx: Heart Failure
Toxicity: Hypotension
What organic nitrate can be used to treat heart failure?
Nitroglycerin
When using Nitroglycerin, what happens to stroke volume and Left Ventricular End-Diastolic Pressure?
LV End-Diastolic Pressure: Dec
SV: No change
Nitroprusside
NO Releasing
Relaxation of arterial and venous circulation
Tx: Hypertensive Emergencies
Toxicity: Hypotension
What organic nitrate can be used to treat hypertensive emergencies?
Nitroprusside
When using nitroprusside, what happens to stroke volume and Left Ventricular End-Diastolic Pressure?
LV End-Diastolic Pressure: Dec
SV: Inc
Hydralazine
Direct Vasodilator
Arterial Circulation
Tx:
- Heart Failure
- Severe Hypertension
Toxicity: Hypotension
When using hydralazine, where does it work?
Directly increases cGMP leading to relaxation
When using hydralazine, what happens to stroke volume and Left Ventricular End-Diastolic Pressure?
LV End-Diastolic Pressure: Dec
SV: Inc
Decreased afterload
What direct vasodilator can be used to treat heart failure (In combination) or severe hypertension?
Hydralazine
Minoxidil
Direct Vasodilator
Arterial Circulation
K+ ATP channel opener
Tx:
- severe hypertension
Toxicity: Fluid retenion
What direct vasodilator is a K+ ATP channel opener?
Minoxidil
What direct vasodilator can results in a side effect of fluid retention?
Minoxidil
Diazoxide
Membrane Channel Dilator
K+ Channel Activator (efflux)
Tx: Hypertensive Emergencies
Toxicity: Hypoglycemia
What drug is a K+ channel activator used to treat hypertensive emergencies?
Diazoxide
What membrane channel dilator can have a side effect of hypoglycemia?
Diazoxide
Ca2+ Channel Blockers
Membrane Channel Dilator
Non-selective
Arterial circulation
Dihydropyridine–nifedipine
Phenylalkylamine–verapamil
Benzothiazapine–diltazem
Blocks contractions in heart and smooth muscle
What phosphodiesterases are located in cardiac muscle? smooth muscle?
Heart: PDE3
Smooth Muscle: PDE3 and PDE5
What is the function of phosphodiesterase in cardiac muscle? smooth muscle?
Heart:
- PDE3 converts cAMP into AMP, which prevents contraction
Smooth muscle:
- PDE5 converts cGMP into GMP, preventing relaxation
- PDE3 converts cAMP into AMP, which prevents contraction
Milrinone, Inamrinone, Cilostazol
Phosphodiesterase (PDE3) inhibitors
Located in cardiac and smooth muscle
- prevents PDE3 from converting cAMP into AMP
- cAMP will activate PKA which will phosphorylate proteins and lead to contraction
Tx: Heart Failure
What drugs prevents PDE3 from converting cAMP into AMP, therefore creating more forceful contractions for the treatment of heart failure?
Milrinone, Inamrinone, Cilostazol
Sildenafil, Tadalafil
Phosphodiesterase (PDE5) inhibitors
Located in smooth muscle
- prevents PDE5 from converting cGMP into GMP
- cGMP results in decreased Ca2+ leading to smooth muscle relaxation
Tx: Erectile Dysfunction
What drug is used to treat erectile dysfunction?
Sildenafil, Tadalafil
PDE5 inhibitors
What drug prevents PDE5 from converting cGMP into GMP, resulting in smooth muscle relaxation?
Sildenafil, Tadalafil
Renin-Angiotensin Blockers
Smooth muscle dilator
- Angiotensin Converting Enzyme (ACE) Inhibitors
- Angiotensin Receptor Blockers
- Renin Inhibitors
- Arterial (dominant) and Venous Circulation
Fenoldopam
Vasodilator
Dopamine 1 Receptor
Arterial and Venous Circulation
Inc RBF and Na+ Excretion
Tx: Hypertensive Crisis
What vasodilator drug binds dopamine 1 receptor for the treatment of hypertensive crisis?
Fenoldopam
What vasodilator drug increases renal blood flood and Na+ excretion?
Fenoldopam
Prazosin
Vasodilator
Alpha-adrenergic blocker (prevents NE binding)
Arterial and Venous Circulation
What drug is an alpha-adrenergic antagonist resulting in vasodilation?
Prazosin
Albuterol, Pirbuterol, Terbutaline, Salmeterol, Formoterol
B2 agonist
Bronchodilators
inc cAMP activates PKA leading to relaxation
Toxicity: Tachycardia
What B2 agonists can be used for bronchodilation?
Albuterol, Pirbuterol, Terbutaline, Salmeterol, Formoterol
What AE can you get from B2 agonists?
Tachycardia
Ipratropium, Tiotropium
Anti-cholinergic
Bronchodilators
Prevents muscarinic receptors from contracting respiratory muscles
Mucous secretion
What anti-cholinergic drugs can be used as a bronchodilator and to increase mucous secretions?
Ipratropium, Tiotropium
Theophylline, Aminophylline
Methylxanthine
Bronchodilators
- increased mucociliary clearance
Phosphodiesterase Inhibition
Adenosine Receptor Antagonism
What bronchodilator drug can work as a phosphodiesterase inhibitor and/or Adenosine Receptor Antagonist?
Theophylline, Aminophylline
