A1 receptors are implicated in sleep promotion by inhibiting wake-promotingcholinergic neurons in thebasal forebrain.[6] A1 receptors are also present in smooth muscle throughout the vascular system.[7]
The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.[citation needed]
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. At the neuron'ssynapse, it reducessynaptic vesicle release.[citation needed]
In the heart, A1 receptors play roles in electrical pacing (chronotropy anddromotropy), fluid balance, local sympathetic regulation, and metabolism.[9]
Collectively, these mechanisms lead to an myocardial depressant effect by decreasing the conduction of electrical impulses and suppressingpacemaker cells function, resulting in a decrease inheart rate. This makes adenosine a useful medication for treating and diagnosingtachyarrhythmias, 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 rapidIV push duringcardiac resuscitation.[citation needed] The rapid infusion causes a momentary myocardial stunning effect.
In normal physiological states, this serves as protective mechanisms. However, in altered cardiac function, such ashypoperfusion caused byhypotension,heart attack orcardiac arrest caused by nonperfusingbradycardias, 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.[citation needed]
Metabolically, A1AR activation by endogenous adenosine across the body reduces plasmaglucose,lactate, andinsulin levels, howeverA2aR activation increased glucose and lactate levels to an extent greater than the A1AR effect on glucose and lactate.[21] Thus, intravascular administration of adenosine increases the amount of glucose and lactate available in the blood for cardiac myocytes. A1AR activation also partially inhibitsglycolysis, slowing its rate to align with oxidative metabolism, which limits post-ischemic damage through reduced H+ generation.[22]
In the state of myocardial hypertrophy and remodeling, interstitial adenosine and the expression of the A1AR receptor are both increased. After transition to heart failure however, overexpression of A1AR is no longer present.[23] Excess A1AR expression can induce cardiomyopathy, cardiac dilatation, and cardiac hypertrophy.[24] Cardiac failure may involve increased A1AR expression and decreased adenosine in physical models of cardiac overload and in dysfunction induced by TNFα.[25] Heart failure often involves secretion of atrial natriuretic peptide to compensate for reduced renal perfusion and thus, secretion of electrolytes. A1AR activation also increases secretion of atrial natriuretic peptide from atrial myocytes.[26][27]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Townsend-Nicholson A, Baker E, Schofield PR,Sutherland GR (March 1995). "Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1".Genomics.26 (2):423–425.doi:10.1016/0888-7543(95)80236-F.PMID7601478.
^Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (March 2005). "Role of A1 adenosine receptors in regulation of vascular tone".American Journal of Physiology. Heart and Circulatory Physiology.288 (3):H1411 –H1416.doi:10.1152/ajpheart.00684.2004.PMID15539423.S2CID916788.
^abcdeHeadrick JP, Peart JN, Reichelt ME, Haseler LJ (May 2011). "Adenosine and its receptors in the heart: regulation, retaliation and adaptation".Biochimica et Biophysica Acta (BBA) - Biomembranes.1808 (5):1413–1428.doi:10.1016/j.bbamem.2010.11.016.hdl:10072/35871.PMID21094127.
^Romagnoli R, Baraldi PG, IJzerman AP, Massink A, Cruz-Lopez O, Lopez-Cara LC, et al. (September 2014). "Synthesis and biological evaluation of novel allosteric enhancers of the A1 adenosine receptor based on 2-amino-3-(4'-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene".Journal of Medicinal Chemistry.57 (18):7673–7686.doi:10.1021/jm5008853.hdl:10481/87954.PMID25181013.
^Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, et al. (March 2002). "BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy".Circulation.105 (11):1348–1353.doi:10.1161/hc1102.105264.PMID11901047.S2CID14866962.
^Greenberg B, Thomas I, Banish D, Goldman S, Havranek E, Massie BM, et al. (August 2007). "Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study".Journal of the American College of Cardiology.50 (7):600–606.doi:10.1016/j.jacc.2007.03.059.PMID17692744.S2CID37858957.
^Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC (October 2007). "The effects of KW-3902, an adenosine A1-receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance".Journal of the American College of Cardiology.50 (16):1551–1560.doi:10.1016/j.jacc.2007.07.019.PMID17936154.
^Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, et al. (October 2008). "The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment".Journal of Cardiac Failure.14 (8):631–640.doi:10.1016/j.cardfail.2008.08.010.PMID18926433.
^Lorbar M, Chung ES, Nabi A, Skalova K, Fenton RA, Dobson JG, et al. (November 2004). "Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals".Canadian Journal of Physiology and Pharmacology.82 (11):1026–1031.doi:10.1139/y04-108.PMID15644943.
^Lakatta EG (June 2004). "Beyond Bowditch: the convergence of cardiac chronotropy and inotropy".Cell Calcium.35 (6):629–642.doi:10.1016/j.ceca.2004.01.017.PMID15110153.
"Adenosine Receptors: A1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2020-09-20. Retrieved2007-10-25.
