Interstitial adenosine: the measurement, the interpretation.

In the current issue, Gidday et al. report on their observations in “Heterogeneity and Sampling Volume Dependence of Epicardial Adenosine Concentrations.” I read their report with some anticipation. Was this the long awaited critical assessment of the epicardial disc technique for obtaining estimates of interstitial adenosine concentrations? The other promise was in the word “heterogeneity,” which stimulated my long standing (Yipintsoi et al., 1973) interest in figuring out why the range of normal myocardial blood flows is so broad, at all levels of spatial resolution (Bassingthwaighte, King and Roger, 1989). Could local adenosine concentrations be the governor, as proposed originally by the senior author, Robert Berne (1963)? The two aspects of the title, the heterogeneity of interstitial fluid (ISF) adenosine concentrations, [Ado]isf, and the accuracy and reproducibility of methods for estimating [Ado]isf, are linked: the methods need to be well worked out in order to contemplate the physiology. All currently available methods for estimating [ADO]isf are indirect. There are various ways of collecting “sweat” or transudate from the epicardial surface, using a small well (Hanley et al., 1983), or epicardial drippings (Decking et al., 1988; Heller and Mohrman, 1988; Mohrman and Heller, 1990). Placing absorbent discs on the epicardium gives estimates similar to the transudates (Tietjan et al., 1990; Headrick et al., 1991). Gidday et al. (1991) report average values of about 470 nm, using discs. Transudates and disc fluids have the disadvantage, for interpretation, of representing mainly or only the subepicardial interstitium. Methods for estimating the whole heart average myocardial interstitial adenosine from measures of flows, from membrane and capillary wall permeabilities, from volumes of distribution, and from the venous outflow adenosine concentrations (Bassingthwaighte et al., 1985; Wangler et al., 1989; Gorman et al., 1991) are also indirect, but do attempt to take into account the known and measurable flow heterogeneities. The applications of these methods give widely disparate estimates of interstitial adenosine levels, as reviewed in Table 1, taken from Gorman et al. (1991). No two methods have been applied simultaneously to one heart. What is more awkward is that the most direct measures are local and the global measures can only give an average. TABLE 1 Estimates of [ADO]isf in isolated guinea-pig hearts Gidday et al. (1991) provide data from open chested dog hearts that give three important results: Epicardial discs of small volume and of minimal thickness do equilibrate with the subepicardial tissue within one to 2 mins, and should therefore be useful for estimating local subepicardial [Ado]isf. Epicardial discs of greater thickness, and epicardial well chambers of 100 μl volume, do not equilibrate to levels of [Ado]isf comparable to the thin discs. (I calculate, below, that this is due to the fact that 2 mins is not adequate time for diffusional equilibration.) [Ado]isf, as measured using thin epicardial discs, fluctuates in time and varies between pairs of locations on the surface of the heart. My job in this editorial is two-fold: to analyze their data at a more physicochemical level, and to try to express how their observations contribute to the understanding of [Ado]isf and its basis. The potential role of [Ado]isf in vasoregulation provides incentive for such analysis, but it is not the only goal: it is also important to gain an understanding of purine uptake and metabolism in the heart and in particular to understand the relationships between the production of adenosine from ATP and its concentrations in the ISF and the effluent blood.