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Adenosine, receptors, effects and use

Adenosine exerts its effects via P1 purinergic receptors which are called A1, A2 (A2A, A2B) and A3.

The activation of the A1 receptors inhibits adenylcyclase, decreases the concentration of intracellular cAMP and induces opening of potassium channels, which indirectly reduces calcium penetration into the cell.

The stimulation of the A2 receptors has an opposite effect, it activates adenylcyclase.

The effects of A3 receptor stimulation are not well characterised; it is known however that their stimulation induces mast cell degranulation and release of various pro-inflammatory transmitters. Inosine may be the principal agonist of A3 receptors.

The effects of adenosine resulting from stimulation of A1, A2 and A3 receptors which have often opposing effects are extremely complex.

1. Cardiovascular effects
   • Heart:
     Adenosine slows sinus rythm and especially atrioventricular conduction; it has a bradycardic effect (A1 effect) and can be used to treat supraventricular tachycardia. It acts by inducing opening of potassium channels which, by allowing the outflow of potassium increases cellular polarization. This action is similar to that of acetylcholine. It could reduce the importance of the cardiac damage observed during post-ischemic reperfusion.
   • Vessels:
     By stimulation of A2 receptors, adenosine dilates systemic and coronary vessels as well as glomerular efferent arterioles. Its vasodilator action is partially dependant on the presence of the endothelium. By stimulation of the A1 receptors, it elicits a vasoconstriction of afferent glomerular arterioles.
     It stimulates (A2 effect) and inhibits (A1) renin secretion.
     It inhibits platelet aggregation (A2).
     It has an algesic effect :injected by intra-arterial route, in particular intracoronary, it induces pain. Released during an attack of angina pectoris, it alerts the patient to stop physical activity.
2. Bronchial effect: adenosine administered in an aerosol elicits a bronchoconstriction (A1 effect) in asthmatic patients, but not in healthy people. It is possible that it is involved in the pathophysiology of asthma.
3. Effect on the central nervous system: adenosine has complex effects. It has sedating and anticonvulsive effects (A1), it reduces (A1) or increases (A2) release neurotransmitters such as norepinephrine and glutamic acid.
   Agonists of adenosine receptors which penetrate into the brain have anticonvulsive effects; certain antagonists could facilitate memorization.
   At the level of the spinal cord, adenosine could have an analgesic effect and morphine induces its release. This effect contrasts with its algesic action in coronary vessels.

	A1 effect	A2 effect
Heart	Slowing of the rythm Negative inotropic effect
Vessels	Vasoconstriction	Vasodilation
Bronchi	Bronchoconstriction	Bronchodilation
Central nervous system	Sedation Anticonvulsive effect Decrease of neurotransmitter release	Complex stimulant effects Increase of neurotransmitter release
Thrombocytes		Platelet aggregation inhibition
Mast cells		Degranulation
Intestinal secretions		Inhibition

Principal A1 and A2 effects of adenosine

4. Other effects: Adenosine modulates a certain number of immune reactions and exerts antiinflammatory effects by stimulation of A2 receptors, those of neutrophils in particular.
   It takes part in the regulation of the production of erythropoietin in a complex way: it might inhibit it by A1effect and might stimulate it by A2 effect.

Therapeutic use

Adenosine itself is used as an antiarrhythmic in the treatment of paroxysmal supraventricular tachycardia. It is administered by intravenous bolus under electrocardiographic control in a specialized unit. The most frequent adverse effects of this treatment are severe bradycardia, dyspnea, bronchospasm. It is used as an adjunct to thallium-201 for myocardial imaging in patients unable to exercise adequately.

Adenosine monophosphate has been proposed as a veinotonic, but its mechanism of action is not well elucidated.

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