The Phosphodiesterase 3 Inhibitor Cilostazol Dilates Large Cerebral Arteries in Humans without Affecting Regional Cerebral Blood Flow

Abstract

Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using ¹³³Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (V_MCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). V_MCA decreased 21.5 ± 5.7% after cilostazol and 5.5 ± 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 ± 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 ± 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.

Keywords

Phosphodiesterase inhibitor Intracranial vasospasm Stroke Cilostazol

Cilostazol (Pletal) is a vasodilator and antiplatelet drug used in the treatment of intermittent claudication (Sorkin and Markham, 1999). Cilostazol may also play a future role in the secondary prevention of ischemic stroke because it significantly decreases the risk of stroke recurrence in stroke patients (Gotoh et al., 2000) and has both neuroprotective and antithrombotic effects (Choi et al., 2002; Kohda et al., 1999).

Cilostazol is a dual inhibitor of phosphodiesterase type 3 (PDE3) and cellular adenosine reuptake (Liu et al., 2001). The cyclic nucleotide PDE family consists of enzymes responsible for the hydrolysis of the 3′ phosphoester bond of the cyclic nucleotide second messengers, cyclic AMP and cyclic GMP. By terminating the messenger signal, PDEs play a pivotal role in the regulation of cyclic nucleotide signaling, and the multiple subtypes and varied tissue distribution make PDEs promising drug targets for a variety of diseases (for review see Beavo, 1995). PDE3 inhibitors may have potential in the treatment of delayed cerebral vasospasm (DCV) (Arakawa et al., 2001; Khajavi et al., 1997). DCV is the major cause of cerebral ischemia after subarachnoid hemorrhage and has a high impact on mortality and morbidity (Zhang et al., 1998). The condition is potentially treatable, but results have been somewhat disappointing to date because the vasodilators tested have limited efficacy or cause hypotension that further compromises cerebral perfusion.

Cilostazol is a marketed PDE3 inhibitor with a favorable safety profile (Pratt, 2001). Cilostazol dilates cerebral arteries in vitro (Birk et al., 2004a; Shiraishi et al., 1998), and the effect is not dependent on a functional vascular endothelium or nitric oxide tone (Birk et al., 2004a). This is important, because dysfunction of the endothelium or of the nitric oxide–cyclic GMP pathway has been proposed to participate in the pathogenesis of DCV (Sobey, 2001). Based on these animal studies, we hypothesized that cilostazol may be a cerebrovascular dilator, but because of blood–brain barrier permeability, species differences and other factors, it is not always possible to extrapolate. We therefore decided to investigate the effect of cilostazol on the large cerebral arteries with corresponding measurements of regional cerebral blood flow (rCBF) and blood flow velocity of the middle cerebral artery (MCA) in normal participants.

MATERIALS AND METHODS

Design and participants

The study was designed as a double-blind, randomized crossover trial in which opaque gelatin capsules containing placebo (lactose, potato starch, magnesium stearate, and talc) or containing two 100-mg cilostazol tablets were administered by mouth on two study days separated by at least 1 week. The participants were randomized to receive active treatment on the first or second study day in a balanced fashion using a computer program (R v. 1.8.1., R Foundation for Statistical Programming).

Sixteen healthy participants were included in the study after a full medical history was collected and a physical examination performed. The participants had no neurologic or cardiovascular disorders, including migraine, and had no daily intake of any medication except oral contraceptives. Four participants did not complete the study: one withdrew after experiencing severe migrainelike headache after receiving cilostazol on day 1, and another due to circumstances unrelated to the study. One participant was excluded because of vomiting a few minutes after the intake of placebo, and another because of a potentially severe adverse event after cilostazol causing junctional escape nodal beats on the ECG with no clinical manifestations. Twelve participants (six men and six women) aged 26 ± 2.0 years and weighing 54 to 100 kg (mean 72.75 ± 14.8 kg) completed the study. All participants gave their informed consent before inclusion. The study was approved by the ethical committee of Copenhagen County and the Danish Medicines Agency, and was conducted according to the Helsinki II declaration.

Experimental protocol

The participants arrived at the clinic at 8.00 am, free from headache. The participants fasted (water was allowed) for least 8 hours before the start of the study (Bramer and Forbes, 1999), and no medication, except oral contraceptives, was allowed during the same period. The participants rested in the supine position for 30 minutes and then received 200 mg cilostazol or placebo by mouth. After the intake of cilostazol or placebo, the participants were allowed the intake of one bread roll with no spread (Bramer and Forbes, 1999). Because preliminary experiments (data not shown) revealed no significant changes in any parameters during the first hour postdose, the participants were allowed to move freely for 45 minutes before resuming the same supine position for an additional 30 minutes before recommencing measurements. Side effects were recorded throughout the period. The participants were discharged from the laboratory 4 hours postdose. V_MCA, peripheral artery diameters, and vital signs were recorded at T_–20, T_–10, and T₀ and then every 15 minutes until 4 hours postdose, except during the brake. Adverse events were recorded every 15 minutes throughout the study. Single photon emission computerized tomography (SPECT) was performed at T₀, T₁₂₀, and T₂₄₀.

Cerebral blood flow velocity

Blood flow velocity in the middle cerebral artery (V_MCA) was recorded bilaterally using hand-held 2MHz probes and transcranial Doppler (TCD; Multidop X, DWL, Sipplingen, Germany). A time-averaged mean over four cycles each comprising approximately 4 seconds or approximately 4 cardiac cycles was used as final measure for each time point. Identification of the MCA and marking reproducible fix points was done as previously described (Kruuse et al., 2000; Thomsen and Iversen, 1993). The same experienced investigator performed all insonations and the participants served as their own controls (Thomsen and Iversen, 1993). End-tidal PCO₂ (PETCO₂) was recorded simultaneously with the TCD measurements using an open mask that caused no respiratory resistance (Datex Normocap 200, Roedovre, Denmark). V_MCA measurements at T₀, T₁₂₀, and T₂₄₀ were performed immediately after CBF measurements to obtain corresponding values. The participants remained in exactly the same supine position during SPECT and TCD measurements. Because rCBF_MCA equals the product of V_MCA and cross-sectional area of the MCA, changes in cross-sectional area were calculated as ΔA = (rCBF_MCA(2) ϗ V_MCA(2)⁻¹) ϗ (V_MCA(1) ϗ rCBF_MCA(1)⁻¹)−1 (Dahl et al., 1989).

Diameter of peripheral arteries

The diameter of the frontal branch of the right temporal artery and the left radial artery (point of maximal pulsation at the distal volar wrist crease) was measured using a high-resolution ultrasound scanner 20 MHz, bandwidth 15 MHz (Dermascan C, Hadsund, Denmark)(Nielsen et al., 1990). Marks were drawn on the skin and the coordinates of these recorded to ensure reproducibility of the measuring points from day to day. Because of technical problems, data from the temporal artery could only be obtained from 11 participants. All measurements were done by the same technician.

Systemic hemodynamics

Heart rate and blood pressure (BP) was recorded using an autoinflatable cuff (Omega 1400, Orlando, FL, U.S.A.). ECG was monitored on an LCD screen and recorded on paper at selected time points (Cardiofax V, Nihon-Cohden, Japan).

Cerebral blood flow measurement

The examination was performed with the subject in the supine position, in quiet surroundings with eyes closed and ears unplugged. Four markers were drawn on the skin to ensure accurate repositioning in each acquisition. PETCO₂ was measured during each examination (Datex Normocap 200, Roedovre, Denmark). CBF was measured with ¹³³Xe inhalation (Ceretronix XAS SM 32C, Randers, Denmark) and SPECT, using a brain-dedicated gamma camera (Ceraspect, DSI, Waltham, MA, U.S.A.). The system uses a stationary annular NaI crystal and a fast-rotating collimator. A dynamic protocol of ¹³³Xe inhalation using the Kanno-Lassen algorithm was used (Kanno and Lassen, 1979; Kruuse et al., 2000). Calculation of flow in the perfusion territories of the major cerebral arteries was performed by fitting standard vascular regions of interest. Regional blood flow in the territory of the MCA (rCBF_MCA) was calculated as mean of the right and left side, because there was no difference between the sides.

Statistical methods

All data are presented as means and standard deviations, unless otherwise stated. Baseline was calculated as the mean of the measurements of time points T_–20 and T_–10. Coefficient of variation (CV) was calculated as the standard deviation of difference between measurements divided by group means and reported in percentage (Thomsen and Iversen, 1993).

Effects over time for each variable (in absolute values) on each treatment day were analyzed using univariate analyses of variance with the factors time and participants. To avoid mass significance, the following time points were selected for analysis: baseline, 120 minutes, and 240 minutes. If an overall effect of time was found, significant changes were localized with Dunnett test. Differences between cilostazol and placebo were analyzed using the area under the curve (normalized against baseline) as summary measure with paired two-tailed t-tests. All analyses were performed with SPSS for Windows 11.5 (SPSS Inc., Chicago, IL, U.S.A.), and P < 0.05 was considered significant.

RESULTS

The superficial temporal artery diameter was significantly smaller on cilostazol days (P = 0.03). There were no other significant differences in baseline values between cilostazol and placebo days (Table 1).

Compared with placebo, cilostazol did not change systolic BP (P = 0.23) or mean BP (P = 0.28), but a minor decrease was seen in diastolic BP (P = 0.03) with a 10.1 ± 5.5% maximum decrease at T₁₅₀ (Table 2). Heart rate increased significantly after cilostazol administration (P = 0.01); peak increase was 22.4 ± 21.7% at T₁₆₅.

There were no changes after cilostazol for global CBF (P = 0.77) or for rCBF_MCA (P = 0.82) when compared with placebo Fig. 1. Day-to-day CV of baseline was 9.2% for global CBF. PETCO₂ measured during CBF acquisition decreased significantly over time after both cilostazol (P = 0.01) and placebo (P = 0.001) administration. The change from baseline was less than 5% in both treatments, and there was no difference between treatments (P = 0.25). rCBF was consequently not corrected for PETCO₂.

V_MCA decreased over time after cilostazol treatment (P < 0.001), but not after placebo (P = 0.18), and with a significant difference between treatments (P = 0.02). The decrease in velocity after cilostazol apparently did not reach a plateau within the observation period (Fig. 2). At the last time point measured (T₂₄₀), the decrease in V_MCA was 21.5 ± 5.7% after cilostazol treatment and 5.5 ± 12.2% after placebo treatment compared with baseline. The mean difference in response between placebo and cilostazol at T₂₄₀ was 18.0% (10.6% to 25.4%, 95% CI). The calculated change in cross-sectional area at T₂₄₀ was 35.6 ± 31.4% after cilostazol treatment and 5.2 ± 13.5% after placebo treatment compared with baseline. Mean difference from placebo was 30.4% (11.4% to 49.3%, 95% CI). The change in cross-sectional area represents a change in MCA diameter of 15.6 ± 14.5% after cilostazol treatment and 2.3 ± 6.6% after placebo treatment. PETCO₂ measured during TCD scans changed significantly over time after placebo (P = 0.005) and after cilostazol (P = 0.002) treatments. The mean decrease compared with baseline was 4.9 ± 4.8% after placebo and 5.3 ± 4.3% after cilostazol treatment at T₂₄₀. There was no difference between treatments (P = 0.94), so we did not correct V_MCA for PETCO₂.

Fig. 1.

Mean global cerebral blood flow (CBF) (± SD) measured with ¹³³Xe inhalation and single photon emission computerized tomography. There were no changes over time after 200 mg cilostazol ● or placebo ○ treatment or between treatments.

Fig. 2.

Mean flow velocities in the middle cerebral arteries (± SD) determined with transcranial Doppler ultrasonography after 200 mg cilostazol ● or placebo ○ treatment. Cilostazol significantly reduced flow velocity compared with placebo.

TABLE 1.

Baseline mean values and standard deviations in the experimental and control groups

	Placebo	Cilostazol	P*
Global CBF (mL·100 g⁻¹ · min⁻¹)	46.2 ± 7.8	45.9 ± 8.0	0.79
rCBF_MCA (mL · 100 g⁻¹ · min⁻¹)	45.3 ± 7.8	45.1 ± 8.2	0.86
V_MCA (cm/s)	78 ± 14	76 ± 15	0.25
Radial artery diameter (mm)	2.35 ± 0.43	2.37 ± 0.44	0.67
Temporal artery diameter (mm)	1.18 ± 0.28	1.08 ± 0.28	0.03
PETCO₂ (mm Hg)	37.9 ± 4.6	38.5 ± 3.1	0.63
Systolic blood pressure (mm Hg)	111 ± 13	114 ± 13	0.27
Diastolic blood pressure (mm Hg)	66 ± 9	67 ± 8	0.71
Heart rate (min⁻¹)	56 ± 10	56 ± 8	0.84

Paired t-test.

Temporal artery diameter increased significantly compared with placebo (P < 0.001). At T₂₄₀ the change was 17.6 ± 12.3% compared with baseline. At the same time point, mean difference from placebo was 8.3% (–0.2% to 16.7%, 95% CI), which was not significantly different (P = 0.055, one-sample t-test). A considerable overlap was seen between the graphs for placebo and cilostazol (Fig. 3), and the difference was only significant because baseline was different between the two study days, which makes the interpretation of the results difficult. The radial artery diameter similarly increased after cilostazol compared to placebo (P = 0.04); the change compared with baseline was 12.6 ± 8.6% at T₂₄₀ (Fig. 3). Mean difference from placebo at T₂₄₀ was 12.1% (1.8% to 22.4%, 95% CI).

Fig. 3.

Mean diameter (± SD) of the radial (●, ○) and temporal (θ, ○) artery after 200 mg cilostazol (filled symbols) or placebo (open symbols) treatment, measured with high-resolution ultrasonography. Cilostazol significantly dilated both arteries.

Facial flushing, seen in 8 of 12 subjects (P = 0.03), and headache, seen in 7 of 12 subjects (P = 0.02), was more frequent after cilostazol treatment than after placebo treatment (2 of 12 and 1 of 12 subjects, respectively). Headache data will be published separately.

DISCUSSION

We have developed the combination of methods applied in the present study to provide an extensive and precise description of pharmacologic effects on cephalic hemodynamics. For CBF measurement, positron emission tomography (PET) and magnetic resonance techniques provide better spatial resolution than ¹³³Xe SPECT, but this is of minor importance in pharmacologic studies because no major variation has been described in the regional response of cortical cerebral blood flow to drugs (Edvinsson and Krause, 2001). The day-to-day CV on CBF measurement was 9.2% in the present study, which is similar to that found in previous studies that have used the same method (Vorstrup, 1988). Similar reproducibility on CBF measurements is found using PET (Carroll et al., 2002), whereas both PET and SPECT are clearly superior in terms of day-to-day reproducibility to magnetic resonance (Carroll et al., 2002).

TABLE 2.

Blood pressure, heart rate, and end-tidal PCO₂ values in the experimental and control groups

	PCO₂ (mm Hg)		Systolic BP (mm Hg)		Diastolic BP (mm Hg)		Heart rate (min⁻¹)
Time	Placebo	Cilostazol	Placebo	Cilostazol	Placebo	Cilostazol	Placebo	Cilostazol

Baseline	37.9 ± 4.6	38.5 ± 3.1	111 ± 13	114 ± 13	66 ± 9	67 ± 8	56 ± 10	56 ± 8
0.00	36.8 ± 5.6	37.5 ± 3.2	113 ± 13	117 ± 13	68 ± 9	68 ± 8	55 ± 8	62 ± 11
75.00	38.2 ± 5.0	39.4 ± 3.0	114 ± 10	113 ± 12	64 ± 7	62 ± 7	57 ± 10	62 ± 8
90.00	39.6 ± 5.2	39.6 ± 2.7	110 ± 15	114 ± 18	64 ± 5	58 ± 6	60 ± 12	66 ± 13
105.00	38.1 ± 5.6	38.7 ± 2.4	113 ± 13	110 ± 13	63 ± 6	62 ± 7	59 ± 12	66 ± 13
120.00	37.8 ± 5.3	37.9 ± 3.5	112 ± 12	115 ± 9	65 ± 7	63 ± 7	59 ± 10	66 ± 12
135.00	38.0 ± 5.6	38.3 ± 3.0	111 ± 12	112 ± 13	64 ± 9	62 ± 7	55 ± 8	63 ± 12
150.00	37.9 ± 5.1	38.5 ± 3.3	112 ± 10	112 ± 10	65 ± 7	60 ± 7	57 ± 11	62 ± 13
165.00	37.8 ± 5.3	37.4 ± 3.6	111 ± 13	111 ± 8	63 ± 6	62 ± 6	56 ± 10	67 ± 15
180.00	36.8 ± 5.4	37.3 ± 3.7	114 ± 12	111 ± 9	64 ± 7	61 ± 10	60 ± 10	63 ± 12
195.00	38.0 ± 4.7	38.4 ± 2.8	112 ± 12	113 ± 10	66 ± 9	61 ± 8	55 ± 11	65 ± 13
210.00	37.7 ± 5.1	38.1 ± 2.4	115 ± 12	112 ± 10	64 ± 8	64 ± 11	60 ± 12	66 ± 13
225.00	37.3 ± 4.8	37.3 ± 2.8	114 ± 13	115 ± 10	67 ± 8	64 ± 8	57 ± 11	66 ± 14
240.00	36.1 ± 5.2	36.4 ± 3.1	117 ± 11	119 ± 9	69 ± 8	66 ± 7	60 ± 11	49 ± 17

Transcranial Doppler measurements of velocity (V_mean) as stand-alone are difficult to interpret because velocity is dependent on both the diameter of the MCA and rCBF_MCA, but they are useful in combination with quantitative rCBF. TCD measurements are most precise in the MCA with a CV of 26% between subjects, 20% between sides, 16% between days, and 7% 5 minutes apart (Thomsen and Iversen, 1993). To reduce the impact of intersubject and interobserver variability of TCD measurements, the present study was designed as a crossover study and the same trained investigator performed all measurements. In the present study, the day-to-day CV of V_MCA at baseline was 6.7%, suggesting relatively high reproducibility. An alternative to these measurements could be magnetic resonance angiography, but this is difficult to time with CBF measurement, and its precision is not yet sufficiently documented and may not be high enough to detect modest pharmacologic effects. High-frequency ultrasound determination of the diameter of the superficial temporal artery and radial artery is highly accurate and reproducible as documented in many previous studies (Iversen et al., 1992; Iversen et al., 1990).

Pharmacology of cilostazol

Cilostazol is a dual inhibitor of PDE3 and cellular adenosine reuptake (Liu et al., 2001). Furthermore, in high concentrations (10 μmol/L), cilostazol inhibits recombinant human PDE5, one of the major cyclic GMP hydrolyzing enzymes (Sudo et al., 2000), and correspondingly increases cyclic CMP in a cyclic nucleotide assay (Birk et al., 2004a). However, PDE5 inhibition does not appear to play any significant role in the functional relaxant response to cilostazol (Birk et al., 2004a), and the highly potent and selective PDE5 inhibitor sildenafil does not dilate the MCA or increase CBF in a similar experimental setup as the present (Kruuse et al., 2003; Kruuse et al., 2002). Inhibition of adenosine reuptake may likewise participate in the relaxant response to cilostazol, because adenosine is a dilator of human cerebral arteries in vitro (Hardebo and Edvinsson, 1979). However, the infusion of adenosine in doses up to 120 μg · kg⁻¹ · min⁻¹, which dilated the superficial temporal artery and caused marked systemic effects, did not dilate the MCA significantly (Birk, 2004b). We therefore suggest that among the known pharmacodynamic effects of cilostazol, PDE3 inhibition is the most likely candidate to mediate any cerebrovascular effect.

Systemic hemodynamic effects

Cilostazol dilated all arteries examined to a similar degree, which suggests a general vasodilating effect on peripheral arteries. Similar changes have been seen in the dorsal pedal artery (Okuda et al., 1992). The arterial dilatation did not cause significant hemodynamic changes apart from a slight decrease in diastolic BP. Heart rate increased significantly, which could be a compensatory mechanism. However, cilostazol, like other PDE3 inhibitors, is believed to have a direct positive chronotropic effect on the heart (Schror, 2002).

Effect of PDE3 inhibition on large cerebral arteries

PDE3 is expressed in human aortic vascular smooth muscle cells (Palmer and Maurice, 2000), but PDE3 expression has not been demonstrated directly in cerebral arteries in any species. However, functional studies suggest a role. Cilostazol dilated rabbit MCA in vitro by a cyclic AMP-mediated mechanism (Shiraishi et al., 1998), and the PDE3 inhibitor siguazodan dilated canine basilar arteries, although with low efficacy (Willette et al., 1997). Using TCD, the PDE3 inhibitor milrinone showed a 20% increase in V_MCA in patients during general anesthesia after a coronary bypass operation (Sulek et al., 2002). This observation would suggest either MCA constriction or an increase in CBF (Dahl et al., 1989). The study had no control group, and mean baseline values were less than 40 mm · s⁻¹, which is lower than reference values (Thomsen and Iversen, 1993). The most likely explanation is that the increase in V_MCA reflected a spontaneous increase in CBF after recovering from the surgical procedure. Using angiography, milrinone has been shown to prevent or even reverse the development of vasospasm in a canine subarachnoid hemorrhage model (Khajavi et al., 1997). This was also shown in a preliminary open study of seven patients treated with selective intraarterial infusion of milrinone into the lumen of the affected artery (Arakawa et al., 2001). The present results strongly support that PDE3 plays a role in the regulation of the diameter of the large cerebral arteries. We found an approximately 30% increase in MCA cross-sectional area, which is at least equivalent to the responses to the most potent arterial dilators that have previously been studied in man: glyceryl trinitrate, histamine, calcitonin gene–related peptide (Iversen et al., 1989; Lassen et al., 1998; Lassen et al., 1995). The decrease in V_MCA is not likely explained by the slight 10% decrease in diastolic BP, because of CBF autoregulation (Aaslid et al., 1989).

Effect on CBF

In the present study, there was no effect of cilostazol on rCBF within the 4-hour observation period. Because maximum effect was apparently not obtained during this period for some parameters, it cannot be excluded that rCBF increase at a later time point. However, there is no trend in the results (Fig. 1) suggesting this is the case. The mean difference in response between cilostazol and placebo at T₂₄₀ was 4% (–9.6% to 17.4%, 95% CI). This suggests that PDE3 plays a differential role in cerebral arteries and arterioles.

Previous studies (Kobayashi et al., 1985; Oishi et al., 2000; Yu et al., 2000) on the effect of PDE3 inhibition have reached conflicting results. An open ¹³³Xe SPECT study included 14 patients 2 months to 2.5 years after cerebral infarction. Mean increase in global CBF was 11.9 ± 20.3%, P < 0.05, after 2 weeks of treatment with cilostazol 200 mg/d. There was an open control group, but these patients had mixed neurologic diagnoses. In another unblinded study, 20 patients in the chronic stage of cerebral infarction were switched from 200-mg/d ticlopidine to 200-mg/d cilostazol. Using ^99mTc-ECD SPECT, it was suggested that rCBF increased 7% to 12% during cilostazol as compared with ticlopidine treatment in some, but not all, regions of interest (Oishi et al., 2000). However, this method cannot be used to study global CBF changes, only changes in the regional distribution of CBF. The effects of cilostazol in both studies were measured 2 weeks or 3 months, respectively, after obtaining control values. The increase in CBF could therefore reflect a period effect (e.g., delayed recovery after the stroke). Another possible explanation for the CBF increase is that the effect of cilostazol on CBF increased with repeated dosing. The plasma concentrations after the present dose equal plasma concentrations during the standard dosage regimen of 100 mg twice daily (Bramer et al., 1999). Olprinone, another PDE3 inhibitor, increased global CBF 4% to 16% in 15 patients aged 67 ± 8 years as measured by ^99mTc-ECD SPECT (Yu et al., 2000). Apart from using a tracer unsuitable for obtaining absolute rCBF values, this study examined a compound about which little is known regarding PDE3 selectivity, and PETCO₂ was not measured. In summary, the previous studies indicate a minor effect of PDE3 inhibitors on CBF, but study design and methods were not optimal.

Vasodilators are obvious candidates for the treatment of DCV, but may also be harmful, e.g., by counteracting the hypertension that is believed to be beneficial in DCV (Dorsch, 2002). If it dilates cerebral arterioles and thereby increases CBF, this will result in steal phenomena, i.e., the shunting of perfusion to normal areas of the brain. Because cilostazol dilates the MCA without adversely affecting CBF and blood pressure, we suggest that this compound is an interesting candidate for future clinical DCV trials. Adverse events, especially headache, were common and caused four participants to discontinue the study. Used for the treatment of DCV, this may be a lesser problem, considering the severity of the disorder. Furthermore, used in intermittent claudication, headache only caused discontinuation of treatment in 3.7% of the patients on the 100-mg twice-daily dosage compared with 0.3% on placebo. However, it remains to be resolved if the tolerability of cilostazol is different in subarachnoid hemorrhage patients and whether it can be safely used during DCV considering the antiplatelet actions of the drug. Whether the dilatation caused by cilostazol is sufficient to treat DCV, whether cilostazol is also effective in an older age group than studied presently, and whether DCV itself influences the efficacy of cilostazol (Sobey and Faraci, 1998) will have to be tested in future clinical trials.

Footnotes

Acknowledgements

The authors thank Lene Elkjaer and Kirsten Brunsgaard for their excellent technical assistance.

References

Aaslid

Lindegaard

Sorteberg

Nornes

(1989) Cerebral autoregulation dynamics in humans. Stroke 20:45–52

Arakawa

Kikuta

Hojo

Goto

Ishii

Yamagata

(2001) Milrinone for the treatment of cerebral vasospasm after subarachnoid hemorrhage: report of seven cases. Neurosurgery 48:723–730

Beavo

(1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 75:725–748

Birk

Edvinsson

Olesen

Kruuse

(2004a) Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries. Eur J Pharmacol 489:93–100

Birk

Petersen

Kruuse

Guieu

Jonassen

Eisert

Olesen

(2004b) The effect of circulating adenosine on cerebral haemo-dynamics and headache generation in healthy subjects. Cephalalgia. In press.

Bramer

Forbes

(1999) Relative bioavailability and effects of a high fat meal on single dose cilostazol pharmacokinetics. Clin Pharmacokinet 37:13–23

Bramer

Forbes

Mallikaarjun

(1999) Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease. Clin Pharmacokinet 37:1–11

Carroll

Teneggi

Jobin

Squassante

Treyer

Hany

Burger

Wang

Bye

Von Schulthess

Buck

(2002) Absolute quantification of cerebral blood flow with magnetic resonance, reproducibility of the method, and comparison with H₂ ¹⁵O positron emission tomography. J Cereb Blood Flow Metab 22:1149–1156

Choi

Shin

Kim

Lee

Hong

(2002) Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats. J Pharmacol Exp Ther 300:787–793

10.

Dahl

Russell

Nyberg-Hansen

Rootwelt

(1989) Effect of nitroglycerin on cerebral circulation measured by transcranial Doppler and SPECT. Stroke 20:1733–1736

11.

Dorsch

(2002) Therapeutic approaches to vasospasm in subarachnoid hemorrhage. Curr Opin Crit Care 8:128–133

12.

Edvinsson

Krause

, eds (2001) Cerebral blood flow and metabolism. New York: Lippincott Williams & Wilkins

13.

Gotoh

Tohgi

Hirai

Terashi

Fukuuchi

Otomo

Shinohara

Itho

Matsuda

Sawada

Yamaguchi

Nishimaru

Ohashi

(2000) Cilostazol stroke prevention study: a placebo-controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis 9:147–157

14.

Hardebo

Edvinsson

(1979) Adenine compounds: cerebrovascular effects in vitro with reference to their possible involvement in migraine. Stroke 10:58–62

15.

Iversen

Holm

Friberg

(1989) Intracranial hemodynamics during intravenous nitroglycerin infusion. Cephalalgia 9:84–85

16.

Iversen

Nielsen

Garre

Tfelt-Hansen

Olesen

(1992) Dose-dependent headache response and dilatation of limb and extracranial arteries after three doses of 5-isosorbide-mononitrate. Eur J Clin Pharmacol 42:31–35

17.

Iversen

Nielsen

Olesen

Tfelt-Hansen

(1990) Arterial responses during migraine headache. Lancet 336:837–839

18.

Kanno

Lassen

(1979) Two methods for calculating regional cerebral blood flow from emission computed tomography of inert gas concentrations. J Comput Assist Tomogr 3:71–76

19.

Khajavi

Ayzman

Shearer

Jones

Levy

Prayson

Skibinski

Hahn

Chyatte

(1997) Prevention of chronic cerebral vasospasm in dogs with milrinone. Neurosurgery 40:354–363

20.

Kobayashi

Yamaguchi

Katsube

Kitani

Okada

Tsunematsu

(1985) Long-term effect of cilostazol on cerebral blood flow in chronic cerebral infarction. Arzneimittelforschung 35:1193–1197

21.

Kohda

Tani

Nakayama

Adachi

Marukawa

Ito

Ishida

Matsumoto

Kimura

(1999) Effect of cilostazol, a phosphodiesterase III inhibitor, on experimental thrombosis in the porcine carotid artery. Thromb Res 96:261–268

22.

Kruuse

Jacobsen

Lassen

Thomsen

Hasselbalch

Dige-Petersen

Olesen

(2000) Dipyridamole dilates large cerebral arteries concomitant to headache induction in healthy subjects. J Cereb Blood Flow Metab 20:1372–1379

23.

Kruuse

Thomsen

Birk

Olesen

(2003) Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126:241–247

24.

Kruuse

Thomsen

Jacobsen

Olesen

(2002) The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab 22:1124–1131

25.

Lassen

Jacobsen

Pedersen

Sperling

Iversen

Olesen

(1998) The effect of IV human alpha calcitonin gene-related peptide (halphaCGRP) on human cerebral arteries and arterioles in vivo [abstract]. Eur J Neurol 5:63

26.

Lassen

Thomsen

Olesen

(1995) Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine. Neuroreport 6:1475–1479

27.

Liu

Shakur

Yoshitake

Kambayashi Ji

(2001) Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. Cardiovasc Drug Rev 19:369–386

28.

Nielsen

Iversen

Tfelt-Hansen

(1990) Determination of the luminal diameter of the radial artery in man by high frequency ultrasound: a methodological study. Ultrasound Med Biol 16:787–791

29.

Oishi

Mochizuki

Shikata

Satoh

(2000) Effect of cilostazol on cerebral blood flows in chronic stage of cerebral circulation. Keio J Med 49 Suppl 1:A145–A147

30.

Okuda

Mizutani

Ikegami

Ueno

Yamashita

(1992) Hemodynamic effects of cilostazol on peripheral artery in patients with diabetic neuropathy. Arzneimittelforschung 42:540–542

31.

Palmer

Maurice

(2000) Dual expression and differential regulation of phosphodiesterase 3A and phosphodiesterase 3B in human vascular smooth muscle: implications for phosphodiesterase 3 inhibition in human cardiovascular tissues. Mol Pharmacol 58:247–252

32.

Pratt

(2001) Analysis of the cilostazol safety database. Am J Cardiol 87:28D–33D

33.

Schror

(2002) The pharmacology of cilostazol. Diabetes Obes Metab 4(suppl 2):S14–S19

34.

Shiraishi

Kanmura

Itoh

(1998) Effect of cilostazol, a phosphodiesterase type III inhibitor, on histamine-induced increase in [Ca2+]i and force in middle cerebral artery of the rabbit. Br J Pharmacol 123:869–878

35.

Sobey

(2001) Cerebrovascular dysfunction after subarachnoid hemorrhage: novel mechanisms and directions for therapy. Clin Exp Pharmacol Physiol 28:926–929

36.

Sobey

Faraci

(1998) Subarachnoid hemorrhage: what happens to the cerebral arteries? Clin Exp Pharmacol Physiol 25:867–876

37.

Sorkin

Markham

(1999) Cilostazol. Drugs Aging 14:63–71

38.

Sudo

Tachibana

Toga

Tochizawa

Inoue

Kimura

Hidaka

(2000) Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 59:347–356

39.

Sulek

Blas

Lobato

(2002) Milrinone increases middle cerebral artery blood flow velocity after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 16:64–69

40.

Thomsen

Iversen

(1993) Experimental and biological variation of three-dimensional transcranial Doppler measurements. J Appl Physiol 75:2805–2810

41.

Vorstrup

(1988) Tomographic cerebral blood flow measurements in patients with ischemic cerebrovascular disease and evaluation of the vasodilatory capacity by the acetazolamide test. Acta Neurol Scand Suppl 114:1–48

42.

Willette

Shiloh

Sauermelch

Sulpizio

Michell

Cieslinski

Torphy

Ohlstein

(1997) Identification, characterization, and functional role of phosphodiesterase type IV in cerebral vessels: effects of selective phosphodiesterase inhibitors. J Cereb Blood Flow Metab 17:210–219

43.

Mizushige

Ueda

Nishiyama

Seki

Aoyama

Ohkawa

Matsuo

(2000) Effect of olprinone, phosphodiesterase III inhibitor, on cerebral blood flow assessed with technetium-99m-ECD SPECT. J Cardiovasc Pharmacol 35:422–426

44.

Zhang

Lewis

Bernanke

Zubkov

Clower

(1998) Stroke: anatomy of a catastrophic event. Anat Rec 253:58–63