Pentoxifyffine (Trental) Does Not Inhibit Dipyridamole-Induced Coronary Hyperemia: Implications for Dipyridamole-Thaffium-20 1 Myocardial Imaging

Kenneth A. Brown and Bryan K. Slinker

Cardiology Unit ofihe University of Vermont College ofMedicine, Burlington, Vermont

been found to be efficacious in the treatment of inter Dipyndamole-thallium-201imagingis often performedin mittent claudication because of its unique hemorrheo patientsunableto exercisebecauseof peripheralvascular logic effects (9). Thus, many patients with peripheral disease.Manyof these patientsare taking pentoxifylline vascular disease who undergo dipyridamole-thallium (Trental),a methylxanthinederivativewhichmayimprove 201 imaging may be taking pentoxifylline at the time intermittent claudication. Whether pentoxifylline inhibits di of their study. Although in vitro data from rat fat cells pyndamole-inducedcoronaryhyperamialike other math and hippocampal slices suggest that pentoxifylline is a ylxanthinas such as theophyllina and should be stopped much weaker adenosine antagonist than theophylline prior to dipyndamole-thallium-201 imaging is unknown. (7), it is not known whetherpentoxifylline significantly Therefore,we studiedthe hyperemicresponseto dipyn damolein sevenopen-chestanesthetizeddogs after pre inhibits dipyridamole-induced coronary hyperemia in treatmentwith either pantoxifylline(0, 7.5, or i 5 mg/kg vivo and should, therefore, be stopped prior to dipyri i.v.) or theophyllina(3 mg/kg i.v.). Baseline circumflex damole-thallium-20l imaging. Hence, we studied the coronary blood flows did not differ significantly among coronary hyperemic response to dipyridamole in open treatmentgroups.Dipyndamolesignificantlyincreasedcor chest anesthetized dogs in the control state and after onary blood flow before and after 7.5 or 15 mm/kg i.v. pretreatment with pentoxifylline. pantoxifylline (p < 0.002). Neither dose of pantoxifylline significantlydecreasedthe dipyndamole-inducedhypere MATERIALS AND METHODS mia, while peak coronary blood flow was significantly lower after theophylline(p < 0.01).We concludethat pantoxyi Experimental Preparation fylline does not inhibit dipyndamole-induced coronary hy Wecollecteddata in sevenopen-chestrandom sourcedogs peramia even at high doses. of either sex (23—38kg; average weight 27 kg) anesthetized with 25 mg/kg intravenous(i.v.) sodium pentobarbitol 30 mm J NucI Med 1990; 31:1020—1024 after preanesthesia with 1 mg/kg subcutaneous morphine sulfate.The dogswereintubatedand ventilatedwithan initial tidal volume of 15 ml/kg and rate of 12 breaths/mm. Respi ratory rate and tidal volume were adjusted, and sodium bicar hallium-20l (201T1)myocardial perfusion imaging bonate was given, as necessary to maintain pCO2 = 35—45 mmHg, HCO3= 20-28 mmol/l, pH = 7.3-7.4, and arterial in combination with dipyridamole-induced coronary PO2 > 80 mmHg. hyperemia has a sensitivity and specificity for coronary We opened the chest with a median sternotomy, incised artery disease comparable to exercise 201Tlimaging (1), the pericardium, and suspended the heart in a pericardial and has been found to be particularly useful in patients cradle. We placed a perivascular electromagnetic flow probe with peripheral vascular disease who are unable to (Carolina Medical Electronics, King, NC) on the left circum exercise (1—3).Dipyridamole causes coronary hypere flexcoronary artery just distal to the bifurcation of the left mia indirectly via adenosine, and its actions are inhib main coronary artery. A snare of#0 silk was placed just distal ited by aminophylline or theophyffine, methylxanthines to the flow probe so that the vesselcould be occluded to which are potent adenosine antagonists (4—8).Pentox measure zero flow. At the beginning of the experiment and ifylline (Trental) is a methylxanthine derivative that has periodically throughout the protocol, the coronary artery was brieflyoccludedusingthe snare to measurea zero coronary flow signal. A 7F catheter-tip manometer (Millar Instruments, ReceivedOct. 11, 1989; revision accepted Jan. 9, 1990. Forrep.lntscontact:KennethA. Brown,MD,Cardiology(kilt, McClure Houston, TX) with a fluid-filled lumen was placed in the left 1, MediCalCanter Hospital of Vermont, Burlington, VT 0@401. ventricle (LV) via a femoral artery. Fluid-filled catheters were

1020 The Journalof NuclearMedicine•Vol. 31 •No. 6 •June1990 placed in the right atrium and ascending aorta via a jugular problems prevented collection of data during high-dose pen vein and carotid artery, respectively. All fluid-filled catheters toxifylline (15 mg/kg) and theophylline. were connected to Statham P23XL pressure transducers zer oed to a mid-chest reference level. The Millar signal was Data Analysis Left ventricular, right atrial and aortic pressures, surface periodically matched to the left ventricular fluid pressure to correct for drift in the pressure signals. Surface electrodes were lead II ECG, and phasic coronary flow were recorded on paper used to record an ECG, and pacing wires were sutured to the and sampledat 200 Hz on a computer (PDP 11/73, Digital right atrium. Equipment Corp., Maynard, MA). Before digitizing, all signals After completion of the experimental preparation, blood were electronically low-pass filtered ( 100 Hz for pressures, and gases and pH were adjusted as needed, a small additional dose 30 Hz for flow).LeftventriculardP/dt wascalculatedusinga ofsodium pentobarbitol was given (5 mg/kg), pacing at 10%— sliding three-point Lagrangianalgorithm (10). 15% above the native rate was begun, and the preparation For baseline and dipyridamole data records at each study was allowed to stabilize for 30 mm before collecting data. condition, we measured or calculated left ventricular pressure at end-diastole(definedas the time when left ventriculardP/ ExperimentalProtocol dt exceeded a threshold of 10% of maximum dP/dt), heart The protocol consisted of a sequence of drug interventions rate, average coronary blood flow (corrected for the zero level designed to test the interaction of pentoxifylline (Trental) and recorded during occlusion of the snare just distal to the flow dipyridamole (Persantine) in producing changes in coronary probe), peak left ventricular systolic pressure, maximum left blood flow. We recorded the coronary blood flow and hemo ventricular dP/dt, and left ventricular rate-pressure-product dynamic response to dipyridamole at three doses of pentoxi (heart rate X peak systolic pressure) for each beat. Values for fylline: 0 (control), 7.5, and 15 mg/kg i.v. To have a reference all beats recorded (22—50beats) were then averaged to obtain for any pentoxifylline effect, we also recorded the effect of a singlevaluefor each experimentalcondition. In a fewdata theophylline (3 mg/kg i.v.), a known inhibitor of dipyrida records, there were premature beats. If these were single, mole, on the response to dipyridamole. Each dose of pentox isolated events they were included in the average, whereas ifylline or theophylline was infused over ‘@-15—20sec. The runs of two or more beats were excluded. sequence and timing ofdrug interventions is outlined in Figure Statistical Analysis. Summary data are reported as means 1. For each drug intervention, we obtained a baseline record ±s.d. (or as s.c.m. in figures). Statistical comparisons of just before giving the drug and then recorded data during the absolute values of the study variables under the different peak coronary flow response to the drug. In each case, data experimental condition were made with two-way repeated were recorded over two or three respiratory cycles. A complete measures analysis of variance, implemented to account for set of records was obtained in five dogs. In two dogs, technical the missingdata (11, 12).The firstfactorwasbaselinecondi tion versus the dipyridamole peak response, and the second factor was no drug versus 7.5 mg/kg pentoxifylline versus 15 [@cord taselinecontrofl CBF & Hemodynamics] mg/kg pentoxifylline versus theophylline (Figs. 2 and 3). To TDipyridamole@1(0.142mg/kg/mmfor4mmIV): record peak CBF & Hemodynamics

@ Wait for return to CBF baseline Pre-Dp1 4, T Pentoxifylline(7.5mg/kgIV): E Post-Dp. recordpeak CBF & Hemodynamics C Wait 15mm or return to CBF baseline, which ever is longer E E Dipyridamole#2 record peak CBF & Hemodynamics] i @ Wait for return to CBF baseline I 4 V Pentoxifylline ( 15mg/kg IV) I>,I@ Wait15mmor return to CBFbaseline,which everis longer jt@ C 4 0 0 IDipyridamole@3:Hemodynamics4TheophyllinerecordpaakCBF & C)

IV)Wait ( 3 mg/kg for return baseline4to CBF FIGURE 2 Effectofstudycondition(nodrug,7.5 mg/kgi.v.pentoxifylline, 15 mg/kg i.v. pentoxifylline,and 3 mg/kg i.v. theophylline)on IDipyridamole@4:recordpeakCBF&Hemodynamicsbaseline coronary flow (stippled bars) and the coronary hy peremicresponseto dipyndamole(open bars). Data are pre FIGURE 1 sented as mean±s.e.m. Refer to Table 1 for results of the Flowchart depictingexperimentalinterventions. two-wayanalysisof varianceused to analyzethese data.

Dipyridamole-InducedCoronaryHyperemia•BrownandSlinker 1021 I

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FIGURE 3 Effect of study condition(no drug, 7.5 mg/kg i.v. pentoxifylline,15 mg/kg i.v. pentoxifylline,and 3 mg/kg i.v. theophylline)on baselinehemodynamics(stippled bars in each panel)and the hemodynamicresponse to dipyndamole(open bars in each panel).Dataarepresentedasmean±s.e.m.Referto Table1 for resultsof thetwo-wayanalysisof varianceusedto analyze thesedata. assess the effect of the methylxanthines on the coronary to dipyridamole was significantly lower after pretreat hyperemic response to dipyridamole, two-way analysis of ment with theophyffine (p < 0.01). variance was followed by Dunnett's test (12) for multiple Hemodynamic Variables (Figure 3). There was no comparisonsagainst a control (0 mg/kg pentoxifylline)for statistically significant effect of dipyridamole on left both the baseline and dipyridamolevalues across all study ventricular end-diastolic or peak-systolic pressure, heart conditions (pentoxifylline and theophylline). To assess the rate, or rate-pressure-product (Table 1). Dipyridamole immediate effect of pentoxifylline, we compared the baseline before 7.5 mg/kg pentoxifylline to the peak response (—-1mm) slightly increased left ventricular dP/dtmax (p 0.03). after giving pentoxifylline, and the baseline before pentoxifyl Study condition (0, 7.5, and 15 mg/kg pentoxifylline line to the baseline (15—20mm later) before the next dose of dipyridamole using paired t-tests with Bonferroni corrections (13). P values >0.05 were considered to indicate no statisti ISummary TABLE cally significant effect. RepeatedMeasures,of Results from Two Factors, AnalysisandHamodynamicof Variancefor CoronaryFlow, DataDipyndamole RESULTS conditioneffecfStudy effectt Effect of Pentoxifyllineand Theophyllineon Peak Response to Dipyridamole Coronary0.002Rate-pressureflowp = 0.002p = Coronary Blood Flow. The baseline coronary flows 0.47Peak productp = 0.62p = 0.18Heartsystolicpressurep = 0.51p = (Fig. 2) were not significantly different between the four 0.39dP/dtratep = 0.87p = study conditions. Analysis of variance showed that di 0.07LVmaxp = 0.03p = pyridamole significantly increased circumflex coronary 0.87Aorticend-diastolicpressurep = 0.41p = blood flow before and after 7.5 mg/kg or 15 mg/kg of end-diastolicpressurep = 0.001p = 0.01 pentoxifylline. Dunnett's tests showed that neither dose of pentoxifylline significantly decreased the dipyrida . Dipyndamole effect = baseline vs. dipyridamole. mole-induced hyperemia compared to the control state t Study condition effect = no drug vs. 7.5 mg/kg pentoxifylline (p > 0.05), but the peak coronary blood flow response vs 15mg/kgpentoxifyllinevs 3 mg/kgtheophylline.

1022 TheJournalof NuclearMedicine•Vol.31 •No.6 •June1990 and theophylline) did not significantly affect any of minants of coronary blood flow such as heart rate, these hemodynamic variables (Table 1). Aortic end systolic pressure, rate pressure product, left ventricular diastolic pressure was not significantly decreased with dP/dtmax,or end-diastolic pressure. pentoxifylline or theophylline (as assessed with Dun nett's test for comparison against no pentoxifylline). Pentoxifylline Dosage and Mode of Administration Immediate Effect ofPentoxifyiine. Pentoxifylline mi In order to confidently extrapolate our experimental tially caused coronary vasodilation (flow increased from findings to the clinical setting, it is important to exam 71.3 ± 18. 1 to 129.4 ± 18.6 ml/min at 1 mm postin me whether the dosage and mode of administration fusion; p < 0.001), but coronary flow returned to base that we used is comparable to patient use. When ad line (69.6 ±17.3; p = 0.80) before dipyridamole was ministered either orally or intravenously, pentoxifylline given (‘@‘15—20mm later). Similarly, there was no undergoes very rapid and extensive metabolism to by change in left ventricular end-diastolic pressure (4.8 ± products that are active pharmacologically (9). Al 3.6 versus 4.3 ±3.8 mmHg; p = 0.29), peak systolic though there is some first-pass hepatic metabolism, the pressure (129 ±27 versus 131 ±31 mmHg; p = 0.53), major active metabolite (5-hydroxyhexyl) is formed by or heart rate (174 ±24 versus 177 ±21; p = 0.18) red blood cells (9, 17). Therefore, with i.v. injection of comparing the pre-pentoxifylline to pre-dipyridamole pentoxifylline, high levels of metabolites, very similar baseline values. in character to what is observed after an oral dose (9, 18), appear within minutes (1 7, 19). Steady-state DISCUSSION plasma levels in patients taking the standard 400 mg lid oral dose of pentoxifylline are ‘@-60ng/ml and 200 These results show that pentoxifylline, unlike theo ng/ml for the parent drug and major metabolite, re phylline, does not significantly decrease the coronary spectively (9). Similar levels are achieved in man within hyperemic response to dipyridamole. This suggests that 5 mm following i.v. administration of 1—2mg/kg pen pentoxifylline need not be stopped prior to dipyrida toxifylline with a half-life of 0.8—1.1hr for parent and mole-thallium-20l imaging. metabolite (1 7). Unfortunately, no data exist regarding Dipyridamole induces sustained near-maximal vas blood levels in dogs. We chose doses of 7.5 mg/kg and odilation of coronary resistance vessels (4), as well as 15 mg/kg because the lower dose has significant cardiac large coronary arteries (14), and has been used as an hemodynamic effects in dogs (20), and the higher dose adjunct to 201Tlmyocardial perfusion imaging for the assured that effects seen only at very high doses would detection ofcoronary artery disease (1). The hyperemia not be overlooked. Relative to human studies, both the appears to be mediated by adenosine, a potent endog 7.5 mg/kg and 15 mg/kg i.v. infusions represent very enous vasodilator. Dipyridamole has been shown to high doses. Because neither dose had a significant effect inhibit the uptake and degradation of adenosine by on the coronary hyperemia following dipyridamole, and myocardial cells (6) and coronary blood vessels (5). because our study design allowed for the production of Furthermore, dipyridamole has been found to decrease metabolites likely to be present with chronic oral ad the permeability ofthe red cell membrane to adenosine ministration, it is reasonable to conclude that standard and, thus, prevent deactivation by intracellular adeno oral doses of pentoxifyffine are unlikely to significantly sine deaminase (15). Finally, dipyridamole has been reduce dipyridamole-induced coronary hyperemia in shown to enhance coronary vasodilation induced by man. Although our dog model does not mimic the exogenous adenosine (16). Prior studies also have doe human clinical condition exactly and definitive conclu umented that adenosine is effectively antagonized by sions await human studies, it should be noted that all methylxanthines (7, 8). For example, methylxanthines of the current clinical dosing parameters for dipyrida inhibit adenosine-induced cyclic AMP production in mole are based on a dog model (21—23). fat and hippocampal cells and have been shown to displace adenosine agonists from cat cortex binding sites CONCLUSION (6). Thus,it isnot surprisingthattheophyllineinhibits coronary vasodilation induced by dipyridamole (4). Pentoxifylline, unlike theophylline, does not inhibit Prior in vitro studies have demonstrated that pentoxi dipyridamole-induced coronary hyperemia, even at fylline is a relatively weak adenosine antagonist com high doses. This suggests that it need not be stopped pared to other methylxanthines (7). However, the ex prior to dipyridamole-thallium-201 myocardial perfu tent to which pentoxifylline can inhibit the coronary sion imaging. vasodilating properties of dipyridamole in vivo was previously unknown. We found that, unlike theophyl ACKNOWLEDGMENTS line, pentoxifylline does not inhibit dipyridamole The authors thank Nancy Perrine for typing the manu induced coronary hyperemia. The normal hyperemic script,TrishWarshawforpreparingthe figures,CharlesRich response despite pretreatment with pentoxifylline could ardson (University of California, San Francisco Anesthesia not be explained by any impact on physiologic deter Research)for providing our data acquisition software,and

Dipyridamole-InducadCoronary Hyperamia •Brownand Slinker 1023 Drs. Martin LeWinter and Roy Ditchey for their helpful I 1. Milliken GA, Johnson DE. Analysis ofmessy data, Volume review of this manuscript. We are also grateful to Mr. Val R. 1:designedexperiments. New York: Van Nostrand Reinhold; Wagner of Hoechst-Roussel Pharmaceuticals, Inc. for supply 1984. ing the pentoxifylline and to Dr. Alan Ranhosky of Boehrin 12. Glantz SA, Slinker BK. Primer of applied regression and analysis ofvariance. New York: McGraw Hill; 1990. ger-Ingelheim for supplying the injectable dipyridamole. 13. Glantz SA. Primer ofBiostatistics, 2nd edition. New York: McGraw-Hill; 1987. 14. Hintze TH, Vatner SF. Dipyridamole dilates large coronary REFERENCES arteries in consciousdogs. Circulation 1983;68:1321—1327. 15. Brunag RD, Douglas CR, Imai 5, Berne RM. Influence of a 1. Iskandrian AS, Heo J, Askenase A, Segal BL, Auerbach N. pyrimidopyrimidine derivative on deamination of adenosine Dipyridamole cardiac imaging. Am Heart J 1988; 115:432— by blood. Circulation Res 1964; 15:83—88. 443. 16. Afonso 5, O'Brien GS. Enhancement ofcoronary vasodilation 2. Boucher CA, BrewsterDC, Darling RC, Okada RD, Strauss action of adenosine triphosphate by dipyridamole. Circula HW, Pohost GM. Determination of cardiac risk by dipyri tion Res 1967; 20:403—408. damole-thallium imaging before peripheral vascular surgery. 17. Ings RMJ, Nudanberg F, Burrows JL, Bryce TA. The phar NEngIJMed 1985;312:389—394. macokinetics of oxypentiphylline (pentoxifylline) in man 3. Leppo J, Plaja J, Gionet M, Tumolo J, Paraskos JA, Cutler when administered by constant intravenous infusion. Eur J BS. Noninvasive evaluation of cardiac risk before elective Clin Pharmacol 1982;23:539—43. vascular surgery. JAm Coil Cardiol 1987; 9:269—276. 18. Bryce TA, Burrows JL. Determination ofoxpentiphylline and 4. Afonso S. Inhibition of coronary vasodilatory action of di a metabolite, l-(S'hydroxyhexyl)-3,7-dimethylxanthine, by pyridamole and adenosine by aminophylline in the dog. gas-liquidchromatography usinga nitrogen-selectivedetector. Circulation Res 1970;26:743—752. JChromatog 1980;181:355—61. 5. Kaisner S. Adenosine and dipyridamole actions and interac 19. Rieck W, Platt D. Determination of 3,7 dimethyl-l-(5-oxo tions on isolated coronary artery strips of cattle. Br J Phar. hexyl)-xanthine(pentoxifylline)and its 3,7-dimethyl-l-(5-hy macol1975;55:439—445. droxylhexyl)-xanthine metabolite in the plasma of patients 6. Kubler W, Spieckermann PA, Bretschneider Hi. Influence of with multiple diseases using high-performance liquid chro dipyridamole (Persantin) on myocardial adenosine metabo matography. J Chromatog 1984; 306:419—427. lism.JMoilCeilCardiol1970;1:23—28. 20. Maxwell GM. The effects of a new xanthine derivative, 3,7- 7. Fredholm BB, Persson CGA. Xanthine derivatives as adeno dimethyl-l(5-oxohexyl)-xanthin (pentoxifylline) on the gen sine receptor antagonists. Eur J Pharmacol 1982; 8 1:673— cml and cardiac haemonamics of the intact animal. Aust J 676. BiolMedSci 1975; 53:265—271. 8. Wu PH, Barraco RA, Phillis JW. Further studies on the 21. Gould KL. Noninvasive assessment of coronary stenoses by inhibition of adenosine uptake into rat brain synaptosomes myocardial perfusion imaging during pharmacologic coro by adenosine derivatives and methylxanthines. Ger Pharma nary vasodilation. I. Physiologic basis and experimental vali col1984;15:251—4. dation. Am J Cardiol 1978; 4 1:267—278. 9. Dettlebach HR. Aviado DM. Clinical pharmacology of pen 22. Gould KL, Wescott Ri, Albro PC, Hamilton GW. Noninva toxifylline with special reference to its hemorrheologic effect sive assessment of coronary stenosis by myocardial imaging for the treatment of intermittent claudication. J Clin Phar during pharmacologic coronary vasodilatation. II. Clinical macol1985;25:8—26. methodology and feasibility. Am J Cardiol 1978; 41:279—287. 10. Marble AE, McIntyre CM, Hastings-James R, Hor CW. A 23. AibroPC,GouldKL,WescottRi, HamiltonJGW,Williams comparison of digital algorithms used in computing the de DL. Noninvasive assessment of coronary stenoses by myo rivative of left ventricular pressure. IEEE Trans Biomed cardial imaging during pharmacologic coronary vasodilation. Engineering1981;28:524—529. III. Clinicaltrial. Am J Cardiol 1978;42:751—60.

Editorial:PharmacologicStress with Dipyridamole: How Lazy Can One Be?

yen though dipyridamole is still an investigational for detecting significant coronary artery disease (CAD) drug, its application for pharmacologic stress testing in has been shown to be comparable to treadmill exercise conjunction with thallium-20l (2OVfl)imaging has 20Vfl imaging. gained wide acceptance over the last few years (1—6). Although 201T1-dipyridamole imaging is often re The diagnostic efficacy of 201T1-dipyridamoleimaging ferred to as “pharmacologicstress,―this description is not entirely correct. In most instances, no real myocar dial stress, resulting in increased metabolic demand, is

ReceivedApr. 6, 1990; revision accepted Apr. 6, 1990. provoked. The basic principle of 201Tl-dipyridamole Forreprintscontact:FransJ.Th.Wackers,MD,CardiovascularNuclear imaging is to visualize pharmacologically induced het Imaging and Exercise Laboratones, Yale lhiiversity School of Med@1ne, Dept.of DiagnosticRadiologyandInternalMedians.(Sectionof Cardiol erogeneity of myocardial blood flow (7). ogy). New Haven,CT 06510. Intravenous administration of dipyridamole blocks

1024 The Journalof NuclearMedicine•Vol. 31 •No. 6 •June1990