New understanding of circulatory blood flow and arterial blood pressure mechanisms.

The purpose of this article is to emphasize exciting new interpretations we have concluded about the circulation as reported recently.

In exercise, up to moderately high levels, the rate of arterial oxygen delivery (DO2) to skeletal muscle increases directly in proportion to the rate of oxygen consumption (VO2). This physiological, evolutionary, feature avoids ischaemia of the exercising muscle. Oxygen extraction is precisely controlled. Exercising muscle DO2 and hence blood flow control is an example of near universal control of individual tissue blood supply, with appropriate individual tissue DO2. Venous return to the heart, and hence cardiac output (CO), is made up of the total of all tissue regulated blood flows. ‘The heart puts out what it receives’. Hence, the tissues control CO.

DO2 to individual tissues is scaled relative to VO2; DO2/VO2 is around 1.5 for skeletal muscle, oxygen extraction of 2/3, or 0.67. Similarly, for the brain, DO2/VO2 is close to 3, oxygen extraction 1/3.

Under resting conditions the oxygen extraction values, for the brain, are also sustained during changes in arterial blood pressure, over a fairly wide range—this is the well-known phenomenon—‘auto-regulation’ of cerebral blood flow (CBF). Adjustment of cerebral arteriolar resistance sustains correct DO2 in the face of arterial pressure change.

The current assumption that the systemic vascular resistance (SVR) controls arterial blood pressure in health is incorrect, because:

Each tissue regulates its own blood flow sustaining an appropriate DO2 by means of appropriate adjustment of its arteriolar input resistance. Hence, SVR is the net effect of multiple individually regulated arteriolar resistances;

Arterial blood pressure depends on arterial volume; indeed, it is the relationship between pressure and volume which defines arterial wall compliance. Arterial compliance is low relative to venous compliance, which determines the relatively smaller arterial volume. Changes in arterial volume result in changes in arterial blood pressure. So, making a modest shift in blood volume from veins to arteries, or arteries to veins, causes immediate pressure change, without a need for change in total blood volume.

Venous compliance can also, usefully, be expressed as the inverse—venous tone. Venous tone is largely controlled by the sympathetic nervous system. Venous/arterial volume distribution is sustained by ongoing venous sympathetic activity. An increase in arterial pressure will result from an increase in venous wall muscle tension, due to increased sympathetic stimulation. This is veno-constriction, an important distinction from ‘vaso-constriction’.

In our paper, we suggested that the arteriolar sympathetic supply sustains a constant, tonic, state in health, except where there is a gross increase in arterial pressure, when an abrupt protective effect, a sympathetic surge, constricts cerebral arterioles. This prevents excess intracerebral pressure and cerebral damage. However, during experimental increases in arterial pressure, the autoregulation range of pressures with sustained CBF can be extended to higher pressure levels by the addition of sympathetic stimulation. Hence, during the auto-regulation range, extra sympathetic stimulation still allows the compensatory cerebral arteriolar resistance adjustment. The apparent co-activation, where arterial pressure and SVR change together in experimental work either results from the compensatory tissue response to raised arterial blood pressure or is an artefact from sustaining an imposed constant CO. Furthermore, we may need to revise the site of action of drugs raising arterial pressure as they may well act on venous tone rather than on arteriolar resistance. These medications may also interfere with in-tissue regulation of arteriolar resistance, preventing adequate oxygenation.

So, tissues are responsible for modification of input resistance, either specifically for their own need to alter DO2 in parallel with VO2 change, or to resist blood flow change in the face of alterations in arterial blood pressure.

Hence, the two fundamental properties of the circulation are:

Illustration of the circulation, with the venous system depicted as having a much larger capacity and compliance than arterial. Arterial blood pressure is intimately related to the arterial blood volume. Veins blue: capacity 5 × that of arteries. Arteries red: A small change in venous volume causes a large change in arterial volume—and hence pressure. Arterial volume and hence pressure are sustained by the level of venous tone. Venous tone depends mainly on the intensity of the sympathetic outflow from the brain to venous wall musculature. The portal blood flow is shown stippled red and blue, an intermediate drainage from gut to liver. Apart from the emphasis on the different venous and arterial volumes, the tissues, heart, and lung (L) dimensions are arbitrary.

Individual tissues control local blood flow such that they regulate their own rate of DO2. In the normal range, this amounts to maintenance of constant oxygen extraction even when VO2 varies over a considerable range. The total of all individual tissue blood flows becomes venous return and hence CO.

Arterial blood pressure is proportionately related to the arterial volume. It is not determined by SVR. The multiple tissue arteriolar resistance values each normally sustain constant individual DO2 to VO2 ratios (and hence constant oxygen extraction values). These are sustained both with changes in VO2, as in exercise, and during arterial pressure change. Hence, SVR is affected by both tissue metabolism and arterial blood pressure. Arterial blood pressure changes are caused by changes in venous volume, not by SVR change.

Re-examination of arterial blood pressure regulation, in view of the presence of intracerebral baro-receptors.

The higher venous tone sustaining hypertension, but with no increase in total blood volume.

Sites of action of vaso-active drugs (an increase in emphasis on veins).

Effects of hormones on venous tone (e.g. endothelin, NO, angiotensin II).

Redox chemistry and regulation of within-organ/tissue control of oxygen delivery.

Mechanisms which underlay accurate cellular oxygen extraction: including cellular oxygen recognition and arteriolar resistance control.

Role of neuro-humoral and immunological interaction and arterial blood pressure.

Potential for intensive care prioritization of whole body DO2 optimization.

Maintaining DO2 limits the buildup of oxygen debt, potential organ dysfunction and perhaps cognitive impairment.

Removal of partial obstructions to CBF; e.g. carotid endarterectomy with lowering of arterial blood pressure.

Potential treatment for ischaemic heart disease.

Potential for lower doses of existing drugs, or different drugs acting on veins to lower blood pressure.

Therapeutic dividends

This revision of circulatory mechanisms constitutes a paradigm shift and upsets reliance on previous long-term interpretations. It is hoped our account can facilitate transition to a new approach.

Conflict of interest: none declared.