Adenosine A1 receptor
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A1 receptors are implicated in sleep promotion by inhibiting wake promoting cholinergic neurons in the basal forebrain. A1 receptors are also present in smooth muscle throughout the vascular system.
The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.
Activation of the adenosine A1 receptor by an agonist causes binding of Gi1/2/3 or Go protein. Binding of Gi1/2/3 causes an inhibition of adenylate cyclase and therefore a decrease in the cAMP concentration. An increase of the inositol triphosphate/diacylglycerol concentration is caused by an activation of phospholipase C while the elevated levels of arachidonic acid are mediated by phospholipase 2A Several types of potassium channels are activated but N-, P- and Q-type calcium channels are inhibited.
This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor.
Antagonism and agonismEdit
Caffeine, along with theophylline have been found to antagonize both A1 and A2a receptors in the brain. Specific antagonists include 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), and Cyclopentyltheophylline (CPT) or 8-cyclopentyl-1,3-dipropylxanthine (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine (CCPA).
The A1, together with A2a receptors, of endogenous adenosine are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates. This effect on the A1 receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect.
In normal physiological states, this serves as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.
In neonatal medicineEdit
Adenosine antagonists are widely used in neonatal medicine;
Because a reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly and loss of white matter and therefore raise the possibility that pharmacological blockade of A1 may have clinical utility.
Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.
However, we are unaware of clinical studies that have examined the incidence of periventricular leukomalacia (PVL) as related to neonatal caffeine use. Caffeine may reduce cerebral blood flow in premature infants, possibly by blocking vascular A2 ARs. Thus, it may prove more advantageous to use selective A1 antagonists to help reduce adenosine-induced brain injury.
- ↑ Townsend-Nicholson A, Baker E, Schofield PR, Sutherland GR (1995). Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1. Genomics 26 (2): 423–5.
- ↑ Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A (2007). Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study. J. Neurosci. 27 (9): 2410–5.
- ↑ Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (2005). Role of A1 adenosine receptors in regulation of vascular tone. Am. J. Physiol. Heart Circ. Physiol. 288 (3): H1411–6.
- ↑ Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001). International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53 (4): 527–52.
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