Pharmacological Stress Thallium Scintigraphy With 2-Cyclohexylmethylidenehydrazinoadenosine (WRC-0470)
A Novel, Short-Acting Adenosine A2A Receptor Agonist
Background Pharmacological stress imaging with adenosine or dipyridamole is associated with a high incidence of side effects, including hypotension, chest pain, AV conduction abnormalities, and bronchospasm. Although the desired coronary vasodilatory response is mediated primarily by the adenosine A2A receptors, these side effects result from stimulation of the A1, A2B, or A3 adenosine receptors. We hypothesized that a selective adenosine A2A receptor agonist would induce coronary vasodilatation appropriate for pharmacological stress imaging, without evoking adenosine receptor–mediated side effects.
Methods and Results Infusions of a potent and selective A2A adenosine receptor agonist, WRC-0470 (0.1 to 3 μg · kg−1 ·min−1 for 10 minutes), to five open-chest dogs produced dose-related left anterior descending (LAD) and left circumflex (LCx) coronary artery vasodilatation without altering mean arterial pressure, heart rate, left atrial pressure, or left ventricular dP/dt. In the same dogs, adenosine (300 μg · kg−1 · min−1 for 4 minutes) produced coronary vasodilatation that was limited by significant hypotension. To determine the utility of WRC-0470 for pharmacological stress imaging, the hemodynamic responses to WRC-0470 (0.6 μg · kg−1 · min−1 for 10 minutes) and adenosine (250 μg · kg−1 · min−1 for 4 minutes) were compared in dogs with critical LAD stenoses. 201Tl was injected at the peak WRC-0470 stress response. WRC-0470 increased LCx flow nearly fivefold but did not significantly lower mean arterial pressure. Anteroseptal defects were readily apparent in slice images from all dogs. The mean defect ratio (LAD/LCx) was 0.59±0.06.
Conclusions The potent A2A-selective adenosine receptor agonist WRC-0470 is a short-acting coronary vasodilator with potential utility for pharmacological stress perfusion imaging.
Pharmacological stress is frequently induced with adenosine or dipyridamole in patients with suspected CAD before imaging with 201Tl scintigraphy or echocardiography. Since dipyridamole prevents uptake and inactivation of endogenous adenosine by erythrocytes and vascular endothelial cells, both drugs effect dilation of the coronary resistance vessels by the same mechanism: activation of specific cell-surface A2 receptors. Although pharmacological stress was originally introduced as a means of provoking coronary dilatation in patients unable to exercise, several studies have shown that the prognostic value of 201Tl or echocardiographic imaging in patients subjected to pharmacological stress with adenosine or dipyridamole was equivalent to those subjected to traditional exercise stress.1 2 3 4 Although the prognostic value is clear, there is an unusually high incidence of drug-related adverse side effects during pharmacological stress imaging with these drugs. A prospective study of 9256 patients subjected to coronary vasodilatation with adenosine during radionuclide imaging reported that 82% experienced adverse side effects, the most common of which were flushing (37%), chest pain (35%), shortness of breath or dyspnea (35%), headache (14%), ECG changes (9%), and AV conduction block (8%).5 When associated with adenosine, these events are usually transient, but all produce patient discomfort and are sometimes severe enough to require administration of aminophylline or premature termination of the study.5
Data from animal studies suggest that specific adenosine A2A subtype receptors on coronary resistance vessels mediate the coronary dilatory responses to adenosine, whereas subtype A2B receptor stimulation relaxes conductance vessels.6 Evidence from human studies suggests that adenosine-induced AV conduction abnormalities and chest pain are due to activation of adenosine A1 receptors.7 8 9 10 Thus, it is encouraging that pretreatment with a selective adenosine A1 receptor antagonist such as N-08617 8 may prevent at least some of the adverse events associated with adenosine or dipyridamole without hindering the coronary vasodilatation necessary for effective stress imaging.11 Although this strategy may improve patient comfort and safety, a simpler strategy might be to avoid any stimulation of the A1 receptors by designing a compound that had little or no affinity for adenosine A1 receptors but that selectively stimulated only the adenosine A2 receptors responsible for coronary vasodilatation. We postulated that a short-acting, selective adenosine A2A receptor agonist might produce controlled, transient dilatation of the coronary vasculature without producing systemic hypotension or provoking adenosine A1 receptor–mediated adverse events. A number of highly potent and selective adenosine A2 receptor agonists have been synthesized,12 13 14 several of which produce long-lasting systemic hypotension and reflex tachycardia in rats.15 We are not aware of any studies that examined the coronary dilatory responses to these agonists in dogs in vivo.
The goals of the present experimental study were (1) to characterize the systemic hemodynamic and coronary blood flow responses to the intravenous administration of a novel adenosine analogue, WRC-0470 (Fig 1⇓), in dogs and to compare these responses to those after adenosine administration in the same animals and (2) to determine the potential utility of WRC-0470 as a coronary vasodilator for pharmacological stress imaging.
All experiments described in this article were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health, in compliance with the position of the American Heart Association, and with the approval of the Animal Care and Use Committee of the University of Virginia.
Twelve fasted adult mongrel dogs of either sex (weight, 21.5±0.97 kg, mean±SEM) were anesthetized with Innovar (0.08 mL/kg IV) and sodium pentobarbital (6.6 mg/kg IV), intubated, and ventilated on a respirator (Harvard Apparatus) with 4 cm H2O positive end-expiratory pressure. Arterial blood gases were monitored throughout each experiment (model 170, Ciba-Corning), and pH, Pco2, and HCO3 levels were maintained at physiological levels. Both femoral veins were cannulated with 8F polyethylene catheters for the administration of adenosine, WRC-0470, and 201Tl. Additional Innovar anesthetic was also administered intravenously as needed. The right and left femoral arteries were then isolated and cannulated with similar 8F catheters to serve as sites for the collection of arterial blood for blood gas determinations and microsphere reference samples and to monitor systemic arterial pressure. Next, the left main carotid artery was isolated and cannulated with a Millar high-fidelity pressure recording catheter. While the pressure waveform was observed, the Millar catheter was advanced into the left ventricle.
The heart was then exposed through a left lateral thoracotomy and suspended in a pericardial cradle. A flare-tipped polyethylene catheter was inserted into the left atrial appendage for continuous monitoring of left atrial pressure and for the injection of radiolabeled microspheres. A 1-cm section of the LAD was isolated and encircled with an ultrasonic flow probe (Transonic Systems) and snare ligature. A similar flow probe was placed on the LCx.
The ECG, heart rate, arterial and left atrial pressures, LAD and LCx coronary blood flows, and LV pressure and dP/dt were continuously monitored on an eight-channel strip-chart recorder (model 7758D, Hewlett Packard Co).
Protocol 1: Effect of WRC-0470 Dose on Systemic Hemodynamic Parameters (n=5 Dogs)
After baseline hemodynamic measurements of heart rate, arterial and left atrial pressures, LAD and LCx coronary flows, and dP/dt had been collected, adenosine was infused at a dose of 300 μg · kg−1 · min−1 to produce a maximal coronary vasodilatory response. Previous experimental work in our laboratory has shown that this dose of adenosine produces such an effect in dogs within 4 minutes.16 After the peak response, the adenosine infusion was terminated, and all hemodynamic parameters were allowed to return to their baseline values. In our past experience, we have found no evidence of adenosine tachyphylaxis at these doses in dogs. Next, WRC-0470 was infused over a period of 10 minutes at doses of 0.1, 0.3, 0.6, 1.0, and 3.0 μg · kg−1 · min−1, and hemodynamic responses were continuously recorded. Sufficient time was allowed between doses for all parameters to return to their baseline levels. No attempt was made to measure adenosine A1 receptor–mediated ECG changes (eg, PR interval) because it was previously shown that A1 receptor–mediated responses are not easily evoked in the canine heart.17
Protocol 2: Administration of WRC-0470 in Dogs With an LAD Stenosis (n=6 Dogs)
The protocol is summarized in Fig 2⇓. After baseline hemodynamic measurements of heart rate, arterial and left atrial pressures, LAD and LCx coronary flows, and LV dP/dt had been collected, the snare ligature was tightened to produce a critical LAD stenosis. A critical stenosis was defined as no change in resting coronary flow, but a complete abolition of the reactive hyperemic response to a transient 10-second total occlusion. After a brief stabilization period, a left atrial injection of radioactive microspheres was given to assess regional myocardial blood flow. Microspheres have been used extensively in our laboratory, and their use has been described previously.18 Five minutes later, an infusion of adenosine (250 μg · kg−1 · min−1 IV) was begun and continued until ultrasonically measured LCx flow was maximal, at which time a second microsphere injection was given and the adenosine infusion was terminated. Thirty minutes later, after all monitored hemodynamic parameters had returned to baseline, a third microsphere injection was given. On the basis of the results of protocol 1, WRC-0470 (0.6 μg · kg−1 · min−1) was then infused for 10 minutes. Immediately before the infusion was stopped, 201Tl (0.5 to 1.0 mCi) and a fourth microsphere injection were administered simultaneously. The dogs were killed within 5 minutes with an overdose of sodium pentobarbital. Their hearts were removed and sliced into four rings of equal thickness. The slices were trimmed of excess fat and adventitia, placed on a thin piece of cardboard, and covered with cellophane wrap. The slices were imaged directly on the collimator of a conventional gamma camera (model 420, Ohio-Nuclear) with a 25% window centered on the 201Tl photopeak for 28 minutes (maximal count time). To quantify the magnitude of the defects on the uncorrected myocardial slice images, a region of interest was drawn on the defect area visible in the anteroapical regions of the LV wall. A second region of interest was drawn on the normal posterior wall. The defect count ratio was defined as the ratio of the average counts in the LAD defect area region of interest to the average counts in the normal region.
After imaging, the heart slices were divided into 96 endocardial, midwall, and epicardial segments and counted in a gamma well counter (model 5550, Packard Instruments) as previously described.16 The tissue samples were counted within 24 hours for 5 minutes each with 201Tl window settings (50 to 100 keV). Three weeks later, when the 201Tl had decayed, the tissue samples were recounted for microsphere blood flow. The window settings used were 113Sn, 340 to 440; 103Ru, 450 to 550; 95Nb, 680 to 840; and 46Sc, 842 to 1300 keV. The tissue counts were corrected for background, decay, and isotope spillover, and regional myocardial blood flow was calculated with specialized computer software (PCGERDA, Packard Instruments). Transmural activity and flow values were calculated as the weighted average of the corresponding epicardial, midwall, and endocardial samples.
All statistical computations were made with SYSTAT software (Systat Inc), and the results are expressed as mean±SEM. Differences between hemodynamic responses to adenosine with their corresponding baseline values were assessed by use of a paired t test. WRC-0470 comparisons over time were assessed with a repeated measures ANOVA with values of P<.05 considered significant.
WRC-0470 was originally synthesized by Dr Ray Olsson, University of South Florida14 ; additional material was synthesized by Dr Ronald Wysocki, Chemistry Department, Discovery Therapeutics Inc, Richmond, Va. Stock solutions were made in distilled water and diluted in 0.9% NaCl. Adenosine was obtained from Sigma Chemical Co.
Protocol 1: WRC-0470 Dose Response in Normal Dogs
Results from these experiments are summarized in Table 1⇓ and illustrated in Fig 3⇓. Each of the five dogs in this protocol was treated with adenosine before WRC-0470. Within 1 minute of the start of the infusion (0.96±0.4 minutes), adenosine (300 μg · kg−1 · min−1) markedly increased flow through the LAD and LCx and decreased mean systemic blood pressure significantly, from 106 to 77 mm Hg. In addition, in these anesthetized dogs, adenosine produced a slight reflex rise in heart rate, although this change did not reach statistical significance (P=.06). There were no significant effects on either left atrial pressure or LV dP/dt. All hemodynamic parameters returned to their baseline levels within 5 minutes of the end of the adenosine infusion. These results are consistent with those produced previously in our laboratory.11 16 Subsequent sequential 10-minute infusions of WRC-0470 (0.1, 0.3, 0.6, 1, and 3 μg · kg−1 · min−1) produced dose-related increments in LAD and LCx flow; the maximal coronary vasodilatory effect of WRC-0470, which was produced by 1 μg · kg−1 · min−1, was considerably greater than that produced by adenosine (Fig 3⇓). The time to the peak flow response at the 0.6-μg · kg−1 · min−1 dose rate was 2.4±0.5 minutes. Despite the marked coronary vasodilatory response, WRC-0470 did not produce significant systemic hypotension. The highest dose of WRC-0470 tested (3 μg · kg−1 · min−1) reduced mean systemic blood pressure from 104±6 to 88±13 mm Hg (after 10 minutes), but this fall did not achieve statistical significance. As was seen with adenosine, there was a slight reflex rise in heart rate with WRC-0470 that did not reach statistical significance, and there was a trend toward a dose-related increase in LV dP/dt; however, this increase was also not statistically significant. All parameters began to return to baseline levels immediately after the infusion was stopped. After cessation of the 0.1, 0.3, 0.6, 1, and 3 μg · kg−1 · min−1 infusions, LAD and LCx flows returned to within 10% of baseline by 3, 5, 15, 30, and 35 minutes, respectively.
It is apparent from the data shown in Fig 3⇑ that the 0.6-μg · kg−1 · min−1 dose of WRC-0470 produced coronary vasodilatation that was nearly equivalent to that produced by adenosine (300 μg · kg−1 · min−1). Therefore, this dose was used to determine the suitability of WRC-0470 to produce a pharmacological stress response conducive to imaging with 201Tl.
Protocol 2: Administration of WRC-0470 in Dogs With an LAD Stenosis
The measured hemodynamic parameters are summarized in Table 2⇓ for six of the seven dogs instrumented in this protocol. One dog was eliminated from the final analysis because of the lack of a coronary stenosis. As shown in Table 2⇓, setting a critical stenosis on the LAD had no effect on any of the hemodynamic measurements. Each dog was given adenosine (250 μg · kg−1 · min−1 IV) ≈30 minutes before WRC-0470 (0.6 μg · kg−1 · min−1). All measured hemodynamic parameters had returned to their baseline values before WRC-0470 infusion.
The effects of adenosine and WRC-0470 infusions on mean coronary blood flow and systemic arterial blood pressure are compared in Figs 4⇓ and 5, respectively. Adenosine infusion caused LCx flow to increase approximately threefold, from 34±5 to 96±11 mL/min (P<.01), whereas flow in the critically stenotic LAD coronary artery did not change (23±3 versus 23±3 mL/min) (Fig 4⇓, left). At the same time, adenosine caused mean systemic blood pressure to fall from 100±5 to 76±4 mm Hg (P<.01) (Fig 5⇓, left) but had no effect on left atrial pressure, heart rate, or dP/dt. In contrast, WRC-0470 infusion caused LCx flow to increase fivefold, from 26±1 to 124±18 mL/min (P<.01) (Fig 4⇓, right). This marked increase in flow was not accompanied by hypotension (Fig 5⇓) or by changes in any other of the measured hemodynamic parameters (Table 2⇑). Responses to both adenosine and WRC-0470 were nearly identical to those evoked in the first protocol (Fig 3⇑), except that LAD dilatation was prevented by imposition of the stenosis.
Regional Myocardial Blood Flow
Table 3⇓ summarizes regional myocardial blood flow in the endocardium, midwall, epicardium, and transmurally in the LAD and LCx zones of the heart, as determined by radioactive microspheres. Baseline flow was similar before and after adenosine in both the LAD and LCx zones. In the LAD zone, there was slightly lower endocardial flow during WRC-0470 infusion compared with adenosine (0.69±0.08 versus 0.88±0.11 mL · min−1 · g−1), suggesting a greater degree of coronary steal, although this difference did not achieve statistical significance. Also, with both adenosine and WRC-0470 infusions, there was a significant increase in epicardial flow in the critically stenotic LAD zone; however, endocardial, midwall, and transmural average flow did not increase significantly. In the LCx zone, both adenosine and WRC-0470 caused significant increases in absolute coronary flow across the LV wall. Although there was a trend toward a greater percent increase in transmural flow during WRC-0470 (274.7±74%) versus adenosine (172.4±48%) infusion, this difference did not reach statistical significance (P=.08).
201Tl Uptake During WRC-0470 Vasodilator Stress
Fig 6⇓ depicts the transmural microsphere flow ratios (LAD/LCx) at baseline and during WRC-0470 stress and the 201Tl activity ratio (LAD/LCx) as determined by gamma well counting. The 201Tl was injected during peak WRC-0470 stress. The LAD/LCx flow ratio fell from 0.93±0.04 to 0.35±0.06 (P<.01) with WRC-0470 infusion. The 201Tl LAD/LCx transmural activity ratio (0.50±0.05) underestimated the flow disparity as measured by microspheres (0.35±0.06) (P<.01) because of the plateau in tracer extraction at high flow. On ex vivo images of heart slices, anteroseptal defects were readily apparent in all dogs. The mean defect count ratio (LAD/LCx) was 0.59±0.06.
The data from these experiments demonstrate that the highly potent A2A-selective adenosine agonist WRC-0470 produced marked coronary vasodilatation without hypotension that was conducive to 201Tl scintigraphic imaging of a myocardial perfusion defect.
Adenosine Receptor Selectivity
Previous studies in isolated guinea pig hearts established that WRC-0470 is 16 000-fold more selective for the activation of the A2A than A1 receptor.14 WRC-0470 is 11-fold more potent than NECA, a nonspecific adenosine analogue, as a coronary dilator. WRC-0470 is ≈150-fold less potent than NECA at inducing A2B adenosine receptor–mediated relaxations of the guinea pig aorta. The nonselective adenosine receptor antagonists 8-phenyltheophylline and 8-p-sulfophenyltheophylline antagonized both the coronary (A2A) and the aortic (A2B) vasodilatory responses to WRC-0470, indicating that these actions were mediated by adenosine receptors and were not a result of a nonspecific effect.14 Activation of myocardial adenosine A1 receptors evokes negative inotropic, chronotropic, and dromotropic responses in the heart. WRC-0470 activates adenosine A1 receptors only at concentrations exceeding ≈30 μmol/L (Discovery Therapeutics, unpublished data). Because the maximum inhibitory response produced by WRC-0470 in the electrically paced left atrium was less than that produced by NECA, it was concluded that WRC-0470 was a partial agonist of A1 receptors. Furthermore, WRC-0470 antagonized the responses to NECA with a dissociation constant of 21 μmol/L, indicating that WRC-0470 is acting at the same A1 receptor as NECA to induce negative inotropy but that WRC-0470 has a very low affinity for binding to the A1 receptors and has a low intrinsic efficacy for activation of these receptors. When the tissue-dependent variables are eliminated, the comparative molar potency ratios for WRC-0470 and NECA in the isolated atrial and aortic adenosine receptor assay systems used in this study and in the previously published Langendorff heart assay14 may be used to calculate relative selectivities for one receptor subtype versus another. WRC-0470 was thus 5500-fold more selective for activation of the coronary A2A adenosine receptors than the cardiac A1 receptors, 1600-fold more selective for activation of the A2A receptors than the aortic A2B receptors, and 3.5-fold more selective for the A2B than the A1 receptors.
Dose Responses of WRC-0470 in Normal Dogs (Protocol 1)
When administered to anesthetized dogs in the present study, WRC-0470 produced dose-related coronary vasodilatation. In each experiment, we evoked maximal coronary vasodilatation with adenosine before administering WRC-0470, and in each case, WRC-0470 produced significantly greater coronary dilatation than adenosine. It was obvious in these studies that the hyperemic responses to adenosine were limited by concurrent hypotension. The differences in the responses between adenosine and WRC-0470 were striking. As coronary blood flow increased during WRC-0470 infusion, systemic blood pressure changed little. Since the pressure head driving coronary perfusion remained constant, the dilatory responses achievable with WRC-0470 exceeded those inducible with adenosine. Only the highest dose of WRC-0470 tested (3 μg·kg−1·min−1) produced an appreciable hypotensive response (mean blood pressure fell from 104±6 to 88±13 mm Hg) and, although this response was not statistically significant, it appears that the effects on systemic blood pressure became more pronounced as the dose was increased. If WRC-0470 is infused clinically to induce pharmacological stress, a reduction in systemic blood pressure might indicate that the maximal coronary vasodilatory dose has been exceeded.
There are a number of possible explanations for the ability of WRC-0470 to induce coronary vasodilatation at concentrations that did not affect systemic blood pressure. One possibility may be that there is a predominance of A2A receptors in the coronary resistance vessels compared with the systemic circulation. A second possibility is that the A2A receptors in the coronary arteries are more abundant or highly coupled than those in other organs. It might be that the same concentrations of WRC-0470 that evoke coronary vasodilatation also dilate other vascular beds but that the magnitude of that vasodilatation is insufficient to reduce overall systemic blood pressure. A third possibility is that the hypotensive response to adenosine may be mediated in part by A3 adenosine receptors, since specifically blocking these receptors in rats eliminated the hypotensive response to an adenosine analogue.19 In addition, Hannon et al20 recently showed that A3 receptor–mediated hypotension may involve mast cells.
Comparison of Adenosine and WRC-0470
Adenosine-induced vasodilatation in resistance and conductance vessels appears to be mediated by the A2A and A2B receptors, respectively. This is illustrated by the findings that WRC-0470 and CGS-21680 (another highly specific A2A receptor agonist) are extremely potent agonists in an assay for adenosine A2A activity (coronary vasodilatation in the guinea pig isolated heart)12 but are weak agonists in an assay for adenosine A2B activity (relaxation of guinea pig isolated aortas).21 As a highly specific adenosine A2A receptor agonist, WRC-0470 produces marked dilatation of coronary resistance vessels, resulting in diversion of blood flow away from the myocardial perfusion zone distal to a stenosis that produces regional flow heterogeneity and a perfusion defect on a myocardial scintigram.
The present study indicates that the selective adenosine A2A receptor agonist WRC-0470 produced a myocardial perfusion defect (mean, 41% reduction) that was easily detected with 201Tl scintigraphy and similar in magnitude (38%) to the 201Tl perfusion defects observed after adenosine infusion in the same coronary stenosis model.16 The magnitude of flow heterogeneity induced by adenosine in the critically stenosed canine preparation used in this study mimics human responses quite well, and the accuracy of 201Tl scintigraphy in detecting myocardial perfusion defects in dogs is excellent.11 16 In the present study, 201Tl activity underestimated the size of the true flow disparity as measured by microspheres. This is because of the roll-off in extraction of 201Tl at high flow, which is characteristic of all diffusible flow tracers and has been reported previously by us and others.11 16 22 Despite the underestimation of the flow disparity, the mean magnitude of the 201Tl defect (41%) was significant and well within clinically detectable limits.
We chose a canine model for these experiments because of our extensive experience with it and to facilitate comparisons with our previous work, which used adenosine or dipyridamole.16 23 Because the canine adenosine A1 receptor is atypical, we could not assess the effects of WRC-0470 on A1 receptor responses. In addition, receptor binding studies of WRC-0470 to canine A2A and A2B receptors were not performed in these studies. Thus, the preferential binding of the agent to A2A receptors can be inferred only indirectly. Another limitation was that the hemodynamic and coronary flow responses were evaluated in anesthetized rather than conscious dogs. Whether the hemodynamic effects of anesthesia might be different with adenosine compared with WRC-0470 is unknown. Finally, 201Tl imaging was not undertaken with adenosine infusion in this study. Since imaging could be performed only once, it was undertaken only with WRC-0470 administration.
Vasodilator stress perfusion imaging is increasingly being used as an alternative to exercise scintigraphy for detection of CAD and risk stratification. Sensitivity and specificity for detection of CAD are similar for dipyridamole and adenosine, ranging between 85% and 90%. The major potential clinical advantage of WRC-0470 over dipyridamole or adenosine is the reduction in A1, A2B, and A3 receptor–mediated side effects. In a study by Abreu et al,24 79% of 607 patients receiving adenosine for stress perfusion imaging had at least one side effect, including facial flushing in 35%, chest or neck pain in 43%, headache in 21%, and dyspnea in 19%. In the same study, systolic blood pressure fell from 138 to 121 mm Hg and diastolic pressure fell from 78 to 67 mm Hg. O'Keefe et al25 reported that 28 of 340 consecutive patients who received intravenous adenosine for 201Tl imaging developed either second-degree or third-degree AV block. In the study by Gupta et al,4 82% of patients receiving intravenous adenosine had side effects, with flushing in 41%, chest pain in 24%, and dizziness in 20%. Cerqueira et al5 reported the safety profile of adenosine stress perfusion imaging from a registry comprising 9256 consecutive patients. Side effects were reported in 81% of these patients. Although 72 patients experienced transient third-degree AV block, 706 (7%) had either first-, second-, or third-degree AV block, and chest pain occurred in 3207 (35%). In 7% of the patients, the protocol was terminated prematurely. Significant side effects can also occur with dipyridamole infusion. In 3715 patients receiving dipyridamole, the mean systolic blood pressure fell by 14.07 mm Hg, with 11% of patients demonstrating a 20% drop in systolic pressure.26 Thus, side effects, although mostly tolerated, are common with myocardial perfusion imaging with adenosine or dipyridamole. However, it would be desirable to have a pharmacological stress agent capable of producing the required vasodilatation without the adverse side effects. In the present study, we found that WRC-0470 produced greater vasodilatation at its peak pharmacological dose than did adenosine, and without significant systemic hypotension. Clinically, this would be beneficial in preventing a suboptimal stress test and might translate to an enhanced detection rate, especially in CAD patients with mild coronary stenoses. In addition, because of its marked selectivity for the A2A adenosine receptor, it would be expected that fewer of the other A1, A2B, and A3 receptor–mediated side effects (AV conduction abnormalities, chest pain, and perhaps breathing difficulties) would occur during treatment with WCR-0470. It has been shown that both AV block and chest pain are A1 receptor–mediated in humans, because they were prevented by the A1-selective antagonist N-0861.8 Since WRC-0470 has a very low affinity for the A1 adenosine receptors in isolated heart tissues and produces negative inotropic and negative chronotropic responses in vitro and in vivo in rats only at very high concentrations, it is unlikely that the concentrations of WRC-0470 that produce coronary vasodilatation will produce any side effects attributable to adenosine A1 receptor stimulation, such as AV conduction abnormalities and pain.7 8 9 10 Some recent evidence also suggests that the adenosine A3 receptor may play a role in bronchospasm due to the discovery of adenosine A3 receptors on the surface of mast cells.27 Thus, WRC-0470 has the potential to provide comparable or enhanced diagnostic accuracy for CAD detection when used as a pharmacological stress imaging agent, but with a markedly reduced side effect profile. Clinical trials will provide further information regarding the potential advantage.
Selected Abbreviations and Acronyms
|CAD||=||coronary artery disease|
|LAD||=||left anterior descending coronary artery|
|LCx||=||left circumflex artery|
This study was supported in part by Discovery Therapeutics, Inc.
- Received September 29, 1995.
- Revision received April 12, 1996.
- Accepted April 15, 1996.
- Copyright © 1996 by American Heart Association
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