BLOOD SUPPLY TO THE HEART 



1 545 



oxygen content was varied from 18 vol per cent down 

 to 2 vol per cent by dilution with Ringer-Lockc\ 

 solution, the coronary flow increased although the 

 intravascular oxygen tension at the level of the 

 arterioles was kept constant (164). 



metabolites. The mechanism whereby hypoxia 

 operates to increase coronary flow remains obscure. 

 Presumably, metabolites accumulate but their nature 

 and possible effectiveness are unknown. Experiments 

 dealing with this problem in which an extracorporeal 

 circulation of blood is used must be cautiously evalu- 

 ated. Dog blood contains potent vasoconstrictor and 

 vasodilator substances. The red cells, especially, 

 contain a potent vasodilator substance (adenosine 

 triphosphate). This and other substances are readily- 

 made active by hemolysis resulting from minute 

 mechanical trauma and agitation (60). In the heart- 

 lung preparation, coronary flow generally progres- 

 sively increases as the experiment continues, and 

 substances accumulating in the coronary venous 

 blood were originally thought to cause vasodilatation 

 when reinfused into the coronary arteries (17). 

 Hilton & Eicholtz (182), however, could not confirm 

 this in the isolated heart, for replacement of the blood 

 that had circulated for some time by fresh defibrinated 

 blood did not significantly alter flow. 



It is not clear whether or not vasodilator substances 

 exist in the coronary sinus blood of the heart beating 

 within the chest in sufficient concentration to alter 

 coronary blood flow. In recent experiments, blood 

 draining normal, hypoxic, or overperfused (perfusion 

 pressure considerably greater than aortic pressure) 

 hearts has been oxygenated in a dog lung or on a 

 screen and perfused at a controlled pressure through a 

 rotameter into a test coronary artery of the same or 

 second dog, or unoxygenated coronary sinus blood 

 has been perfused into an isolated beating frog heart. 

 These experiments have failed to demonstrate sub- 

 stances having vasoactive, inotropic, or chronotropic 

 properties in the coronary sinus blood (193). On the 

 other hand, injection of coronary sinus blood obtained 

 during cardiac sympathetic nerve stimulation causes 

 a moderate coronary dilatation at the same blood 

 pressure and heart rate (277). 



Intracoronary injection of intermediate metabolites 

 will increase coronary blood flow. Histamine, metabo- 

 lites such as adenosine, adenylic acid, and breakdown 

 products of nucleic acids increase coronary flow in 

 the perfused heart, the human heart-lung preparation 

 and heart in situ (10, 277). However, it has never been 

 demonstrated that the concentration of these sub- 



stances increases within the myocardium during 

 anoxia or increased effort of the heart. Studies on 

 relative coronary vasodilator potency show that 

 adenine is relatively inactive, while adenosine tri- 

 phosphate and adenosine diphosphate have approxi- 

 mately four times the potency of adenosine mono- 

 phosphate, adenosine, and uridine triphosphate 

 (406, 407). In addition to vasodilator properties, 

 some of the purine and pyrimidine derivatives have 

 been demonstrated to have positive inotropic action 

 in the normal and failing heart (52). It is not sur- 

 prising, therefore, that in the open-chest dog with 

 constant pressure perfusion of the coronary arteries, 

 some of these substances (ATP and UTP) with 

 inotropic and vasodilator properties also increase the 

 myocardial oxygen consumption (407). However, 

 since the elevation in coronary blood flow is greater 

 than that necessary to meet the increased oxygen 

 demand, i.e., the coronary A-V oxygen is decreased 

 considerably, the action of such compounds is prob- 

 ably largely on the coronary vessels, and only second- 

 arily on metabolic rate. 



Although it has not been possible to demonstrate 

 in the coronary sinus blood substances having vasoac- 

 tive, chronotropic, or inotropic properties, this does 

 not necessarily rule out an active role of metabolites 

 in regulating coronary flow. As pointed out by Berne 

 (28), although adenosine and adenine nucleotides are 

 not recoverable in the coronary sinus, derivatives of 

 adenosine such as inosine and hypoxanthine appear 

 in the coronary sinus blood during periods of myo- 

 cardial hypoxia, and vasoactive concentrations of 

 adenosine added to coronary arterial blood are re- 

 coverable in the coronary sinus only as inosine and 

 hypoxanthine. Thus, the possibility should be enter- 

 tained that in hypoxia, myocardial nucleotides give 

 rise to adenosine which diffuses out of cardiac cells, 

 induces vasodilatation, but is deaminated and split 

 before separation from the blood can be effected. 



acidosis and alkalosis. In the isolated heart or heart- 

 lung preparation, acidosis induced by administering 

 C0 2 or lactic acid dilates the coronary blood vessels, 

 for coronary flow may increase ( 1 82 ) despite a marked 

 reduction in the rate, output, arterial blood pressure, 

 and contractile force of the myocardium (273). In an 

 intact preparation in the presence of severe respiratory 

 acidosis (from C0 2 administration), or a fixed acidosis 

 (from infusion of HC1 solution), coronary flow in- 

 creases (114), remains constant (134), or decreases 

 (go, 147), while systemic dynamics (blood pressure, 

 heart rate, and cardiac output) are not largely 



