Adenosine Triphosphate

Action:

1. Adenosine is thought to act predominantly via P1 receptors, which are subdivided into
   1. A1 - activation of phospholipase C and modulation of ion channles
   2. A2A - activation of adenylate cyclase
   3. A2B -  activation of phospholipase C, adenylate cyclase and modulation of ion channles
   4. A3 - activation of phospholipase C and modulation of ion channles
2. ATP binds to P2 receptors, which are subclassified into
   1. P2Y - G protein coupled receptors.
   2. P2X - intrinsic ion channel receptors.

Intravenous administration of ATP is followed by rapid uptake by erythrocytes

• Normal plasma ATP concentrations - 2-4 mmol/L
• Normal plasma adenosine concentrations - 0.1-1 mmol/L
• Normal erythrocyte ATP concentrations - 1500-1900 mmol/L
• Normal cellular ATP concentations - 3000-4000 mmol/L

Metabolism is rapid by ecto-nucleotidases on the endothelium.

• ATP is metabolised by ecto-ATPase to ADP
• ADP is metabolised by ecto-ADPase to AMP
• AMP is metabolised by ecto-5' nucleotidase to the active metabolite Adenosine

Clnical applications:

Anaesthesia

• 50-80 mg/kg/min of adenosine Reduces volitile requirements and improves post operative pain
• 50 mg/kg/min of adenosine for 45-60 minutes can alleviate neuropathic pain, hyperalgesia and allodynia for a reasonable period of time
  • The antinociceptive effects are mediated through A1 and A2 receptors localised in the substantia gelatinosa of the spinal cord
• 40-50 mmol/kg of ATP-MgCl2 has been shown to improve survival in shocked patients
  • During ischaemia a rapid and masive depletion of ATP occurs.  This causes an increase in local concentrations of adenosine, inosine and hypoxanthine.  The inhibitory effects of adenosine are:
    • Inhibition of neutrophil superoxide production, neutrophil degranulation and antioxidant activation
    • Inhibition of tumour necrosis factor, interleukin 6, interleukin 8, eicosanoids and complement
    • Inhibition of adhesion molecule expression.
  • ATP induced metabolic effects are:
    • Improved mitochondrial function
    • Improved electrolyte transport
    • Increased intracellular ATP
    • Reduced oxygen consumption
    • Improved P2 receptor binding
    • Normalisation of impaired second messengers cAMP and IP3

The vascular effects are very complex and depend on the relative stimulation of the various receptors

• P1 receptors are located on endothelial cells and mediate a vasodilatation response
• P2Y receptors are located on endothelial cells and mediate a vasodilatation response
• P2X receptors are located on vascular smooth muscle cells and mediate vasoconstriction

• 50-350 mg/kg/min of ATP or adenosine significantly reduce blood pressure (30-40%) by decreasing systemic vascular resitance, with only a small increase in heart rate. Tachyphylaxis and rebound hypertension were not observed
• 150-300 mg/kg/min of ATP and adenosine have been used to control blood pressure during phaeochromocytoma surgery
• 30-50 mg/kg/min adenosine causes coronary vasodilatation without affecting the systemic circulation.  This has been used to decrease the incidence of early coronary artery bypass graft occlusion.

Cardiology

• 100 mg/kg/min causes a predominant decrease in pulmonary arterial pressure.
  • When given intravenously at low doses ATP and adenosine are rapidly metabolised during their passage through the lung.  ATP binds to the P2Y receptor on the pulmonary endothelial cells, activating the nitric oxide system.
• 5 to 20mg ATP (or 6-12mg adenosine) causes normalisation of heart rate during episodes of supraventricular tachycardia.  It can also be used as a diagnostic aid in wide QRS complex tachycardias
  • ATP stimulates the release of potassium which induces an electric current and results in depression of the SA node and slowing of the AV node.  This electrophysiological effect is mediated by A1 receptors
• Infusions up to 140 mg/kg/min are used in combination with an imaging technique for the detection of coronary artery disease

Pulmonology

• Aerosolised ATP at 100 mmol/L improves chloride secretion, evokes ciliary beating and improves mucous secretion by goblet cells in cystic fibrosis.
• UTP at 100 mmol/L is a better choice as adenosine is a brochoconstrictor.
  • The effects on chloride transport are mediated via P2Y2 receptors, which activates inositol phospholipid hyrolysis and calcium metabolism.

Adverse Effects

• General discomfort
• Breathing deeper and more frequently
• headache
• Fluching
• Chest pressure or pain which is angina like, but electrocardiogram signs of myocardial ishcamia are not present.
  • Methylxanthines greatly reduce the pain
  • Dipyridamole just increase the intensity of the pain.
• Nausea
• Sinus bradycardia and atrial fibrillation