BLOOD SUPPLY TO THE HEART 



1561 



primary or empirical must await the necessary 

 measurements under normal conditions of stress 

 without anesthesia or surgical insult. 



DRUGS VERSUS THE CORONARY CIRCULATION 



The pertinent literature has been reviewed (7, 13, 

 49- 68 . 145. '53. 209, 238, 275, 384, 413). Con- 

 sideration will be given here only to the effects of a 

 few selected drugs on the coronary circulation in the 

 normal state and in the presence of coronary artery 

 disease. 



Drugs may be effective in altering the normal and 

 collateral myocardial blood supply by a direct effect 

 on the vasomotor state of the vessels, by an increase 

 or decrease in central blood pressure, by myocardial 

 stimulation or depression, by a change in the cardiac 

 workload through extracardiac phenomena, or by 

 electrolyte, pH or gaseous alterations of the blood 

 perfusing the coronary bed. It is interesting to know 

 whether a drug affects the extravascular and intra- 

 vascular resistances of the coronary bed, but it is 

 more important to know its effect upon the supply of 

 oxygen to the myocardium, the oxygen used by the 

 myocardium, and the efficiency of the heart in the 

 use of its oxygen for the work performed. In addition, 

 a pharmacological agent may be able to improve the 

 oxygen utilization for external work of the heart 

 without an increase in coronary blood flow or oxygen 

 extraction. 



In order to properly evaluate an agent, the follow- 

 ing information is necessary: a) coronary blood flow, 

 b) arteriovenous oxygen difference across the coronary 

 bed, c) blood pressure, d) cardiac output, e) myo- 

 cardial contractility, and /) heart rate. From these 

 data, the myocardial oxygen availability and usage, 

 cardiac work and efficiency can be calculated. 



Few drugs have been completely studied. The 

 pharmacologic agents will be considered from the 

 standpoint of: a) the effects of therapeutic or poten- 

 tially therapeutic drugs on the normal myocardium 

 undergoing normal or excessive stress, and b) the 

 effects of nontherapeutic drugs on the normally 

 stressed myocardium. In the normal and hyper- 

 tensive heart, the ganglionic blockers such as hexa- 

 methonium decrease both cardiac work and myo- 

 cardial oxygen availability but not the oxygen usage 

 (73, 162). Nitroglycerin has no apparent direct effect 

 on the amount of free energy released with each 

 contraction of the myocardium either before or after 

 partial coronary artery occlusion, but rather reduces 



hemodynamic workload by a decrease in left atrial 

 filling pressure (75). Experiments in dogs with 

 sodium nitrite or nitroglycerin injected into the left 

 coronary artery show that the coronary arteries and 

 their small branches dilate (fig. 13) (393), and that 

 the flow increases greatly in both systole and diastole 

 and in the presence of a decreased central coronary 

 pressure, cardiac output, cardiac work, a constant 

 heart rate and only a slight decrease in the systolic: 

 diastolic ratio. Hence, the conclusion is inescapable 

 that these drugs exert a vasodilating action on the 

 coronary vessels (41). This could arise from a direct 

 effect of the drug on the coronary vessels since cardiac 

 metabolism is not increased (decreased coronary 

 A-V oxygen difference and increased coronary flow) 

 (94, 333). Experiments in normal man with nitro- 

 glycerin, however, show an increased coronary blood 

 flow with an increased myocardial oxygen uptake 

 (constant coronary A-V oxygen difference and 

 increased coronary flow), decreased cardiac work and 

 decreased cardiac efficiency (42). Furthermore, in 

 patients with coronary artery disease, this drug does 

 not increase coronary flow while, with a steady 

 oxygen extraction, it decreases cardiac work (de- 

 creased blood pressure and cardiac output) (138). 

 These data raise the old question of the applicability 

 of knowledge obtained in normal animal or human 

 studies to the diseased states. If these studies should 

 be confirmed in patients during anginal attacks, other 

 theories for the action of nitroglycerin must be con- 

 sidered. One theory holds that nitroglycerin blocks 

 the anoxia-inducing effect of the catecholamines on 

 the heart (296), but an antiadrenergic action could 

 not be demonstrated for this drug (94). One might 

 postulate that a decrease in cardiac work secondary 

 to the decrease in blood pressure, in the presence of a 

 stable oxygen consumption, may be helpful to the 

 myocardium despite a calculated decrease in myo- 

 cardial efficiency. Present calculations include only- 

 evaluation of the external efficiency of the heart. If 

 such hearts are using all the oxygen they could 

 extract at a given workload, then a decrease in this 

 work, at the same level of oxygen consumption, might 

 be beneficial. 



With the xanthines mean coronary flow is increased, 

 this being the net result of a marked increase during 

 diastole and a decrease during systole which occurs 

 in the presence of a normal or mildly decreased blood 

 pressure and without significant change in cycle 

 length or systolic: diastolic ratio. Visually, the heart 

 shows increased vigor and its metabolism and work 

 are increased (41). Nikethamide acts similarly by 



