CORONARY FLOW RESERVE Intracoronary papaverine : an ideal coronary vasodilator for studies of the coronary circulation in conscious humans

An ideal coronary vasodilator for studying coronary flow reserve in humans would rapidly produce maximal coronary vasodilation, be short acting to permit repeated measurements, and not alter systemic hemodynamics. The two commonly used vasodilators (dipyridamole and meglumine diatrizoate) do not satisfy these criteria; meglumine diatrizoate does not produce maximal hyperemia and dipyridamole has a long duration of effect (greater than 30 min). In this study we used a subselective coronary Doppler catheter to measure the dose-response kinetics of a shorter acting vasodilator, intracoronary papaverine. In 10 patients with normal coronary vessels, the maximal vasodilator response to papaverine was compared with that to intravenous dipyridamole (0.56 mg/kg infused over 4 min) and intracoronary meglumine diatrizoate. The increase in coronary blood flow velocity after the maximal dose of papaverine (4.8 ± 0.4 peak/resting velocity ratio, mean ± SEM) was nearly identical to that seen after infusion of dipyridamole (4.8 + 0.6) and was significantly greater than that after meglumine diatrizoate (3.1 ± 0.2, p < .01). At maximal hyperemia, mean arterial blood pressure fell 9 + 2% (mean + SEM) after intracoronary papaverine, 8 + 4% after dipyridamole, and 3 + 3% after meglumine diatrizoate. The dose-response kinetics of intracoronary papaverine were studied in 13 patients with normal coronary arteries. In the left coronary artery, maximal vasodilation (5.4 ± 0.6) was achieved with 8 mg in six of eight patients and with 12 mg in all patients. In the right coronary artery, maximal vasodilation (4.8 ± 0.7) was achieved with 6 mg in four or five patients and with 8 mg in all patients. Onset of maximal vasodilation was rapid after papaverine (16 + 1 sec) and meglumine diatrizoate (15 ± 1), but prolonged after dipyridamole (4.8 ± 0.4 min after onset of infusion). The duration of maximal vasodilation was brief after papaverine (49 + 10 sec) and meglumine diatrizoate (8 ± 1 sec), but prolonged after dipyridamole (greater than 4 min). Coronary blood flow velocity returned to within 10% of resting values quickly after papaverine (128 ± 15 sec) and meglumine diatrizoate (42 ± 4 sec). After dipyridamole infusion, however, coronary blood flow velocity remained elevated for greater than 4 min after completion of infusion. These results suggest that papaverine can produce intense, rapid-acting vasodilation of the coronary arteriolar bed equivalent to that stimulated by intravenous dipyridamole without markedly altering systemic arterial pressure. Although the extent and duration of vasodilation was dose dependent, the hyperemic period in all patients was sufficiently brief to allow multiple measurements of coronary reserve over a short period of time. The use of intracoronary papaverine to measure the maximal flow reserve capacity of individual coronary vessels should greatly facilitate studies of the coronary circulation in patients undergoing cardiac catheterization Circulation 73, No. 3, 444-451, 1986. From the Cardiovascular Center and Department of Internal MediPRECISE, repeated measurements of the vasodilator cine, University of Iowa, and the Veterans Administration Hospital, Iowa City. reserve capacity individual coronary vessels in the Supported by grants from the National Heart, Lung, and Blood Insticatheterization laboratory have been hampered by lack tute (HL27633, 14388, and 29976), the Ischemic SCOR (HL3229501), and the Veterans Administration (MRIS 1100.2). This work was of a standardized and easily applicable technique of done during the tenure of a Clinician-Scientist Award from the Amenrproducing maximal coronary vasodilation. An ideal can Heart Association and with funds contributed in part by the Iowa method would rapidly produce maximal coronary vaAffiliate. Address for correspondence: Robert F. Wilson M.D., Cardiovascular sodilation, be short acting to allow multiple measureDivision, Department of Internal Medicine, University of Iowa Hospiments during a single study, and not significantly alter tals and Clinics, Iowa City, IA 52240. Received Sept. 27, 1985; revision accepted Nov. 22, 1985. systemic hemodynamics. 444 CIRCULATION by gest on A uust 7, 2017 http://ciajournals.org/ D ow nladed from DIAGNOSTIC METHODS-CORONARY FLOW RESERVE Many techniques for producing coronary vasodilation in conscious humans have been reported. Intravenous infusion of dipyridamole produces near-maximal coronary vasodilation, but its prolonged effects preclude multiple measurements of coronary vasodilator reserve during a single catheterization. 1A As a consequence, multiple measurements of coronary vasodilator reserve in a single vessel after an intervention such as coronary angioplasty cannot be obtained. Furthermore, sequential measurements of basal and maximally stimulated coronary flow in multiple vessels cannot be performed with dipyridamole. Although intracoronary injection of iodinated contrast media produces brief coronary hyperemia, this stimulus does not cause maximal coronary vasodilation.5 ` Atrial pacing,8 9 isoproterenol infusion,'0 and intracoronary nitroglycerin" similarly produce brief but submaximal rises in coronary flow. Papaverine, an opiate derivative, has been known to produce marked vasodilation through direct relaxation of arteriolar smooth muscle. Although its effect is not specific for the coronary bed, intracoronary administration of papaverine in animals suggests that it may be an attractive coronary vasodilator: its effects are short acting and it produces near maximal decreases in coronary vascular resistance.'2' 13 Furthermore, papaverine administered by the intracoronary route is associated with only minimal changes in systemic blood pressure and heart rate. In previous clinical studies, selective intracoronary injection of papaverine or injection into a coronary bypass graft has appeared to produce only submaximal increases in coronary flow (1.5 to 2.4 increase in resting flow). 1l2l These studies, however, were hampered by methodologic limitations. The techniques used to measure vasodilator reserve after papaverine in these clinical studies (briefly placed electromagnetic flowmeters and xenon 133 washout) have well-known technical limitations that may have been responsible for the submaximal flows observed. Moreover, most studies were done intraoperatively immediately after cardiopulmonary bypass a time when coronary hemodynamics are markedly altered.22 In addition, the dose of papaverine used varied greatly among studies and no dose-response curves obtained in humans have been reported. Thus, discrepancies between the extent of vasodilation observed in carefully controlled animal studies and clinical studies may have resulted from the effects of cardiopulmonary bypass, submaximal doses of intracoronary papaverine, and/or methodologic problems in measuring coronary blood flow. The recent development and validation of a small intracoronary Doppler catheter has enabled selective measurements of instantaneous coronary blood flow velocity in multiple coronary arteries of awake patients undergoing cardiac catheterization?23 The purpose of this study was to assess the dose-response kinetics of intracoronary papaverine and to compare the maximal vasodilative response after papaverine to measurements of coronary vasodilator reserve with two widely used coronary vasodilators, meglumine diatrizoate (Renografin 76) and intravenous dipyridamole.