Hypercapnia or Hipoxia?

[naiad]

By the way, some freedivers don't have contractions and still get into pretty good performances, Stephan Mifsud doing 8:27 (I think) static with no contractions is one example. Makes me wonder if there's a limit to their potential or if there is some other mechanism compensating or if contractions are even necessary.

The best statics and dynamics I have done have been with no contractions, or very few.

 

[wet]

Deep thought,

I appreciate your review. That is an excellent thread you linked, I'll go over it.

I had previously read conflicting data about spleen RBC release, one source said it occurs very soon after starting apnea (I guess 1 minute or less), the other source said it may take 1/2 hour after starting a freediving session before the full benefits of RBC release are felt. That's why I couldn't be sure about the correlation to diaphragm contractions and Hypercapnea.

I've been thinking of the body as a whole system, rather than looking at the individual organs.

I agree that the "pump" idea may be incorrect, or only partly correct, I may have overstated it.

Some people have a heart "defect", a valve which remains open, which closes in most people, do you know whether people with this open valve have more or less contractions than other people, or a gentler "flushing" rather than a discrete pumping ? Same question, regarding heart murmur.

DDeden

 

[DeepThought]

Some people have a heart "defect", a valve which remains open, which closes in most people, do you know whether people with this open valve have more or less contractions than other people, or a gentler "flushing" rather than a discrete pumping ? Same question, regarding heart murmur.

DDeden

I think I see why you're asking but I don't know. The problem is that contractions are so individual that it would be hard to compare between poeple considering rates can go between 2/sec to 1/30 sec.

Would you tend to think that impaired cardiac output would cause them to be over-compensating with contractions or that they would be desensitized to CO2 (and maybe other theorized triggering metabolites) that it would be the other way around?
Of course your theory could be true and still this won't be manifested to a difference between subjects. This could affect apnea performance in so many ways...

I think there was a thread on PFO and maybe a heart murmur here somewhere, if some db members were diagnosed to have those we can try asking and see if there's a common tendency or post a new thread calling for such personal data.

 

[DeepThought]

The best statics and dynamics I have done have been with no contractions, or very few.

Some of my deepest (not really deep, 32-36m) dives had no contractions, which was an exception considering a few meters shallower I did experience contractions those same days. They also felt... better (due to the lack of descriptives). I attributed this to maybe kicking a more pronounced DR due to depth and maybe pulmonary blood shift (though I didn't feel I ran out of air but I theorize you don't need to go below RV for that).
What is your guess?
Did you feel like your state of mind was different when doing those performances? Did you feel hypoxia at the end? was it different than how hypoxia feels usually when you do experience contractions on a max attempt?

 

[wet]

Regarding the aforementioned link, I like the post by Eric F. #89 (How do I link that message here? Permalink? I don't know how...)

The reason I like it, is because he mentioned seals suntanning before diving.

That fits well with the way that I view a natural diving cycle.

At the surface, pnea normoxia rules.
While resting at the surface, (like a backfloating sea otter, or beached elephant seal, or walrus on an iceberg) if the weather is sunny and warm, they absorb solar energy maximally, like sea otters holding out their black flippers at an angle perpendicular to the sun, and vasodilating extremities like a pink walrus in the sun, occasionally yawning (O2 saturation) in a very restful mode.

If weather is cloudy and chilly, seals shiver while at the surface, artificially simulating solar warming by skin muscles moving frictionally the skin, this again warms the blood vessels just under the skin surface, "wasting" oxygen in a completely normal aerobic terrestrial way. Completely anti-apnea, since breath holding above surface provides no benefit to a mammalian diver, and interferes with digestion and delays other important biological processes of the internal organs.

If a walrus is in open water without a perch, it will inflate it's pharyngeal air sac (throat balloon) and just float immobilized at rest, breathing through it's nose aerobically while digesting it's food and probably engaged in some sort of REM-type semi-sleep. Well rested and relaxed before diving again.

DDeden

 

[wet]

I think I see why you're asking but I don't know. The problem is that contractions are so individual that it would be hard to compare between poeple considering rates can go between 2/sec to 1/30 sec.

Would you tend to think that impaired cardiac output would cause them to be over-compensating with contractions or that they would be desensitized to CO2 (and maybe other theorized triggering metabolites) that it would be the other way around?
Of course your theory could be true and still this won't be manifested to a difference between subjects. This could affect apnea performance in so many ways...

I think there was a thread on PFO and maybe a heart murmur here somewhere, if some db members were diagnosed to have those we can try asking and see if there's a common tendency or post a new thread calling for such personal data.

Yes, PFO is what I meant. I just looked at threads with PFO, didn't find any correlation to diaphragm contraction variability. I expect if it did, it would be well known. Therefore, I can see no direct link between the two, not sure though.

I'm now assuming that the cause of diaphragm contractions is due to pH drop at chemoreceptor sites, that pre-dive hyperventilation (of any form) produces alkalosis at those chemoreceptor sites, that O2 level in blood and tissue has no or very little effect on triggering diaphragm contractions (but may affect the intensity or rhythm of them in some unknown way).

Does "pulmonary blood shift" or "shunt" directly correlate to onset of diaphragm contractions, or to spleen rbc release, or to water depth-pressure, or to time after starting breath hold, or to body temperature or to DR initiation? Exactly what triggers the blood shift?

It seems to me that peripheral vasoconstriction is exactly equal to pulmonary blood shift, is there any difference between them?

Speculation:
Hypercapneic acidosis at chemoreceptors causes the blood shift, and only then secondarily diaphragm contractions will occur, only when the blood has begun (and perhaps finished) moving from the extremities and spleen to the core, will the secondary stage, noticeable diaphragm contractions, begin.

I'll continue to view the thread, the answers may be there.
DDeden

 

[wet]

Interesting, I wonder if marine mammals have contractions during normal dives? I think probably not, but maybe their swimming action has the same effect.

Thanks for finding a scientific paper.

Here's another, swimming/size/breathing (but not contractions)

Proc.R.Soc.B: Biol.Sciences 274:471-7

Stroke frequency, but not swimming speed, is related to body size in
free-ranging seabirds, pinnipeds and cetaceans

K. Sato et al.2207

It is obvious, at least qualitatively, that small animals move their
locomotory apparatus faster than large animals: small insects move their
wings invisibly fast, while large birds flap their wings slowly.

[DDeden: Note that winged insects are believed to have developed their wings originally from single cell stalks, fluttered to increase airflow to their spiracles (adult insects have no lungs or gills) during a period of low atmospheric O2 & high atm. CO2. Flight was a later adaptation. The significance of this is that insect flight is very different from both bird flight and bat flight metabolically, and also different from marine animal locomotive metabolism.]

However, quantitative observations have been difficult to obtain from free-ranging swimming animals. We surveyed the swimming behaviour of animals ranging from 0.5kg seabirds to 30000kg sperm whales using animal-borne accelerometers.

Dominant stroke cycle frequencies of swimming specialist seabirds and marine mammals were proportional to mass−0.29 (R2=0.99, n=17 groups), while propulsive swimming speeds of 1–2ms−1 were independent of body size. This scaling relationship, obtained from breath-hold divers expected to swim optimally to conserve oxygen, does not agree with recent theoretical predictions for optimal swimming.

Seabirds that use their wings for both swimming and flying stroked at a lower frequency than other swimming specialists of the same size, suggesting a morphological trade-off with wing size and stroke frequency representing a compromise. In contrast, foot-propelled diving birds such as shags had similar stroke frequencies as other swimming specialists. These results suggest that muscle characteristics may constrain swimming during cruising travel, with convergence among diving specialists in the proportions and contraction rates of propulsive muscles.
===
I wish they had more data on O2-CO2 of blood.

DDeden

 

[trux]

It seems to me that peripheral vasoconstriction is exactly equal to pulmonary blood shift, is there any difference between them?

I wouldn't tell they are equal, but they are definitely bound together. Vasoconstriction is activated by chemicals called vasoconstrictors that usually have opposite effects on specific groups of blood vessels containing different chemo-receptors (i.e. vasopressin receptors or adrenoreceptors). So it is not surprising that blood shift and vasoconstriction are firmly bind together (not speaking about the simple mechanical fact that the blood pressed away from the constricted areas is shifting to those that were dilatated).

Speculation:
Hypercapneic acidosis at chemoreceptors causes the blood shift, and only then secondarily diaphragm contractions will occur, only when the blood has begun (and perhaps finished) moving from the extremities and spleen to the core, will the secondary stage, noticeable diaphragm contractions, begin.

I do not think that hypercapnic acidosis chemoreceptors alone control the blood-shift or contractions. I think it is more complicated than that, and that the release of vasoconstrictors is triggered by the parasympathetic nervous system (or maybe there is even a combination of parasympathetic and sympatethic actions) and that the signal comes from the brain. I think the trigger signal is based on more than just the hypercapnic acidosis.

Although it is interesting, I'd prefer reading some facts than just speculations. It is of course possible, though from personal experience I'd tell that vasoconstriction+blood shift and contractions are definitely not coming together. Very often I get quite strong contractions and do not feel the diving reflex kicking in at all, and oppositely often when I feel strong diving reflex, the contractions are quite soft. However that's just another speculation based on very subjective feelings - I'd prefer reading results of real tests, measurments, and laboratory analyses. I bet that researches in this direction were already done, and I am pretty sure that physiologists measured the level of different vasoconstrictors in blood. And since they know where each vasoconstrictor has their respective receptors, they are certainly able to explain the process of diving reflex vasoconstriction and blood-shift, and possibly able to explain the relation to contractions quite well. Maybe it would not be bad trying to ask some of the real experts (like for example Dr. Lindberg) to post more details about their research on this forum. Or maybe registering on the forum of the World Free Diving Medical Association (WFDMA) and asking some question there may be better than blindly speculate without having access to any hard facts.

Personally I'd expect that vasopressin plays important role in the diving reflex - it not only controls vasoconstriction and vasodilatation, but it has also big influence on the blood viscosity. It is well known that the effect of vasopressin is very negatively influenced by caffeine. So besides the stimulating effects of caffeine, also its interaction with vasopressin is a very good reason to avoid coffee when freediving.

 

[wet]

Trux, would you please insert the word "Speculation" in front of the phrase which you quoted? Else it might be misconstrued as factual. Thanks.
DDeden

 

[trux]

Trux, would you please insert the word "Speculation" in front of the phrase which you quoted? Else it might be misconstrued as factual. Thanks.
DDeden

Yes, sure, done. Sorry about omitting it originally.

 

[DeepThought]

Yes, PFO is what I meant. I just looked at threads with PFO, didn't find any correlation to diaphragm contraction variability. I expect if it did, it would be well known. Therefore, I can see no direct link between the two, not sure though.

Actually, I'd expect this to remain unknown without a serious statistical analysis and even then. As far as I know no one ever collected data about contractions from hundreds of divers while correlating it with such medical conditions relating to cardiac output (that some poeple might be unaware of having). Even then I'd expect this to not show a clear picture as too many things affect contraction rate and onset.

As for blood shunt and pulmonary blood shift I think, like Trux that there just are too many triggers and it's not just a chemoreceptor issue. Some of those triggers overlap and some don't so they are only partially bound. In theory preipheral vasocontriction can happen the second you put a limb in the water due to temprature, I don't know how much this could affect the lungs though. On the other hand I think there are a few other physical and physiological factors that lead to pulmonary blood shift, some are bounded to blood shunt and some are less. I described some of these factors in relation to lung squeeze here: http://forums.deeperblue.net/safety...-now-5.html?highlight=lung+squeeze#post565071
(oh yes, I use permalink. )

As for pulmonary blood shift and contractions, I think they are not bound as this could lead to lung squeeze, and as far as I know contractions are somewhat supressed at the deeper parts of the dive (this could also be due to high ppO2 which was shown to supress contractions).

 

[wet]

Trux, I was thinking of this statement by Will in this thread:

http://forums.deeperblue.net/genera...heory-3.html?highlight=hibernation#post271571

"Firstly, I submit that the collection of functions compiling MDR are all consequences of one of those functions, namely vasoconstriction. Vasoconstriction will 'shunt' blood to internal organs, increasing internal blood pressure in doing so. This and the concommitent decrease in demand for O2 (caused by the vasoconstriction) causes the bradycardia, which progresses in a compound fashion (the more the heart slows, the less O2 it needs, so the more it can slow). Bradycardia must in turn stimulate the vagus nerve to dilate the carotid artery, maintaining a constant cerebral bloodflow. These are the main known symptoms of the MDR".

Conjecture: On a typical non-hyperventilated, rested breath hold, hypercapnea is the driver of both peripheral vasoconstriction (augmented by peripheral cooling), and blood shift to the core, with resulting richer O2 availability at the core and consequently increased blood pressure and reduced HR (bradycardia), followed by diaphragm contractions at an increasing temporal rate, HR will eventually increase as available core O2 is used, BP will increase. A resemblance of diving apnea to hibernation and sleep apnea is due to the reduced production rate of CO2 of the body, rather than the prevalence of oxygen. Hibernation and sleep apnea are dictated by biologic sensory-adjusted rhythmic cycles, so diving apnea in marine animals is also likely dictated thus.
DDeden

 

[trux]

I think that everyone agrees that carbon dioxide plays important or rather primary role in diving reflex, but reducing it just to that is definitely over-simplification. There are more factors playing a role - as shown in the laboratory experiment I already linked before, and which was written by a scientist who reproduced the experiments with thousands of students during 15 years, bradycardia is very well reproducible with very basic simple conditions: face exposed to cold/wet and apnea. And it works even if only one of the factors is present. Also artificially induced hypercapnia (without apnea) leads to bradycardia.


In the document, there is the following diagram displaying the mechanism of diving reflex in simplified form:

image credit © Physiology.org​

(click for a bigger version)​

Surprisingly it tells that PAO2 chemoreceptors are actually significantly more important for starting the diving reflex than pH and PACO2 receptors. That's in direct contrast to the breathing urge feeling and contractions that are more relying on pH and PACO2 chemoreceptors. Frankly told, it surprised me - from other documents I read I was under the opposite impression.

However, as shown not only in these experiments, but also in other researches (i.e. thesis of Dr. Lindberg, or researches on Ama divers), there are huge differences of the strength of the diving response not only depending on the basic conditions, but there are many other factors that play important role, and there are huge differences between individuals.

Apparently the diving reflex is strongly influenced also by stress (moderate stress helps, but extreme stress is counterproductive), and many other physiological, physical, and psychical conditions, but it was proved that the strength and extent of the diving reflex may be learned by experience and training (it is stronger at professional freedivers like Amas or at top competitors).

So you are certainly right that CO2 is a very important clue here, but telling that all the diving reflex, bradicardia, blood shift, vasoconstrictions, and also contractions are nothing else than hypercapnic reaction is on my mind little bit exaggerated. I do not think though that you meant it literally when you wrote it, and I am sure that you are well aware of the complexity.

 

[wet]

Actually, I'd expect this to remain unknown without a serious statistical analysis and even then. As far as I know no one ever collected data about contractions from hundreds of divers while correlating it with such medical conditions relating to cardiac output (that some poeple might be unaware of having). Even then I'd expect this to not show a clear picture as too many things affect contraction rate and onset.

As for blood shunt and pulmonary blood shift I think, like Trux that there just are too many triggers and it's not just a chemoreceptor issue. Some of those triggers overlap and some don't so they are only partially bound. In theory preipheral vasocontriction can happen the second you put a limb in the water due to temprature, I don't know how much this could affect the lungs though.

Deep thought, what theory is this? AFAIK, in (most?) mammals, cold temperature alone doesn't cause generalized peripheral vasoconstriction, and I don't think it causes localized peripheral vasoconstriction, excluding apnea. I'm thinking here of frostbitten limbs, the flesh freezes and dies but the blood vessels still have blood, semi-crystalized and viscous in the capillaries, oxygen unable to flow to the tissue cells, so they die. True there is constriction, but quite different than reversible apneic vasoconstriction. Perhaps I'm mistaken about this?

IOW, in cold water at the same depth (no HV, no wet suits or masks):

Apnea diving (passive exhale) is warmer at the core and colder at the skin surface (with blood shift and contractions which exacerbate heat flow inwards),

Snorkeling (breathing normoxia) is colder at the core and warmer at the skin surface (with shivering which exacerbates the heat flow outwards).

If this is incorrect, I'd appreciate correction.

Importantly, humans can't distinguish by touch alone the difference between cold air, cold metal and cold water simply by skin contact; and although they each conduct heat at different rates, if they are all maintained at the same ambient (blood) temperature, there is no difference in heat conduction.
In another words, if you are in water which is the same temperature as your blood, you can't lose body heat, even though water conducts heat faster than air.

On the other hand I think there are a few other physical and physiological factors that lead to pulmonary blood shift, some are bounded to blood shunt and some are less. I described some of these factors in relation to lung squeeze here: http://forums.deeperblue.net/safety...-now-5.html?highlight=lung+squeeze#post565071
(oh yes, I use permalink. )

As for pulmonary blood shift and contractions, I think they are not bound as this could lead to lung squeeze, and as far as I know contractions are somewhat supressed at the deeper parts of the dive (this could also be due to high ppO2 which was shown to supress contractions).

Does lung squeeze typically occur near surface like SWBO after a deep dive, or while at depth? Can it happen during statics or dynamics near the surface? I'm thinking it is only due to large pressure differential affecting gas pockets in the body, but I don't know.

DDeden

 

[wet]

Trux, the PaO2 chemoreceptors you referred to, to verify, these are not baroreceptors in the carotid sinus? (Don't get upset with my question, I want to be certain.) Thanks for displaying the diagram!

The presence of O2 sensitivity does not disqualify the Hypercapnea as the system driver IMO. In an automobile, a starter starts the engine, but it requires a battery to initiate the starting mechanism. The hypercapnea pumping may require a certain concentration of oxygen ions to function (some sort of electromagnetic polarity). If true, then a diver with insufficient O2 will blackout even though the hypercapnea pumping is functional.

I have to leave, more tomorrow. DDeden

I think that everyone agrees that carbon dioxide plays important or rather primary role in diving reflex, but reducing it just to that is definitely over-simplification. There are more factors playing a role - as shown in the laboratory experiment I already linked before, and which was written by a scientist who reproduced the experiments with thousands of students during 15 years, bradycardia is very well reproducible with very basic simple conditions: face exposed to cold/wet and apnea. And it works even if only one of the factors is present. Also artificially induced hypercapnia (without apnea) leads to bradycardia.


In the document, there is the following diagram displaying the mechanism of diving reflex in simplified form:

image credit © Physiology.org​

(click for a bigger version)​

Surprisingly it tells that PAO2 chemoreceptors are actually significantly more important for starting the diving reflex than pH and PACO2 receptors. That's in direct contrast to the breathing urge feeling and contractions that are more relying on pH and PACO2 chemoreceptors. Frankly told, it surprised me - from other documents I read I was under the opposite impression.

However, as shown not only in these experiments, but also in other researches (i.e. thesis of Dr. Lindberg, or researches on Ama divers), there are huge differences of the strength of the diving response not only depending on the basic conditions, but there are many other factors that play important role, and there are huge differences between individuals.

Apparently the diving reflex is strongly influenced also by stress (moderate stress helps, but extreme stress is counterproductive), and many other physiological, physical, and psychical conditions, but it was proved that the strength and extent of the diving reflex may be learned by experience and training (it is stronger at professional freedivers like Amas or at top competitors).

So you are certainly right that CO2 is a very important clue here, but telling that all the diving reflex, bradicardia, blood shift, vasoconstrictions, and also contractions are nothing else than hypercapnic reaction is on my mind little bit exaggerated. I do not think though that you meant it literally when you wrote it, and I am sure that you are well aware of the complexity.

 

[trux]

Deep thought, what theory is this? AFAIK, in (most?) mammals, cold temperature alone doesn't cause generalized peripheral vasoconstriction, and I don't think it causes localized peripheral vasoconstriction, excluding apnea. I'm thinking here of frostbitten limbs, the flesh freezes and dies but the blood vessels still have blood, semi-crystalized and viscous in the capillaries, oxygen unable to flow to the tissue cells, so they die. True there is constriction, but quite different than reversible apneic vasoconstriction. Perhaps I'm mistaken about this?

Vasoconstriction and vasodilatation in skin and in underlaying layers is used to thermoregulation too, but you are right that this is a different mechanism. What Deep Thought meant was actually diving reflex triggered by submerging the face into cold water (or cooling it with ice) - as it is well documented in the experiments I quoted in my previous post and shown on the diagram above, it can initiate certain degree of bradycardia and diving reflex too, and indeed practically immediately. It does not work though so well with cooling limbs.

Does lung squeeze typically occur near surface like SWBO after a deep dive, or while at depth? Can it happen during statics or dynamics near the surface? I'm thinking it is only due to large pressure differential affecting gas pockets in the body, but I don't know.

In the quoted thread about lung squeeze, it was speculated that part of lung squeeze injuries happen actually due to barotrauma on surfacing due to reduced lung volume after the dive because of delayed reverse blood shift.

 

[trux]

Trux, the PaO2 chemoreceptors you referred to, to verify, these are not baroreceptors in the carotid sinus?

I quote from the document:

FIG. 4 Principal components of the diving response. Solid arrows indicate stimulation, dashed arrows inhibition. CNS, central nervous system.Inputs primarily from trigeminal receptors on the upper part of the face are integrated by the respiratory and cardiovascular centers in the medulla oblongata (in the brainstem), generating neural signals to the lung, heart, and arterioles that include both sympathetic and parasympathetic divisions of the autonomic nervous system. During longer dives, chemoreceptive inputs from aortic and carotid bodies help maintain these effects. Bradycardia reduces cardiac output and therefore should reduce blood pressure, but in humans this effect is more than compensated for by the increase in blood pressure brought about by peripheral vasoconstriction, with the ultimate result that blood pressure increases during a dive in humans. Although arterial chemoreceptors may respond to pH and P[SIZE=-2]CO[/SIZE]2 as well as to P[SIZE=-2]O[/SIZE]2, during diving P[SIZE=-2]O[/SIZE]2 seems to be the more important in regulating cardiovascular center outputs (14). Based on figures from Gooden (14) and Hochachka and Somero (16).

As you certainly know PAO2 means partial pressure of oxygen, hence both pressure and percentage are important.

The presence of O2 sensitivity does not disqualify the Hypercapnea as the system driver IMO. In an automobile, ....

That's not the question. It is clear that during apnea there are usually both hypercapnia and hypoxia, but it is not always so during the experiments, so you can indeed distinguish between the two. In medicine you can relatively easily separate effects of hypoxia or hypocapnia on PAO2, pH and PACO2 chemoreceptors, because you can induce hypoxia without hypercapnia, and hypercapnia without hypoxia (i.e. by breathing enriched gas mixtures), and as well you can change blood pH for the test independently on hypercapnia. So it should be pretty easy to confirm or deny which chemoreceptors are really responsible for the reactions.

 

[trux]

What Deep Thought meant was actually diving reflex triggered by submerging the face into cold water (or cooling it with ice) - as it is well documented in the experiments I quoted in my previous post and shown on the diagram above, it can initiate certain degree of bradycardia and diving reflex too, and indeed practically immediately.

In fact this brings me to the question what would AIDA judges tell if I came to the statique competition with a bag of ice and put it under my face during the attempt? Or if I filled my mask with cold water?

 

[wet]

In fact this brings me to the question what would AIDA judges tell if I came to the statique competition with a bag of ice and put it under my face during the attempt? Or if I filled my mask with cold water?

Trux, I think it sounds uncomfortable, like an ice cream headache!

While I looked at that document you linked, I didn't find the words "Carbon Dioxide" mentioned anywhere (perhaps I missed it?, I'll review again).

I did find CO2 mentioned only here:

"Although arterial chemoreceptors may respond to pH and PCO2 as well as to PO2, during diving PO2 seems to be the more important in regulating cardiovascular center outputs (14)".

Since the subject of the document is respiration (pnea & apnea in simulated diving), and since CO2 is a major part of respiration, I would have expected CO2 to be prominent in a document about human respiration.

Do you think they forgot about it?

Rather significant omission IMO, considering that without CO2, we can't breathe.
Having read the document further, I'm even more wary of "simulated" diving data.

DDeden

 

[trux]

Yes, the do mention CO2 in that part. Their claim PAO2 chemorecptors are playing more important role than pH and PACO2 chemoreceptors (as I already wrote) rather surpirsed me. That should be very easily verifiable, so I wonder that they would claim something like that if it was not true. On the other hand, I know very well, that hypercapnia alone (with no hypoxia associated to it) leads to bradycardia too, so I have rather serious doubts about their claim.

EDIT:

Having read the document further, I'm even more wary of "simulated" diving data.

There is nothing wrong with the data, and nothing wrong with the experiments. The purpose of the experiments was not showing the influence of CO2, but the influence of facial thermo sensors and apnea. In this document they simply did not go into the depths to analyze hypoxia and hypercapnia in apnea separately, which itself would not be too bad. The only surprising is the menitoned claim about the PAO2 receptors, but since I do not now what led the to the conclusion, I cannot comment.