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EDITORIAL FOCUS
ESSAYS ON APS CLASSIC PAPERS
Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195
ABSTRACT
This essay looks at the historical significance of an APS classic paper that is freely available online:
Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204: 317–322, 1963 (http://ajplegacy.physiology.org/cgi/reprint/204/2/317).
75% of the oxygen delivered by the coronary blood flow, and the coronary venous oxygen tension is 18 mmHg. This means that there is little oxygen extraction reserve for the myocardium. Despite this constraint, myocardial oxygen consumption increases as much as fivefold during exercise when heart rate and myocardial contractility are elevated. The increase in myocardial oxygen consumption can only occur by a similar increase in oxygen delivery provided by augmented coronary blood flow.
Although there is a feedforward sympathetic 
-adrenoceptor coronary vasodilation component to the increase in coronary blood flow during exercise (7, 10, 11, 21), the primary cause of the augmented coronary flow is via a local metabolic mechanism. The local metabolic vasodilator mechanism that matches coronary blood flow to myocardial oxygen consumption is the subject of Berne's (Fig. 1) seminal paper (2).
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In 1963, Berne (2) and also Gerlach, Deuticke, and Dreisbach (9) proposed that adenosine mediates local metabolic control of coronary blood flow. Figure 2 from Berne's classic paper (2) diagrams the hypothesis in what we now call a negative-feedback control scheme. The idea is that the balance between oxygen supply and myocardial oxygen consumption is reflected in the intracellular myocardial oxygen tension (PO2). If myocardial oxygen consumption increases (as during exercise), then there will be a fall in cardiac myocyte PO2 that will lead to the breakdown of adenine nucleotides (ATP, ADP, AMP) and to the generation of adenosine that diffuses out of the cardiac cell. The adenosine crosses the interstitial space to act on adenosine receptors on coronary arteriolar smooth muscle to cause vasodilation. The ensuing increase in coronary blood flow delivers more oxygen to the myocardium and thus returns myocardial PO2 back toward the normal operating range. This is a negative-feedback control scheme where myocardial PO2 is the sensed, controlled variable, and any deviation of myocardial PO2 from the normal operating range is the error signal.
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Berne's seminal paper (2) stimulated hundreds of subsequent studies testing the adenosine hypothesis and elucidating the biochemistry of adenine nucleotides in the myocardium. In this brief essay it is not possible to cite many of the important papers. However, there have been a number of reviews that may be used to trace the history of the adenosine hypothesis and to find the references alluded to. Berne reviewed the field in 1964 (3) and in 1980 (4); Feigl critically examined the hypothesis in 1983 (8); Olsson and Pearson extensively considered the relevant biochemistry in 1990 (16); and Tune et al. (21) have reviewed the recent literature.
Figure 3 presents a simplified contemporary diagram of adenosine kinetics in the myocardium. Rectangular boxes represent enzymes; ovals, blocking agents; and two-way single-barbed arrows indicate facilitated transmembrane diffusion. Much of this detail was unknown in 1963.
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Throughout the four decades during which the adenosine hypothesis has been tested, the major problem has been to obtain an appropriate measurement of adenosine concentrations in cardiac interstitial fluid, where adenosine acts on vascular smooth muscle A2 adenosine receptors. Olsson et al. (15) found that 94% of the total adenosine in the myocardium was bound to S-adenosylhomocysteine (SAH), a compartment not readily diffusable to the interstitial space. This indicates that total myocardial tissue measurements of adenosine are not suitable for indicating the interstitial fluid concentrations. Deussen and coworkers (6) ingeniously used this finding to estimate the free adenosine in cardiac cells by adding excess homocysteine to drive the SAH hydrolase reaction backward to produce SAH and analyzing for this compound. Rubio and Berne (17) introduced the use of buffer washings from the pericardial sack for adenosine measurements. However, Kusachi and Olsson (14) demonstrated that adenosine levels in pericardial sack washings were the result of highly variable equilibration rates and thus unreliable. Van Wylen and coworkers (22) introduced the use of microdialysis tubing threaded through the myocardium to obtain buffer samples for adenosine measurements. However, this method gives very high values, not consistent with other estimates [Stepp et al. (19)]. The high adenosine concentrations are probably due to nucleotides and nucleosides leaking from injured cardiomyocytes as the heart continues to beat against the microdialysis tubing foreign body.
One logical way to estimate interstitial adenosine concentration is to measure the adenosine level in venous plasma draining from the heart. However, plasma contains adenosine deaminase (ADA) that degrades adenosine, and blood cells take up adenosine from the plasma. It is now recognized that adenosine can be retained in plasma by mixing the blood sample as it is drawn with an ice-cold "stop solution" that contains enzyme inhibitors and an inhibitor of cellular adenosine uptake. The other difficulty with venous measurements is that vascular endothelial cells avidly take up adenosine so that much of the adenosine in the interstitial fluid does not reach the plasma. Kroll and Stepp (13) used the multiple-indicator technique to determine endothelial adenosine uptake kinetics, thus permitting a calculation of interstitial adenosine concentrations from coronary venous plasma measurements.
An important way to test a transmitter hypothesis is to employ agents that block the action of the proposed mechanism. Berne's group observed that the weak adenosine receptor-blocking agent aminophylline modestly decreased the reactive hyperemia that follows the ischemia of a brief coronary occlusion [Curnish, Berne, and Rubio (5)]. Olsson's group introduced the use of an intracoronary infusion of ADA to inactivate adenosine in the cardiac interstitial fluid (18). This was followed by a number of studies from different laboratories using ADA. In general, the results were that ADA treatment modestly reduced ischemic coronary vasodilation but not during more physiological conditions. There ensued a lively discussion as to whether sufficient ADA reached the interstitial space to inactivate the physiological rate of adenosine production. The consensus in the mid-1980s was that adenosine was involved in ischemic vasodilation and remained an attractive but incompletely tested hypothesis for physiological coronary vasodilation.
In 1988 Bache et al. (1) published a very important paper where the potent adenosine-receptor antagonist 8-phenyltheophylline (8-PT) was used to test the role of adenosine in coronary vasodilation during exercise. This adenosine blockade significantly decreased ischemic reactive hyperemia following coronary occlusions but had no effect on coronary blood flow at rest or during exercise.
The Bache et al. study (1) would seem to defeat the adenosine hypothesis for physiological coronary vasodilation during exercise. However, the logical counterargument was put forward that if (as postulated) adenosine is part of a high-gain negative-feedback controller then the high gain would result in additional adenosine being released to overcome the competitive adenosine-receptor blockade due to 8-PT. In a high-gain system, the myocardial PO2 would only need to fall slightly (undetectably) for a great amount of adenosine to be released and overcome the receptor blockade (Fig. 2).
The experimental answer to the high-gain argument is to determine interstitial adenosine concentrations when 8-PT is used. This was done by Tune et al. (20), who used the Kroll method for estimating myocardial interstitial fluid adenosine concentrations. 8-PT did not result in an increase in interstitial adenosine concentration during exercise and would have had to increase more than tenfold to overcome the competitive adenosine-receptor blockade. This experiment, in effect, defeats the adenosine hypothesis for physiological coronary vasodilation.
In contrast to the negative conclusion about the role of adenosine in the physiological control of coronary blood flow, adenosine's role in protecting the myocardium during ischemia has become more and more recognized during stunning and preconditioning [Headrick et al. (12)].
Berne's seminal original observation (2) has come full circle. The original experiments demonstrated the pathophysiological breakdown of ATP to adenosine during cardiac hypoxia. This has been confirmed many times in many ways and is now uncontested. The extrapolation of the findings during hypoxia to the hypothesis that adenosine mediates physiological control of coronary blood flow without ischemia or hypoxia has not survived.
An enduring aspect of Berne's original paper (2) is that it set forth a mechanistically rational, cogent, testable hypothesis that links coronary blood flow to myocardial oxygen consumption. This established the logical framework for finding the local metabolic negative-feedback controller(s) of coronary blood flow. We still use Berne's formulation in seeking the physiological mechanism that keeps us alive whenever we increase our heart rate.
ACKNOWLEDGMENTS
This paper was supported by National Heart, Lung, and Blood Institute Grant HL-49822.
FOOTNOTES
Address for correspondence: E. O. Feigl, Dept. of Physiology and Biophysics, Univ. of Washington School of Medicine, Box 357290, Seattle, WA 98195–7290 (E-mail: efeigl{at}u.washington.edu)
REFERENCES
-adrenergic control. Circ Res 82: 1312–1322, 1998.
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