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Effect of Nitroglycerin and Dipyridamole on Regional Left Ventricular Blood Flow During Coronary Artery Occlusion

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Effect of Nitroglycerin and Dipyridamole on Regional Left Ventricular Blood Flow During Coronary Artery Occlusion Effect of Nitroglycerin and Dipyridamole on Regional Left Ventricular Blood Flow during Coronary Artery Occlusion LEWIS C. BECKER From the Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514 and Johns Hopkins University School of Medicine, Department of Medicine, Baltimore, Maryland 21205 A B S T R A C T Coronary vasodilators have been vari- INTRODUCTION or have no effect ously reported to increase, decrease, Coronary vasodilators increase myocardial blood flow upon blood flow to ischemic myocardium. Conse- in hearts with normal coronary arteries and may also quently, the effects of two different types of dilators, increase flow when coronary artery occlusive disease nitroglycerin (TNG) and dipyridamole, were studied is present (1). However, in the latter situation, in- with radioactive microspheres in open-chested dogs be to after coronary artery ligation. Given as a bolus i.v. creased flow may merely going myocardial injection, 0.4 mg TNG resulted in an increase in regions fed by normal vessels rather than areas sup- blood flow to nonischemic areas of myocardium and a plied by obstructed vessels. While some investigators preservation of flow to ischemic regions, despite a fall have found that vasodilators increase flow to com- blood pressure and promised myocardium (2-8), others have found a de- in blood pressure. 5 min later crease or no change (9-14). Fam and McGregor (11) nonischemic flow were back to base line, and a small be re- selective increase in flow to ischemic myocardium have pointed out that these discrepancies may per g, P < 0.05). During lated in part to differences in action among the various was found (0.15-0.18 ml/min coronary dilators. Nitrates (e.g. nitroglycerin), which an 0.2 mg/min infusion of TNG, and also after 1 mg/kg effect mainly large epicardial conductive arteries, may i.v. dipyridamole, ischemic flow was maintained in while non- the face of a 20-30%o reduction in blood pressure. selectively increase flow to ischemic areas, In this setting, nonischemic flow was unchanged nitrate dilators (e.g. dipyridamole), which affect pri- With marily small precapillary resistance vessels, may de- during TNG and doubled after dipyridamole. crease flow in areas of myocardial ischemia by dilating the addition of methoxamine in both dilator groups, arterioles in nonischemic areas ("coronary steal"). blood pressure retumed to base line while flow to The purpose of this paper was to study in more ischemic areas increased above base-line values (TNG, of vasodilators on left ven- 0.16-0.20 ml/min per g, P < 0.01; dipyridamole, 0.18- detail the effects cornary 0.31 ml/min per g, P < 0.05). Epicardial ST segment tricular blood flow distribution during regional myo- elevations increased during TNG infusion and were cardial ischemia. Radioactive microspheres were used unchanged after dipyridamole, but with addition of to separate subendocardial and subepicardial flows methoxamine, ST segments became less elevated in in ischemic and normal regions. Measurements were both drug groups, concomitant with the observed in- made during drug-induced hypotension and repeated crease in collateral blood flow. These data indicate after blood pressure had been returned to base line thaA both types of coronary vasodilators, when used with the alpha-adrenergic agonist methoxamine. in conjunction with methoxamine to support blood pressure, reduce collateral resistance, increase collat- METHODS eral flow, and reduce epicardial ST-segment ele- 30 mongrel dogs weighing 16-25 kg were anesthetized with vations. sodium pentothal, 25 mg/kg, followed by 0.4 cm3/kg of mixture containing 10 g alphachloralose in 100 cm3 polyethylene glycol 400. Supplemental doses of the chloralose mixture were given as necessary. Respiration with room air was Received for publication 27 May 1976 and in revised form maintained by Harvard pump (Harvard Apparatus Co., Inc., 25 August 1976. Millis, Mass.) and cuffed endotracheal tube. The heart was The Journal of Clinical Investigation Volume 58 December 1976 *1287-1296 1287 exposed through a left thoracotomy. Aortic and left atrial was vigorously agitated on a mechanical mixer for 1-2 min. pressures and heart rate were monitored continuously. Blood was simultaneously withdrawn from brachial and Cardiac output was measured by indocyanine green dilu- femoral arteries with a Harvard pump (Harvard Apparatus tion with left atrial injection (2 mg dve), femoral artery Co., Inc.) at 1.4 cm3/min for 3 min, beginning just before sampling (Gilford densitometer, 43 ml/min, Gilford Instru- microsphere injection. These collections were used to quanti- ments Laboratories, Inc., Berlin, Ohio), and a dynamic tate myocardial flow as described below. calibration technique (15). Calibration and experimental In a group of 10 dogs, 0.4 mg nitroglycerin in 5 ml saline curves were adjusted to approximately the same height. was then given rapidly i.v. The nitroglycerin solution was In five dogs an insulated wire was sutured to left atrial prepared bv dissolving a crushed sublingual tablet in saline. appendage for pacing. With limited dissection, ligatures At the peak of hypotension, about 30 s after nitroglycerin, were passed around the anterior descending cornarv artery 1-2 million microspheres labeled with a second nuelide, (LAD)' or most of its major branches. 141Ce (15 ,um), were injected into the left atrium and ref- Regional left ventricular blood flow was measured with erence blood samples collected. Although a true steady state radioactive microspheres. The method is based on the princi- was not present, it is likelv that most of the microspheres ple that microspheres injected into the left atrium distribute reached mvocardial and reference sites within the first systemically in proportion to blood flow and because of their 30 s while the blood pressure remained reduced (18). size are trapped in precapillarv arterioles in their first 5 min after nitroglycerin, when systemic hemodvnamic passage through the circulation. The number of particles changes had disappeared, a third set of microspheres iabeled in any region of myocardium, reflected bv the radioactivity, is with 85Sr was given. proportional to flow. The microspheres used were mainly In another group of eight dogs, nitroglycerin was given as 15+5 ,um in diameter, obtained from the 3M Co. (Minneapolis, an i.v. infusion. 1 h after ligation, after control injection of Minn.) as 1 mCi of nuclide suspended in 10 cm3 of 10% 169Yb microspheres, 0.4 mg nitroglycerin was given rapidly dextran with one drop of Tween 80 to minimize clumping. i.v. and a constant infusion of 0.2 mg in 5 cm3 saline/min They were labeled with one of the gamma-emitting nu- started with an infusion pump (Sigmamotor, Inc., Middleport, clides 169Yb, 14'Ce, or 85Sr. In some experiments, spheres N. Y.). 10 min later microspheres labeled with 141Ce (15 of 8-10 um diameter labeled with 14'Ce, 5'Cr, or 46Sc gm) were given. While continuing nitroglycerin, an i.v. drip were used (described below). Slightly higher ratios of inner of methoxamine hydrochloride (20 mg in 1,000 cm3 saline) wall to outer wall radioactivity have been found with 15 ,um was begun and titrated to bring the mean aortic blood pres- spheres than with 8-10 Am spheres or diffusible indicators sure back to its prenitroglycerin level. This usually took (16). However, the differences have been small, and all of 5-10 min. Microspheres labeled with 85Sr were then given. these tracers appear to measure full thickness flows and In another group of seven dogs the effects of the non- directional flow changes equally well (16). nitrate coronarv vasodilator dipyridamole were studied. The extent and degree of myocardial ischemia was esti- 1 h after coronarv ligation 169Yb microspheres were injected. mated from ST-segment elevation in epicardial electrocardio- 1 mg/kg dipyridamole was then given as an i.v. bolus and grams (17). These were recorded at 10-15 sites on the anterior flow was measured 10 min later with 14'Ce (15 ,tm) spheres. left ventricular surface at vessel bifurcations to allow easy The duration of action of a single i.v. bolus of dipyridamole relocation. A 0.01-inch diameter, insulated, braided stainless has been shown to be greater than 15 min (19). The drtug steel wire was attached to the V lead of a standard electro- was obtained in ampules of 2 cm3 containing 10 mg dipyrida- cardiograph. A 1-mm loop in the end was held manually mole, 4 mg tartaric acid, and 100 mg polvethylene glvcol against the epicardial surface with just enough pressure to 600 (Boehringer-Ingelheim, Ltd., Elmsford, N. Y.). After ad- produce minimal distortion in the wire. Elevation of the ST justment of mean aortic blood pressure to the predrug level segment was measured from the base line to a point on the with i.v. methoxamine, flow was again measured with 85Sr ST segment 0.10 s after the onset of ventricular activation spheres (approximately 10 min after 141Ce spheres). at a standardization of 1 mV/mm. Recordings were made at In an additional group of dogs the effects of nitroglvc- each site before comary artery ligation and just after each erin and dipyridamole were studied at constant heart rate microsphere injection. The ST-segment deviation present and mean aortic pressure. Flow was measured after 60 before ligation was subtracted from that present afterwards min of ischemiiia with 7-10 ,um 1'4Ce microspheres and epi- to determine the change due to ischemia. Sites with more than cardial electrocardiograms recorded. Three dogs were given 2 mV ST elevation before coronary occlusion were seen nitroglycerin 0.4 mg followed bv an infusion of 0.2 mg in occasionally (usually related to coronary artery manipulation) 5 cm3 saline/min; two other dogs received a single i.v.
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