BLOOD SUPPLY TO THE HEART 



1563 



It would appear that our concepts of the "ideal" 

 agent for coronary artery disease must be revised. 



Information is confusing regarding the coronary 

 effects of khellin, a drug used in the eastern Medi- 

 terranean regions since ancient times in renal colic 

 and ureteral spasm. Interest in its possible cardiac 

 effect arose as the result of the discovery that, orally 

 or intravenously, it acts for many hours as an ex- 

 tremely potent coronary vasodilator in the heart-lung 

 preparation and in the heart in situ. In the doses 

 used, it has no effect on the general blood pressure 

 and does not increase the oxygen requirements of 

 the heart, i.e., it acts only to relax the intrinsic smooth 

 muscle of the coronary arterioles (153). However, 

 others (109) did not find it effective on the coronary 

 or systemic circulation of the anesthetized dog. 



There is little doubt that digitalis augments 

 ventricular contractility and the peripheral circulation 

 (48, 314). However, in normal human subjects, 

 strophanthus apparently has a deleterious effect 

 since it decreases cardiac work and efficiency without 

 altering coronary flow, oxygen supply, or usage of 

 the myocardium (31). Conversely, in the patient with 

 congestive heart failure, it has a salutary effect by 

 acting to increase cardiac work and efficiency without 

 using more oxygen or altering the coronary circula- 

 tion. This is another case in which the action of a 

 drug is entirely different in the normal subject from 

 what it is in the diseased subject. 



Ever since Favarger (110), in 1887, claimed that 

 excessive tobacco smoking produced coronary vaso- 

 constriction which, repeated over many years, 

 gradually resulted in organic heart disease, tobacco 

 has been considered an important cause of coronary 

 disease. The alterations of the ECG (T-wave depres- 

 sion and sagging of the S-T segment) and of the BCG 

 in the normal heart, or the heart with coronary 

 arterial disease, that follow inhalation of tobacco 

 smoke or administration of nicotine, have been 

 generally thought to result either from coronary- 

 arterial constriction or from an increase in the work 

 of the heart beyond the capacity of the coronary 

 arteries to supply the necessary metabolic require- 

 ments of the myocardium. Observations on the 

 normal heart of the anesthetized dog do not support 

 this view. Intracoronary nicotine injection greatly 

 increases myocardial contractility, and in dogs pre- 

 treated with Dopa, nicotine increases considerably 

 the myocardial catecholamine concentration (202). 

 The circulatory responses to administration of 

 cigarette smoke or nicotine generally include elevation 

 of heart rate, blood pressure, cardiac output, cardiac 



work, left coronary flow, myocardial oxygen usage, 

 and a decrease in coronary vascular resistance. The 

 coronary oxygen extraction may be decreased, and 

 often the oxygen usage may be transiently unchanged 

 or decreased (213). These responses can all be blocked 

 by injection of tetraethylammonium chloride. These 

 effects parallel those observed with epinephrine 

 injection and are presumably related to its release. 

 The response to nicotine of the coronary flow, in dogs 

 with coronary insufficiency from coronary arterial 

 ligation or gradual coronary artery narrowing, is 

 considerably less than in dogs with normal coronary 

 arteries (20); in the isolated atherosclerotic rabbit 

 heart, it decreases coronary flow (364). In normal 

 man, earlier findings indicate that cigarette smoking 

 increases coronary blood flow and heart rate, and 

 decreases coronary vascular resistance in the presence 

 of reduced systemic dynamics, whereas in patients 

 with coronary artery disease, smoking causes no 

 appreciable change in coronary flow and myocardial 

 oxygen consumption in the presence of increased 

 heart rate, blood pressure, cardiac output, and cardiac 

 work (304). This suggests that the electrocardio- 

 graphic changes observed during smoking are the 

 result of a relatively deficient oxygen supply to the 

 myocardium in the presence of increased oxygen 

 needs (increased cardiac work). Later reports from 

 the same laboratory indicate, in subjects both normal 

 and with coronary artery disease, that smoking 

 increases heart rate, blood pressure, and left ventricu- 

 lar work but does not alter coronary flow or cardiac 

 oxygen usage (306). Decision as to the action of 

 smoking and nicotine in human subjects must be 

 deferred until the various neurohumoral responses 

 evoked are better understood and better methodology 

 is available. 



Certain agents which increase coronary blood flow 

 will not be discussed because of the scant information 

 available. Isoproterenol, histamine, antihistamines, 

 heparin, Dicumarol, ethanol, 5-hydroxytryptamine, 

 Amplivix, and RA-8 increase coronary flow in animal 

 preparations (62, 200, 224, 238, 299, 384). Reports 

 are conflicting regarding Metrazol, quinidine, 

 quinine, and morphine (299, 318, 384). Only two 

 drugs, Pitressin and angiotensin, decrease coronary 

 blood flow without a decrease in central blood 

 pressure (150). 



For clinical use in angina pectoris, drugs are 

 evaluated in patients by methods involving their 

 ability to alter the electrocardiographic response to 

 an exercise test or by drug-placebo (double blind) 

 studies (70, 157). The selection of patients for these 



