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The coronary microcirculation
EDITORIALS
The Coronary Microcirculation* WOLFGANG SCHAPER, MD, PhD JUTTA SCHAPER, MD
Bad Nauheim, West German Federal Republic
In a recent issue of this Journal' eminent cardiologists daringly attacked an unsolved issue that is hotly argued among physiologists : myocardial microcirculation . Research in this field was clearly stimulated by the grave problem of coronary heart disease, and the report of Sherf et al.' is pertinent to our present understanding of this problem . Years ago we all wanted to measure coronary blood flow because we hoped to separate, on the basis of blood flow, the diseased from the healthy part of the myocardium . But we were soon disillusioned and had to accept the fact that overall blood flow is not a good discriminatory index. We should have known from evidence at autopsy that coronary heart disease causes regional disturbances of flow and, hence, regional disturbances of contractility and metabolism . Progress in understanding these disturbances has been rapid and we can now visualize the lesion within a coronary artery with angiography . We can almost quantitate disturbances in regional ventricular motility, we can draw blood samples selectively from cardiac veins to show abnormal regional metabolism and we have the gamma camera to estimate regional blood flow . With all these marvelous gadgets at hand we are able to unravel the pathophysiology of ischemic heart disease in many patients-but not all . Patients have been described who had clear clinical findings of acute myocardial infarction but whose coronary angiograms, obtained at some safe interval later, revealed normal coronary arteries . Autopsy reports have been published in which acute myocardial infarction, notably of the subendocardium, had developed in the presence of old coronary lesions . Why did the patients in these cases die of acute myocardial infarction when From the Max-Planck-Institut fur Physiologische and Klinische Forschung, Abteilung fur Experimentelle Kardiologie, Bad Nauheim, West German Federal Republic . Manuscript received May 4, 1977, accepted May 25, 1977 . Address for reprints: Wolfgang Schaper, MD, Max-Planck-Institut fur Physiologische and Klinische, Forschung, W . G . Kerckhoff-lnstltut, Abteilung fur Experimentelle Kardiologie, Sprudelhof 11, 6350 Bad Nauheim, West German Federal Republic .
nothing new had happened to their coronary arteries? In some, an occluding thrombus may have recanalized to such an extent that coronary angiography revealed no abnormality . In others, a fresh thrombus may have been lysed after death by still intact endothelium . Careful analysis of the reported cases shows that there is no proved reported case in which the patient had normal coronary arteries at the moment of acute myocardial infarction . Yet cases remain that cannot be explained away . When we have a patient with normal coronary arteries but with angina pectoris and evidence for abnormal myocardial lactate metabolism, we usually seek refuge in the diagnosis of "small vessel disease ." This is a proved entity, but it cannot be documented during life although some patients have undergone myocardial biopsy to provide such documentation . When we focus on small coronary arteries to explain angina when the ischemic nature of the patient's complaint cannot be doubted we can consider two possible mechanisms : changes in the structure of small arteries (that is, small vessel disease) or dysfunction of structurally normal small arteries. The latter possibility has, we believe, not been discussed before, and Sherf and his colleagues' are probably the first to introduce this concept . Although physiologist,-, in the field of myocardial microcirculation appreciate this new clinical interest in their research, they are not in an enviable position : They have very few answers to the many questions of the clinicians . When we examine what is known about mammalian cardiac microcirculation we have to admit that we do not know which vascular structure is responsible for regulation . We also do not know the nature of the biochemical mechanism that links blood flow to myocardial metabolism .
Vascular Structures That Possibly Regulate Flow Three classes of vascular structures are now discussed as probable regulators of blood flow : so-called resistance vessels, precapillary sphincters and contractile endo-
Editorials published by the Journal reflect the views of the authors and do not necessarily represent the views of the Journal or of the American College of Cardiology .
1008
December 1977
The American Journal of CARDIOLOGY Volume 40
EDITORIALS
thelial cells . Resistance vessels range in size from small arteries to precapillary arterioles . They are known to produce the greatest portion of the decrease in pressure within the arterial system and they have traditionally been considered the regulators of blood flow . As a whole they determine the arterial blood pressure . They are termed resistance vessels because the sum of all arteriolar luminal surface areas is so large that very small changes in smooth muscle tone can produce enormous changes in flow. From the point of view of economy the resistance vessels are indeed the ideal flow regulators . Precapillary sphincters occur in many vascular provinces in the mammalian circulation . Their presence in the heart was claimed some 40 years ago, but convincing electron microscopic evidence of their existence is lacking. On the basis of microcinematographic data, Honig et al . 2 believe that precapillary sphincters occur
in the heart. But the finding that all capillaries are not necessarily perfused in the beating heart with the body at rest can also be explained by the view that resistance vessels govern flow . It doesn't make much sense to equip almost the entire arterial tree with lots of contractile material but to grant functional importance only to that one smooth muscle cell at the entrance of a capillary. However, nature need not comply with common sense . When small pieces of heart muscle are fixed by immersion, as in the studies of Sherf et al ., 1 the capillary lumen is almost always occluded . One cause is a protruding endothelial cell . It is known that endothelial cells contain contractile materials, and there is documented evidence that these cells can, upon electrical stimulation, block corpuscular flow (that is, red blood cells) in capillaries . This was observed in frog mesentery,
FIGURE 1 . Capillary after perfusion fixation with glutaraldehyde . The vessel wall is thin and the nucleus of the endothelial cell is flattened . Note the close apposition to the surrounding myocardial cells . Figures 2, 3 and 4 show differences in appearance of small blood vessels after immersion fixation . (X30,000, reduced by 17 percent .)
December
1977
The American Journal
of
CARDIOLOGY Volume
40
1009
EDITORIALS
but cinematographic techniques have so far not produced evidence in the mammalian heart (atrium and ventricle) of this type of behavior . On the contrary, mammalian cardiac capillaries show a complete lack of vasomotion in Bing's films . 3 They give the impression of being completely passive structures, an observation that lends support to the traditional view that the "resistance vessels" govern coronary blood flow . When, on the other hand, heart muscle is fixed by perfusion these protruding endothelial cells are not observed except under one condition : when small arterioles undergo growth transformation in the neighborhood of ischemic heart muscle as in collateral growth . The question of whether endothelial cells play a role in the regulation of mammalian coronary blood flow is not answered . We tend to believe that protruding endothelial cells are either a transitory phenomenon in vascular growth or a fixation artifact. In perfusion fixation at physiologic pressure all small vessels show an open lumen, and they are in close connection with the surrounding myocardial cells (Fig . 1) . In immersion fixation the configuration of the vessels depends (1) on the contractile state of the heart (that is, there are more open vessels in relaxed than in strongly contracted myocardial tissue), and (2) on the
actual filling of these vessels at the time of fixation (Fig . 2 to 4) . A time lag in immersion fixation results in a very thin endothelial layer showing numerous blebs and pronounced vesiculation . The small vessels have usually lost contact with the surrounding myocardial cells in immersion fixed tissue . Because the course of most arterioles, capillaries and venules is parallel to the longitudinal axis of the muscle cells, only transversely cut sections reflect the true diameter and wall thickness and also the distribution of the capillaries, arterioles and venules within the myocardium . Although we believe that coronary blood flow is regulated by the resistance vessels, we do not exclude the possibility of a dual regulatory mechanism : one that controls overall blood flow according to myocardial oxygen consumption, and another that is responsible for "fine tuning" at the microcirculatory level . From studies by Lilbbers and his school^ it is quite evident that neither the classic Krogh's cylinder model nor a countercurrent oxygen supply is present in the heart but rather a network of capillaries in which the direction of flow varies almost continually . This strongly suggests a microcirculatory regulation that does not affect the overall level of organ perfusion .
FIGURE 2 . Capillary after immersion fixation in glutaraldehyde . The vessel is compressed by the contracted myocardial cells . Note the close proximity to the surrounding myocardium (X30,000, reduced by 30 percent .)
FIGURE 3 . Capillary after immersion fixation . The vessel is partly open and it is somewhat distant from the myocardial cells . Next to the vessel lies a satellite cell showing a very long extension (X9,000, reduced by 27 percent .)
1 01 0
December 1977 The American Journal of CARDIOLOGY
Volume 40
EDITORIALS
The Mechanism of Vasomotion
In spite of the prevailing ignorance concerning which vascular structure regulates flow we can probably agree on the compromise that the regulating mechanism acts on rather small vessels . However, the nature of this mechanism is in itself a controversial issue . The excellent correlations between myocardial oxygen consumption and coronary blood flow and between the generation and maintenance of left ventricular pressure suggest a link between the elementary energy-transducing process at the level of the sarcomere on the one hand and small vessel tone on the other . Because these correlations hold for the isolated blood-perfused heart as well as for the isolated heart perfused with salt solutions containing glucose and pyruvate, the regulation of coronary blood flow appears to he totally dominated by myocardial metabolism . Although Feigl showed that sympathetic stimulation produces coronary vasoconstriction5 and that parasympathetic stimulation produces vasodilatation, 6 these responses occur under physiologic conditions masked by the overriding effects on cardiac metabolism . It is not known whether autonomic influences can, under pathologic conditions, override the metabolic regulation . The link between myocardial metabolism and small vessel tone is also not firmly established . A comprehensive theory by Berne 7
4
_. Z*
- -_ .
FIGURE 4 . A small arteriole after immersion fixation shows a partly occluded lumen with a bulging endothelial nucleus (X13,800, reduced by 32 percent .)
states that the link between cardiac metabolism and vascular tone is established by adenosine . Adenosine is a good candidate for a regulatory transmitter for three reasons : (1) It is a potent coronary vasodilator ; (2) it is a breakdown product of adenosine triphosphate (ATP) ; and (3) it can leave the myocardial cell and can thereby act on small neighboring blood vessels. The difficulties with this theory are severalfold : It is unlikely that physiologic regulation of flow necessitates breakdown of ATP to adenosine at the level of the sarcomere or of the mitochondria because adenosine is likely to be destroyed during the passage through the cytosol owing to the presence of the inactivating enzyme adenosine deaminase. If the adenosine stems from a sarcolemmal ATP compartment this obstacle is bypassed but there is no longer a direct link between the generation of force and vascular tone . Kiiblers and Olssons postulated that adenosine, which does rapidly accumulate at the onset of ischemia, may stem from cyclic adenosine monophosphate (AMP), and Schaper et al . 10 described a perivascular "satellite-cell" that is biochemically equipped to produce adenosine . This satellite cell also possesses long extensions that protrude deep between myocardial cells and that may function as samplers of oxygen availability. These latter two hypotheses are still firmly based on Berne's hypothesis7; they differ only slightly as to the origin of the vasodilating adenosine. Arguments against the adenosine hypothesis are that adenosine cannot be formed in the presence of ATP and adenosine diphosphate (ADP) . which inhibit the enzyme 5' nucleotidase . The argument is not entirely conclusive because the sarcolemmal ATP or cyclic AMP concentration may be below the inhibiting concentration . The fact that aminophylline and caffeine and its derivatives block the action of exogenous adenosine cannot be used as evidence that endogenous adenosine is not responsible for regulation of coronary flow. Recently a more "modern" class of chemicals, the prostaglandins, has been discussed as a possible regulator of coronary blood flow, but conclusive evidence is missing . Our continual hope that the currently fashionable class of compounds will solve our problems is a very strong reflection of our ignorance . Conclusions : Summarizing, we confess that we do not know with absolute certainty which type of vascular structure regulates coronary blood flow. Equally vague is our knowledge regarding the coupling between myocardial metabolism and coronary blood flow as well as the mechanism of smooth muscle relaxation . We tend to believe that two vascular structures are responsible for the regulation of blood flow : Arterioles probably regulate overall blood flow, and precapillary and perhaps also capillary structures are probably responsible for the efficient distribution of blood flow on the microcirculatory level . The close correlation between myocardial metabolism and coronary blood flow is very suggestive for a metabolite of energy transduction . Adenosine, after all, is not a bad candidate .
December 1977
The American Journal of CARDIOLOGY
Volume 40
1 01 1
EDITORIALS
References 1 . Short L, Ben-Shaul Y, Lieberman Y, et al : The human coronary microcirculation : an electron microscopic study. Am J Cardiol 39 :599-608, 1977 2 . Honig CR : Control of smooth muscle actomyosin by phosphate and by VAMP : possible role in metabolic autoregulation . Microvasc Res 1 :133-146, 1968 3 . Tillmans H, Ideda S, Hansen H, et al : Microcirculation in the ventricle of the dog and turtle . Circ Res 34:561-569, 1974 4 . Lubber$ DW: Die Bedeutung des Sauerstoffdruckes fur die O r Versorgung des normalen and insuffizienten Herzens . In, Heart Failure : Pathophysiological and Clinical Aspects (Reindell H, Keul J, Doll E, ad) . Stuttgart, Thieme-Verlag, 1968, p 287 5 . Feigl ED : Control of myocardial oxygen tension by sympathetic coronary vasoconstriction in the dog . Circ Res 37 :88-95, 1975
1 01 2
December 1977
The American Journal of CARDIOLOGY
6 . Feigf ED: Reflex parasympathetic coronary vasodilatation elicited from cardiac receptors in the dog . Circ Res 37 :175-182, 1975 7 . Bane R: Cardiac nucleotides in hypoxia : possible role in regulation of coronary blood flow. Am J Physiol 204 :317-322, 1963 8 . Kubler W, Spieckermann PG, Bretschneider HJ : Influence of dipyridamol (Persantin) on myocardial adenosine metabolism . J M01 Cell Cardiol 1 :23-38, 1970 9 . Olsson RA : Changes in content of purine nucleoside in canine myocardium during coronary occlusion . Circ Res 28 :301-306, 1970 10 . Borgers M, Schaper J, Schaper W : Adenosine-producing sites in the mammalian heart : a cytochemical study . J Mol Cell Cardiol 3 :287-296, 1971
Volume 40
The Coronary Microcirculation* WOLFGANG SCHAPER, MD, PhD JUTTA SCHAPER, MD
Bad Nauheim, West German Federal Republic
In a recent issue of this Journal' eminent cardiologists daringly attacked an unsolved issue that is hotly argued among physiologists : myocardial microcirculation . Research in this field was clearly stimulated by the grave problem of coronary heart disease, and the report of Sherf et al.' is pertinent to our present understanding of this problem . Years ago we all wanted to measure coronary blood flow because we hoped to separate, on the basis of blood flow, the diseased from the healthy part of the myocardium . But we were soon disillusioned and had to accept the fact that overall blood flow is not a good discriminatory index. We should have known from evidence at autopsy that coronary heart disease causes regional disturbances of flow and, hence, regional disturbances of contractility and metabolism . Progress in understanding these disturbances has been rapid and we can now visualize the lesion within a coronary artery with angiography . We can almost quantitate disturbances in regional ventricular motility, we can draw blood samples selectively from cardiac veins to show abnormal regional metabolism and we have the gamma camera to estimate regional blood flow . With all these marvelous gadgets at hand we are able to unravel the pathophysiology of ischemic heart disease in many patients-but not all . Patients have been described who had clear clinical findings of acute myocardial infarction but whose coronary angiograms, obtained at some safe interval later, revealed normal coronary arteries . Autopsy reports have been published in which acute myocardial infarction, notably of the subendocardium, had developed in the presence of old coronary lesions . Why did the patients in these cases die of acute myocardial infarction when From the Max-Planck-Institut fur Physiologische and Klinische Forschung, Abteilung fur Experimentelle Kardiologie, Bad Nauheim, West German Federal Republic . Manuscript received May 4, 1977, accepted May 25, 1977 . Address for reprints: Wolfgang Schaper, MD, Max-Planck-Institut fur Physiologische and Klinische, Forschung, W . G . Kerckhoff-lnstltut, Abteilung fur Experimentelle Kardiologie, Sprudelhof 11, 6350 Bad Nauheim, West German Federal Republic .
nothing new had happened to their coronary arteries? In some, an occluding thrombus may have recanalized to such an extent that coronary angiography revealed no abnormality . In others, a fresh thrombus may have been lysed after death by still intact endothelium . Careful analysis of the reported cases shows that there is no proved reported case in which the patient had normal coronary arteries at the moment of acute myocardial infarction . Yet cases remain that cannot be explained away . When we have a patient with normal coronary arteries but with angina pectoris and evidence for abnormal myocardial lactate metabolism, we usually seek refuge in the diagnosis of "small vessel disease ." This is a proved entity, but it cannot be documented during life although some patients have undergone myocardial biopsy to provide such documentation . When we focus on small coronary arteries to explain angina when the ischemic nature of the patient's complaint cannot be doubted we can consider two possible mechanisms : changes in the structure of small arteries (that is, small vessel disease) or dysfunction of structurally normal small arteries. The latter possibility has, we believe, not been discussed before, and Sherf and his colleagues' are probably the first to introduce this concept . Although physiologist,-, in the field of myocardial microcirculation appreciate this new clinical interest in their research, they are not in an enviable position : They have very few answers to the many questions of the clinicians . When we examine what is known about mammalian cardiac microcirculation we have to admit that we do not know which vascular structure is responsible for regulation . We also do not know the nature of the biochemical mechanism that links blood flow to myocardial metabolism .
Vascular Structures That Possibly Regulate Flow Three classes of vascular structures are now discussed as probable regulators of blood flow : so-called resistance vessels, precapillary sphincters and contractile endo-
Editorials published by the Journal reflect the views of the authors and do not necessarily represent the views of the Journal or of the American College of Cardiology .
1008
December 1977
The American Journal of CARDIOLOGY Volume 40
EDITORIALS
thelial cells . Resistance vessels range in size from small arteries to precapillary arterioles . They are known to produce the greatest portion of the decrease in pressure within the arterial system and they have traditionally been considered the regulators of blood flow . As a whole they determine the arterial blood pressure . They are termed resistance vessels because the sum of all arteriolar luminal surface areas is so large that very small changes in smooth muscle tone can produce enormous changes in flow. From the point of view of economy the resistance vessels are indeed the ideal flow regulators . Precapillary sphincters occur in many vascular provinces in the mammalian circulation . Their presence in the heart was claimed some 40 years ago, but convincing electron microscopic evidence of their existence is lacking. On the basis of microcinematographic data, Honig et al . 2 believe that precapillary sphincters occur
in the heart. But the finding that all capillaries are not necessarily perfused in the beating heart with the body at rest can also be explained by the view that resistance vessels govern flow . It doesn't make much sense to equip almost the entire arterial tree with lots of contractile material but to grant functional importance only to that one smooth muscle cell at the entrance of a capillary. However, nature need not comply with common sense . When small pieces of heart muscle are fixed by immersion, as in the studies of Sherf et al ., 1 the capillary lumen is almost always occluded . One cause is a protruding endothelial cell . It is known that endothelial cells contain contractile materials, and there is documented evidence that these cells can, upon electrical stimulation, block corpuscular flow (that is, red blood cells) in capillaries . This was observed in frog mesentery,
FIGURE 1 . Capillary after perfusion fixation with glutaraldehyde . The vessel wall is thin and the nucleus of the endothelial cell is flattened . Note the close apposition to the surrounding myocardial cells . Figures 2, 3 and 4 show differences in appearance of small blood vessels after immersion fixation . (X30,000, reduced by 17 percent .)
December
1977
The American Journal
of
CARDIOLOGY Volume
40
1009
EDITORIALS
but cinematographic techniques have so far not produced evidence in the mammalian heart (atrium and ventricle) of this type of behavior . On the contrary, mammalian cardiac capillaries show a complete lack of vasomotion in Bing's films . 3 They give the impression of being completely passive structures, an observation that lends support to the traditional view that the "resistance vessels" govern coronary blood flow . When, on the other hand, heart muscle is fixed by perfusion these protruding endothelial cells are not observed except under one condition : when small arterioles undergo growth transformation in the neighborhood of ischemic heart muscle as in collateral growth . The question of whether endothelial cells play a role in the regulation of mammalian coronary blood flow is not answered . We tend to believe that protruding endothelial cells are either a transitory phenomenon in vascular growth or a fixation artifact. In perfusion fixation at physiologic pressure all small vessels show an open lumen, and they are in close connection with the surrounding myocardial cells (Fig . 1) . In immersion fixation the configuration of the vessels depends (1) on the contractile state of the heart (that is, there are more open vessels in relaxed than in strongly contracted myocardial tissue), and (2) on the
actual filling of these vessels at the time of fixation (Fig . 2 to 4) . A time lag in immersion fixation results in a very thin endothelial layer showing numerous blebs and pronounced vesiculation . The small vessels have usually lost contact with the surrounding myocardial cells in immersion fixed tissue . Because the course of most arterioles, capillaries and venules is parallel to the longitudinal axis of the muscle cells, only transversely cut sections reflect the true diameter and wall thickness and also the distribution of the capillaries, arterioles and venules within the myocardium . Although we believe that coronary blood flow is regulated by the resistance vessels, we do not exclude the possibility of a dual regulatory mechanism : one that controls overall blood flow according to myocardial oxygen consumption, and another that is responsible for "fine tuning" at the microcirculatory level . From studies by Lilbbers and his school^ it is quite evident that neither the classic Krogh's cylinder model nor a countercurrent oxygen supply is present in the heart but rather a network of capillaries in which the direction of flow varies almost continually . This strongly suggests a microcirculatory regulation that does not affect the overall level of organ perfusion .
FIGURE 2 . Capillary after immersion fixation in glutaraldehyde . The vessel is compressed by the contracted myocardial cells . Note the close proximity to the surrounding myocardium (X30,000, reduced by 30 percent .)
FIGURE 3 . Capillary after immersion fixation . The vessel is partly open and it is somewhat distant from the myocardial cells . Next to the vessel lies a satellite cell showing a very long extension (X9,000, reduced by 27 percent .)
1 01 0
December 1977 The American Journal of CARDIOLOGY
Volume 40
EDITORIALS
The Mechanism of Vasomotion
In spite of the prevailing ignorance concerning which vascular structure regulates flow we can probably agree on the compromise that the regulating mechanism acts on rather small vessels . However, the nature of this mechanism is in itself a controversial issue . The excellent correlations between myocardial oxygen consumption and coronary blood flow and between the generation and maintenance of left ventricular pressure suggest a link between the elementary energy-transducing process at the level of the sarcomere on the one hand and small vessel tone on the other . Because these correlations hold for the isolated blood-perfused heart as well as for the isolated heart perfused with salt solutions containing glucose and pyruvate, the regulation of coronary blood flow appears to he totally dominated by myocardial metabolism . Although Feigl showed that sympathetic stimulation produces coronary vasoconstriction5 and that parasympathetic stimulation produces vasodilatation, 6 these responses occur under physiologic conditions masked by the overriding effects on cardiac metabolism . It is not known whether autonomic influences can, under pathologic conditions, override the metabolic regulation . The link between myocardial metabolism and small vessel tone is also not firmly established . A comprehensive theory by Berne 7
4
_. Z*
- -_ .
FIGURE 4 . A small arteriole after immersion fixation shows a partly occluded lumen with a bulging endothelial nucleus (X13,800, reduced by 32 percent .)
states that the link between cardiac metabolism and vascular tone is established by adenosine . Adenosine is a good candidate for a regulatory transmitter for three reasons : (1) It is a potent coronary vasodilator ; (2) it is a breakdown product of adenosine triphosphate (ATP) ; and (3) it can leave the myocardial cell and can thereby act on small neighboring blood vessels. The difficulties with this theory are severalfold : It is unlikely that physiologic regulation of flow necessitates breakdown of ATP to adenosine at the level of the sarcomere or of the mitochondria because adenosine is likely to be destroyed during the passage through the cytosol owing to the presence of the inactivating enzyme adenosine deaminase. If the adenosine stems from a sarcolemmal ATP compartment this obstacle is bypassed but there is no longer a direct link between the generation of force and vascular tone . Kiiblers and Olssons postulated that adenosine, which does rapidly accumulate at the onset of ischemia, may stem from cyclic adenosine monophosphate (AMP), and Schaper et al . 10 described a perivascular "satellite-cell" that is biochemically equipped to produce adenosine . This satellite cell also possesses long extensions that protrude deep between myocardial cells and that may function as samplers of oxygen availability. These latter two hypotheses are still firmly based on Berne's hypothesis7; they differ only slightly as to the origin of the vasodilating adenosine. Arguments against the adenosine hypothesis are that adenosine cannot be formed in the presence of ATP and adenosine diphosphate (ADP) . which inhibit the enzyme 5' nucleotidase . The argument is not entirely conclusive because the sarcolemmal ATP or cyclic AMP concentration may be below the inhibiting concentration . The fact that aminophylline and caffeine and its derivatives block the action of exogenous adenosine cannot be used as evidence that endogenous adenosine is not responsible for regulation of coronary flow. Recently a more "modern" class of chemicals, the prostaglandins, has been discussed as a possible regulator of coronary blood flow, but conclusive evidence is missing . Our continual hope that the currently fashionable class of compounds will solve our problems is a very strong reflection of our ignorance . Conclusions : Summarizing, we confess that we do not know with absolute certainty which type of vascular structure regulates coronary blood flow. Equally vague is our knowledge regarding the coupling between myocardial metabolism and coronary blood flow as well as the mechanism of smooth muscle relaxation . We tend to believe that two vascular structures are responsible for the regulation of blood flow : Arterioles probably regulate overall blood flow, and precapillary and perhaps also capillary structures are probably responsible for the efficient distribution of blood flow on the microcirculatory level . The close correlation between myocardial metabolism and coronary blood flow is very suggestive for a metabolite of energy transduction . Adenosine, after all, is not a bad candidate .
December 1977
The American Journal of CARDIOLOGY
Volume 40
1 01 1
EDITORIALS
References 1 . Short L, Ben-Shaul Y, Lieberman Y, et al : The human coronary microcirculation : an electron microscopic study. Am J Cardiol 39 :599-608, 1977 2 . Honig CR : Control of smooth muscle actomyosin by phosphate and by VAMP : possible role in metabolic autoregulation . Microvasc Res 1 :133-146, 1968 3 . Tillmans H, Ideda S, Hansen H, et al : Microcirculation in the ventricle of the dog and turtle . Circ Res 34:561-569, 1974 4 . Lubber$ DW: Die Bedeutung des Sauerstoffdruckes fur die O r Versorgung des normalen and insuffizienten Herzens . In, Heart Failure : Pathophysiological and Clinical Aspects (Reindell H, Keul J, Doll E, ad) . Stuttgart, Thieme-Verlag, 1968, p 287 5 . Feigl ED : Control of myocardial oxygen tension by sympathetic coronary vasoconstriction in the dog . Circ Res 37 :88-95, 1975
1 01 2
December 1977
The American Journal of CARDIOLOGY
6 . Feigf ED: Reflex parasympathetic coronary vasodilatation elicited from cardiac receptors in the dog . Circ Res 37 :175-182, 1975 7 . Bane R: Cardiac nucleotides in hypoxia : possible role in regulation of coronary blood flow. Am J Physiol 204 :317-322, 1963 8 . Kubler W, Spieckermann PG, Bretschneider HJ : Influence of dipyridamol (Persantin) on myocardial adenosine metabolism . J M01 Cell Cardiol 1 :23-38, 1970 9 . Olsson RA : Changes in content of purine nucleoside in canine myocardium during coronary occlusion . Circ Res 28 :301-306, 1970 10 . Borgers M, Schaper J, Schaper W : Adenosine-producing sites in the mammalian heart : a cytochemical study . J Mol Cell Cardiol 3 :287-296, 1971
Volume 40