No abstract

INDICATOR-DILUTION studies of the coronary circulation will contain information especially concerning the heterogeneity of capillary transit times, information which potentially can be resolved from outflow curves if both a vascular reference substance, one confined to the coronary circulation, and a diffusible substance, one which leaves the vascular space, have been injected simultaneously. One would expect the heterogeneity to change with changes in the vasomotor tone, and this change, in turn, to affect the manner of presentation 'of diffusible substrates to muscle cells, where they are utilized. It therefore seemed important to us to develop a way of characterizing the heterogeneity of capillary transit times in the myocardium and to use this to define the manner in which the heterogeneity alters in response to changes in vasomotor control. The essence of this methodology is to carry out a set of indicator-dilution experiments, to develop a model of events at the level of the capillary net, and, with this, to try to dissect from the data information concerning the heterogeneity of capillary transit times.

SUMMARY Although the exchange of labeled water between blood and tissue in the heart has usually been assumed to be flow-limited, the outflow patterns of labeled water, relative to intravascular references, in a multiple indicator dilution experiment, have appeared to be anomalous in terms of the models used to explain the transport of less permeable substances. Data showing a change in the shape of the labeled water outflow curve after vasodilation and after the infusion of toxic doses of 2,4-dinitrophenol led us to propose a new model for labeled water permeation which includes barriers at both the capillary wall and the sarcolemmal membrane. This model explains adequately the form of the outflow curve, provides parameters related to the permeability at the two barriers, and gives an estimate of the ratio of the intracellular to interstitial space. Dinitrophenol infused intra-arterially in a dose sufficient to cause S-T elevation in the electrocardiogram is found to reduce the sarcolemmal water permeability by an order of magnitude, but to have no effect on capillary water permeability. We conclude that water transport in the heart is barrier-limited at both the capillary and sarcolemmal membranes and that sarcolemmal water permeability is probably mediated at least in part by a structure sensitive to the effects of dinitrophenol, presumably a protein channel. Since the outflow patterns of inert gases resemble that of labeled water, it is possible that oxygen distribution is also barrierlimited.ALTHOUGH cell membranes are known to be highly permeable to water, they do reduce the rate of diffusion of water molecules to about a hundred thousandth that of free diffusion.1 Despite this fact it has been hypothesized that the membrane permeability is high enough and blood flow is slow enough that the distribution of labeled water in an organ such as the heart, where intercapillary distances are small, is flow-limited at physiologic rates of perfusion.213 At this point in time, however, it has been possible to quantitatively corroborate this assumption only for the liver . 4 This organ is very specialized, in terms of the structure of its basic microcirculatory unit, the hepatic sinusoid. There is no significant barrier to small molecules corresponding to the capillary membrane, and the plasma membranes of the hepatocytes are massively expanded in area by virtue of their innumerable microvillous processes. In addition, the mean sinusoidal transit time is much longer than that in the capillaries of a visceral organ perfused at arterial pressure.On the other hand, there is evidence that the distribution of labeled water in the brain is barrier-limited at high but physiologic perfusion rates. "7 In the heart, the organ we wish to consider here, Ziegler and Goresky 8 have shown that the shape of the outflow concentration-time curve for labeled water in a multiple indicator dilution experiment could not be explained by the assumption of flow-limited exchange unless the additional assumption of random diffusional capillary...

The beta-adrenergic blockade-induced reduction in myocardial norepinephrine overflow during sympathetic stimulation was examined by use of the multiple indicator-dilution technique. A kinetic model incorporating the effects of flow, capillary permeability surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate the rate of local release of norepinephrine into the interstitial space. The model was tested by first examining the effects of two drugs that increase myocardial norepinephrine overflow during sympathetic stimulation by differing mechanisms: desmethylimipramine, a norepinephrine uptake inhibitor, and phentolamine, an alpha-adrenergic blocker. The uptake inhibitor was demonstrated to reduce interstitial uptake and the alpha-blocker to increase local neurotransmitter release, without change in blood flow. The beta-adrenergic blocker, in contrast, reduced coronary blood flow and decreased the capillary norepinephrine permeability surface product but did not change the rate of local release. The decreased norepinephrine overflow after beta-blockade was deduced to result from the decrease in transcapillary flux and secondary increase in interstitial uptake.

The kinetics of tracer oxygen distribution in the brain microcirculation of the awake dog were investigated with the multiple indicator dilution technique. A bolus containing 51Cr-labeled red blood cells, previously totally desaturated and then resaturated with [18O]2 (oxygen), 125I-albumin, 22Na, and [3H]water, was injected into the carotid artery, and serial anaerobic blood samples were collected from the sagittal sinus over the next 30 seconds. The outflow recovery curves were analyzed with a distributed-in-space two-barrier model for water and a one-barrier model for oxygen. The analysis provided an estimate of flow per gram brain weight as well as estimates for the tracer water and oxygen rate constants for blood-to-brain exchange and tracer oxygen parenchymal sequestration. Flow to tissue was found to vary between different animals, in concert with parallel changes in oxygen consumption. The 18O2 outflow curves showed an early peak, coincident with and more than half the magnitude of its vascular reference curve (labeled red blood cells), whereas the [3H]water curve increased abruptly to a low-in-magnitude curve at low flow values and to a small early peak at high flow values. Analysis indicates that the transfers of both 18O2 and [3H]water indicators from blood to brain are barrier-limited, with the former highly so because of the large red blood cell capacity for oxygen, and that the proportion of the tracer oxygen returning to the circulation from tissue is a small fraction of the total tracer emerging at the outflow.