Endogenous Adenosine, We love you!

To fully understand our evolving ideas on mind and loss of mind and hypercapnia, you must read the following blogposts at the very least…

The Potential two Step Marker for Bipolar Depressive Illness that we are suggesting [to start] and our post on How to Save a Manic Depressive Life.

1] https://ofsoundmind.life/2020/11/09/we-have-a-2-step-marker-for-bipolar-illness/ We have a potential new 2 step biomarker for bipolar illness. Ventilatory issues and [hidden] hyp


2]  https://ofsoundmind.life/2020/11/11/how-to-save-a-manic-depressives-life/

Paula and I have identified a ventilatory injury/defect in the depressive stage of manic depressive insanity. Kraepelin seems to have identified the same injury/defect over 100+ years ago. This is what is guiding us to new research to connect the dots. It is a lot of fun. It is something that scientists can follow up on. And we think this will make a huge difference in the new updated understanding of the reversible syndrome of bipolar illness and its treatment. this is how we have gotten to learn about adenosine and its ability to inhibit respiration rate in the face of hypercapnia……to be continued.

Adenosine Formation and Adenosine Levels

“Adenosine is always present both within and outside cells, since it is at a crossroads between different metabolic pathways. Levels of adenosine in cells and tissue fluids is in the nanomolar range under physiological conditions (estimates range between ten and a few hundred nanomolar), but rise substantially in different forms of cellular distress…… 

Increasing Oxygen Supply and/or Decreasing Oxygen Demand by Adenosine

Vascular reactivity

The ability of adenosine to increase blood flow through tissues has long been known and adenosine has been proposed to be a major mediator of the adaptation of blood flow to metabolic demand.20……..


The level of adenosine and the expression of adenosine receptors are regulated so that the signaling via one or more of the receptors increases in cellular stress and distress. Adenosine via its receptors will tend to limit the consequences of the potentially damaging stimuli. This is achieved in multiple ways. There is a strong link between adenosine and signaling in hypoxia. In different ways adenosine can increase oxygen supply and decrease oxygen demand. This can occur both in the short term and in the long term. Angiogenesis is stimulated by adenosine and adenosine mediates some forms of preconditioning. A particularly intriguing role of adenosine is in the regulation of various aspects of inflammation. The precise roles of the different receptors appear to differ in a time- and tissue-dependent manner. What is beneficial in one tissue at one time may be detrimental at another time or place. For this reason, and because adenosine plays so many roles therapeutic efforts may be frustrated.

Fredholm, B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Nature Cell Death Differ 14, 1315–1323 (2007). https://doi.org/10.1038/sj.cdd.4402132

Inhibition of the hypercapnic ventilatory response [HCVR] by adenosine in the retrotrapezoid nucleus [RTN} in awake rats

Neuropharmacology. 2018 Aug; 138: 47–56 doi: 10.1016/j.neuropharm.2018.05.029 PMCID: PMC6054885 NIHMSID: NIHMS971242 PMID: 29857188 Bárbara Falquetto,1,* Luiz M. Oliveira,2,* Ana C. Takakura,2 Daniel K. Mulkey,3 and Thiago S. Moreira4

In the present study, we identify a role of the ADO receptors in the reduction of breathing under hypercapnia challenge

Summary:   The brain regulates breathing in response to changes in tissue CO2/H+ via a process called central chemoreception. Neurons and astrocytes in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors. The role of astrocytes in this process appears to involve CO2/H+-dependent release of ATP to enhance activity of chemosensitive RTN neurons. Considering that in most brain regions extracellular ATP is rapidly broken down to adenosine by ectonucleotidase activity and since adenosine is a potent neuromodulator, we wondered whether adenosine signaling contributes to RTN chemoreceptor function. To explore this possibility, we pharmacologically manipulated activity of adenosine receptors in the RTN under control conditions and during inhalation of 7–10% CO2 (hypercapnia). In urethane-anesthetized or unrestrained conscious rats, bilateral injections of adenosine into the RTN blunted the hypercapnia ventilatory response. The inhibitory effect of adenosine on breathing was blunted by prior RTN injection of a broad spectrum adenosine receptor blocker (8-PT) or a selective A1-receptor blocker (DPCPX). Although RTN injections of 8PT, DPCPX or the ectonucleotidase inhibitor ARL67156 did not affected baseline breathing in either anesthetized or awake rats. We did find that RTN application of DPCPX or ARL67156 potentiated the respiratory frequency response to CO2, suggesting a portion of ATP released in the RTN during high CO2/H+ is converted to adenosine and serves to limit chemoreceptor function. These results identify adenosine as a novel purinergic regulator of RTN chemoreceptor function during hypercapnia.

Keywords: RTN, purinergic signaling, breathing, adenosine, central chemoreflex


The multiple purinergic mechanisms that determine the dynamics of the HCVR is key in the strategies to better understand the functional role of chemoreceptors neurons in the RTN on chemoreception. In the present study, we identify a role of the Adenosine [ADO] receptors in the reduction of breathing under hypercapnia challenge. Degradation of ATP in the RTN will contribute to the reduction in the HCVR not only by removing the excitatory actions of ATP, but also by producing adenosine, which is inhibitory at the level of RTN.


  • Neurons and astrocytes in the RTN function as respiratory chemoreceptors
  • ATP is rapidly broken down to adenosine by ectonucleotidase activity
  • Blocking A1- or NTPAse attenuate the hypercapnia ventilatory response inhibition
  • Adenosine act as a novel purinergic regulator of RTN chemoreceptor function.


Adenosine synthesis and the control of inflammation “Adenosine accumulates in response to inflammation and ischemia.” 

J Immunol. Author manuscript; available in PMC 2011 Feb 10.Published in final edited form as:J Immunol. 2010 Aug 15; 185(4): 1993–1998. doi: 10.4049/jimmunol.1000108PMCID: PMC3036969NIHMSID: NIHMS264003PMID: 20686167 Much Ado about Adenosine: Adenosine Synthesis and Function in Regulatory T Cell Biology Peter B. Ernst,*†‡James C. Garrison,§ and  Linda F. Thompson

Physiological effects of hyperchloraemia and acidosis

J. M. Handy, N. Soni

BJA: British Journal of Anaesthesia, Volume 101, Issue 2, August 2008, Pages 141–150, https://doi.org/10.1093/bja/aen148     Published: 04 June 2008……Significant snippets to be aware of re: this topic!!!!!!…clinical application of in vitro data is flawed. In nature, acidosis inevitably results in an integrated host response that encompasses far more than the metabolic functions of the cell…….Teleology…

Acidosis is a common occurrence in mammals. Indeed, any burst of exercise results in an acidosis and the ability of mammals to recover from extreme exercise and from pathophysiological acidosis of respiratory and metabolic origin is impressive…… ……Although the disease state may be different, there is little doubt that normal mammalian physiology is designed to deal with acidosis, at least initially. It is worth considering this approach further through the rigorously studied model of exercise physiology……. the combined effects of acidosis concurrent with associated metabolic alterations in the whole organism may be markedly different from those seen in isolated preparations……….Exercise: a physiological model of acidosis

Adenosine and hypercapnia attacks are all connected to control of inflammation and to breathing. and the brain….it is S-o-o-o-o-o cool!!!!!

Common, youbiological scientists….come help us!


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