Cardiac output and tissue perfusion are determined by viscosity (flow resistance), which is determined by the capillary gate mechanism. There are two types of capillary flow resistance:

1. static flow resistance due to accelerated capillary senescence secondary to smoking, toxic chemicals, chronic emotional stress, and so forth.

2. dynamic flow resistance that is determined by the operation of the capillary gate mechanism. Carbon dioxide is the primary regulator of the capillary gate. All cells produce CO2 as an end product of the Krebs cycle. Increased Krebs cycle activity induced by exercise increases CO2 generation, which opens the capillary gate, increases tissue perfusion, and removes the carbon dioxide. Inhaling Carbogen (a mixture of oxygen and carbon dioxide) can also open the capillary gate. Autonomic balance also regulates the capillary gate. Stress generally increases sympathetic tone and activity, and closes the capillary gate. Relief of stress allows parasympathetic activity to open the capillary gate. All this is explained in my paper describing the mammalian stress mechanism (aka "stress repair mechanism")

Please have a look at our paper: Intensive Care Med. 2009 Nov;35(11):1893-9. doi: 10.1007/s00134-009-1591-4. Epub 2009 Jul 29. Dose-dependent benefit of nitroglycerin on microcirculation of patients with severe heart failure.

A glorious mix of very different things. Not all antihypertensive drugs are vasodilators. Vasodilating an artery or a vein is not the same thing and has not the same effect. At the capillary level, the hematocrit itself is a more potent regulation factor (stress and viscosity) that any other one. More it is elevated, less there is a useful flow inside the tissue (with a low limit of ourse). Lot of things to consider.

There is a simple explanation for the observation that carbon dioxide, nitroprusside (NTP), nitroglycerin (NTG) and other "vasodilators" reduce viscosity, increase fibrin split products, and improve cardiac output: they all release nitric oxide (NO) from the vascular (capillary) endothelium. NO binds to Ca+, which inhibits calcium-dependent thrombin, paralyzes the generation of insoluble fibrin in capillaries, accelerates the disintegration of insoluble fibrin (via thrombin-activated fibrinolysis inhibitor) and thereby "opens" the capillary gate. Carbon dioxide is the safest, least expensive, most convenient, and most effective treatment because it not only reduces microvascular flow resistance, but also enhances the release of oxygen from the hemoglobin molecule and thereby optimizes tissue oxygenation better than the alternatives. In addition, it exaggerates respiratory chemoreceptor function, improves respiratory drive, and offsets the respiratory depression of opioids.

The very term "vasodilator" is a misnomer. The muscular arterial tree functions as a "secondary heart" that expands to accommodate the bolus of blood ejected by the heart during systolic contraction. During diastole, the arterial tree slowly contracts to restore its resting diameter, which efficiently propels blood toward the periphery. Mammalian blood flow is infinitely efficient on account of the shape and size of mammalian red cells, which form "aggregates" that abolish turbulent flow resistance. This explains the superior exercise tolerance of mammals. The turbulent "pulse wave" that originates in the distal aorta and propagates throughout the arterial tree during mammalian diastole is a secondary mechanism that mobilizes particulate deposits from the inner walls of arteries to prevent atherosclerosis and "tunnels" through arterial thromboses to maintain arterial patency. Mammalian hemodynamic physiology thus combines extreme efficiency with atherosclerosis resistance. The pulse wave generates lateral forces that are perceived as the palpable pulse and measured as "blood pressure." Blood pressure as conventionally measured is thus only distantly, indirectly, and confusingly related to cardiac output, tissue perfusion, and tissue oxygenation. The force that propels blood toward capillary beds is so small that it cannot be detected by conventional instruments, and it has never been successfully measured (to the best of my knowledge). It might be assessed by somehow comparing the difference between atmospheric pressure and residual diastolic arterial pressure in the aftermath of the turbulent pulse wave that momentarily halts forward blood flow during diastole.

Flow is related to pressure to some extent, but dilating vessels does not improve blood flow everywhere and even can lead to a disaster.

And inhibiting calcium dependant thrombin would suppress activated protein C production, the most powerfull anticoagulant and profibrinolytic and antiplatelets agent

I would argue that flow is only circumstantially related to conventional blood pressure measurement. It's very deceptive. Mammalian blood flow is "non-Newtonian" as opposed to just about every other fluid we ordinarily encounter. Mammalian blood flow is truly "laminar" and physicians have yet to fully comprehend its significance. It might be compared to electrical superconductivity. The study of Hof et al successfully photographed water pipe flow turbulence about ten years ago, and proved that turbulence is the sole source of pipe flow resistance in Newtonian fluids. It was an amazing, truly revolutionary study. It essentially refutes conventional concepts including shear stress, Reynolds Numbers, the Hagen–Poiseuille equation, blood pressure, mean pressure, pulmonary artery pressure, systemic vascular resistance pulmonary vascular resistance, and so forth. It explains why attempts to derive cardiac output from arterial cannula waveforms have failed.

The argument that inhibiting calcium dependent thrombin would undermine the beneficial effects of Protein C is interesting, but I'd reason that this theoretical consideration is insignificant when insoluble fibrin generation and stabilization has been abolished by thrombin inhibition, because insoluble fibrin generation in capillaries is what closes the capillary gate and inhibits tissue perfusion. I would guess that the main significance of Protein C is that it inhibits venous coagulation. In arteries pulsatile turbulence is the primary bulwark against thrombosis. It disrupts strands of insoluble fibrin that entangle red cells into clots. That is the reason that thrombus formation is relatively rare in arteries as compared to veins.

Diastolic pulsatile turbulence is also the secret of atherosclerosis resistance in mammals.

However in vessels smaller than 1/4 mm, which represent the huge majority of the flow tree non laminar flow does not exist.. and this has to be taken into account.

@Corstiaan den Uil

Hello, thank you for the recommendation, I liked your paper. The data suggest a decrease in delta P and an increase in capillary blood flow.

To me that suggests that the blood is diverted into the venules and not into the tissue which was at the core of my question. Could you comment on that?

Sorry, I wanted to say that laminar flow doesn't exist in microcirculation (not non laminar.)

Beware, that nitroglycerin has very particular properties compared to other vasodilators, could be very different with others products.

Most potent "vasodilators" such as nitroprusside, nitroglycerin, calcium channel blockers and beta blockers exert their beneficial effects in capillaries, where they bind to Ca+, which inhibits thrombin activity. Thrombin is the "universal enzyme of energy transduction" in the body. It converts ATP into cell and extracellular enzyme activities. It energizes TAFI (Thrombin Activated Fibrinolysis Inhibitor) and the interaction of factors VII, VIII IX and X that generates insoluble fibrin in capillaries, which inhibits capillary flow. So, inhibiting thrombin activity accelerates the spontaneous disintegration of insoluble fibrin by plasmin. This reduces capillary flow resistance and enhances cardiac output, cardiac efficiency, tissue perfusion, and tissue oxygenation. The reduction of flow resistance alters the turbulent diastolic pulse wave that produces the lateral forces that explain blood pressure, causing blood pressure to fall at the same time that tissue perfusion and oxygenation improves. In other words, blood pressure is NOT the "driving force" of blood flow. This mistaken belief became entrenched after Walter B. Cannon, a prominent Harvard researcher in the WWI era published his persuasive book called "The Wisdom of the Body." What is forgotten today is the therapeutic benefits of hypercarbia, which directly releases nitric oxide from the vascular endothelium. NO binds avidly to Ca+, inactivates thrombin, and opens the capillary gate. Carbon dioxide is the primary regulator of the capillary gate.

The above answer is really puzzling, just to be polite. I have worked years on microcirculation and have been director of research in the plasmatic business. I could argue point by point. But it is not worth it. Strange knowledge... it is just like fake news...

Regarding Dr. Trove's dismissive comments: Stress theory and capillary gate theory were the prevailing paradigm of medical research for some 30 years following the discovery of DNA, and based on the famous ideas of Dr. Hans Selye that a single "stress mechanism" converts the genetic blueprint into embryological development and then remains active for the duration of life to regulate tissue repair and physiology. Selye's ideas were never disproved, but they were abandoned because nobody could find any clue of any testable mechanism that might explain how Selye's theory worked. I have discovered and described Selye's long sought "mammalian stress mechanism." The knowledge is neither "strange" nor "fake" and such comments suggest ignorance or worse. Any researcher or physician worthy of the name would be excited by the mere prospect of such a discovery. Anyone interested in the discovery can download copies of my published papers via my website: www.stressmechanism.com. Stress theory is now poised to resume its rightful place as the prevailing paradigm of medical and biological research. It promises to revolutionize medicine. Dr. Trove might note that the mammalian stress mechanism confers a fresh theory of anesthesia, analgesia and allostasis that reflects and extends the famous research of George Washington Crile, who should be remembered as the Father of modern anesthesia, and repudiates the unscientific and unfounded ideas of Dr. Ralph Waters that are summarized in my published paper called "Four Forgotten Giants of Anesthesia History." The surgical stress syndrome could be abolished altogether, and surgery could be re-revolutionized with great benefit to public health if these fundamental principles were re-discovered.

Madness is rare in individuals - but in groups, parties, nations, and ages it is the rule. Friedrich Nietzsche

“There are three kinds of intelligence: one kind understands things for itself, the other appreciates what others can understand, the third understands neither for itself nor through others.  The first kind is excellent, the second good, and the third kind useless.”--Niccolo Machiavelli

Well, that's not a philosophical forum, Dr Coleman. I have (and think more than most people) always be opened to new idea and mechanism's. I agree that microcirculatory flow is very particular. But it doesn't work as you state it. And the mechanisms you described concerning thrombin and everything else are false. If I follow your statements, nothing should work anymore at the capillary level.

Particularly the protective mechanism including tye thrombin thrombomodulin complex and generation of activated protein C, that"s would be weird. No ?

I would be delighted to entertain whatever questions you might have, but first you must read at least one of my papers so you know what to ask. There is no way you could have read anything in the short interval between communications. By definition, my proposed capillary gate mechanism, and my description of the stress mechanism will be "different" from what you presently assume and believe. I am proposing an entirely new mechanism based on published information that has accumulated from research unrelated to stress theory during the past 40 years.

I'll do it, don't worry. But some of your mechanisms above are dreams...

The "dreams" are founded on published research, and guided by the reasoning of scientists far more knowledgeable than me. I suggest that you begin by reading my original description of the "Stress Repair Mechanism" that was published before I realized that the mechanism is exclusive to mammals, and that it confers a unified theory of biology that explains embryology, evolution, anatomy, ethology, taxonomy, the Cambrian Explosion, and Dinosaurs. As an anesthesiologist you should also be interested in the paper called "Four Forgotten Giants of Anesthesia History".

 “All great truths begin as blasphemies”—George Bernard Shaw

"All truth passes through three stages. First, it is ridiculed, second it is violently opposed, and third, it is accepted as self-evident."

Arthur Schopenhauer, Philosopher, 1788-1860