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CARDIOVASCULAR
Centre de Recherche Pierre Fabre, Castres Cedex, France
Received May 27, 2005; accepted July 15, 2005.
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Abstract |
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), peripheral neuronal inhibition (Moskowitz, 1992), and inhibition of transmission through second-order neurons of the trigeminocervical complex (Hoskin et al., 1996), leading to inhibition of the effects of activated nociceptive terminal afferents (Goadsby, 2000).
Donitriptan, which has been evaluated for efficacy in the acute relief of migraine headache in phase II clinical trials (Dukat, 2001), and other triptans (Létienne et al., 2003a) augmented cerebral oxygen utilization and tissue metabolism. This additional mechanism of action may also be relevant to the acute headache-relieving effects of triptans as a whole. However, our previous studies in the anesthetized pig (Létienne et al., 2003a,b) showed that the triptans increased arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head but also produced concomitant carotid vasoconstriction. Consequently, it was not possible to determine whether these events occurred independently.
The aim of the present investigation was therefore to determine whether donitriptan and sumatriptan produced similar effects on jugular venous blood gas parameters in a model in which triptans are considered not to produce cranial vasoconstriction. Thus, the study was performed in anesthetized rats, and the effects of donitriptan on cranial regional vascular beds were carefully investigated.
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Materials and Methods |
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Animal Preparation. Rats (n = 65) were anesthetized with sodium pentobarbitone (50 mg/kg i.p.; SANOFI Research Center (Montpellier, France). Animals were tracheotomized and mechanically ventilated (60 cycles/min, 2.5 ml/cycle; Harvard Apparatus Inc., Holliston, MA). Oxygen supply, respiratory rate, and tidal volume were adjusted to keep arterial blood gas values within physiological limits (ABL 510; Radiometer, Copenhagen, Denmark). Rectal temperature was maintained at 38°C by means of a rectal thermocouple attached to a homeothermic blanket control unit (Harvard Apparatus Inc.). Catheters were inserted into the right carotid artery to administer drugs or vehicle and into the abdominal aorta, via the right femoral artery, to measure arterial blood gases and systemic arterial pressure continuously with a pressure transducer (Staham P10EZ; Viggo-Spectramed, Oxnard, CA) connected to an amplifier (Gould Instrument Systems Inc., Cleveland, OH). The right jugular vein was also cannulated to measure venous blood gases. The left carotid artery was carefully cleaned of surrounding connective tissue, and blood flow was measured with a flow probe (model 1R; Transonic Systems Inc., Ithaca, NY).
Experimental Protocol. Rats were allowed at least 30 min for hemodynamic and blood gas parameters to stabilize. Pharmacological protocols were carried out in seven separate groups of rats. In group 1, rats (n = 10) received a 10-min infusion of vehicle (a mixture of 40% polyethylene glycol 300 in 0.9% sterile saline). In groups 2, 3, and 4, rats received an infusion of donitriptan (2.5, 10, or 40 µg/kg; n = 8 per dose). In group 5, rats (n = 8) received an administration of sumatriptan (630 µg/kg). The doses of donitriptan and sumatriptan used were chosen from previous studies in the anesthetized pig as those inducing maximal carotid vasoconstriction (John et al., 1999) and maximal effects on oxygen saturation in jugular venous blood (Létienne et al., 2003a). In groups 6 and 7, rats were pretreated by an i.v. bolus of GR 127935 (0.63 mg/kg), a relatively selective 5-HT1B/1D receptor antagonist (Skingle et al., 1996). The effects of GR 127935 alone were evaluated in group 6 (n = 6), and in group 7 (n = 5) donitriptan was infused at 10 µg/kg over 10 min after GR 127935 administration. Drug/vehicle was infused via the intracarotid route over 10 min.
Two additional groups were constituted to study regional blood flows in the presence of donitriptan (10 µg/kg; n = 6) or vehicle (n = 6) administered over 10 min as described previously. Blood gas and pH values were measured 10, 20, and 30 min after the end of vehicle or triptan administration.
Regional Blood Flow. The fluorescent microsphere technique was chosen for the simultaneous determination of regional blood flows. Indeed, fluorescent microsphere technology has been demonstrated to be a reliable alternative to radioactive microspheres for measuring regional blood flows in rats (Chien et al., 1995; Gervais et al., 1999).
Blue-green fluorescent microspheres were administered at the end of stabilization, and blue fluorescent microspheres were administered 20 min after the end of infusion (vehicle or donitriptan). Four hundred thousand fluorescent microspheres (blue-green or blue fluorescent label, 15 ± 0.1 µm in diameter) were injected into the left ventricle of the anesthetized rat. A reference blood sample was withdrawn from the abdominal aorta via the femoral artery at a rate of 1 ml/min. At the end of the experiment, the left kidney, lung, thoracic muscles, tongue, ears, eyes, cranial muscles, dura mater, brain stem, cerebellum, hypothalamus, right and left cerebral hemispheres were removed, blotted, and weighed. Dura mater was the smallest sample of tissue with only 40 to 50 mg. All samples >1 g were cut up (kidney, lung, and thoracic muscle). All tissue samples and reference blood samples were then processed for fluorescence quantification. Tissue samples were individually digested in 4 N KOH solution for 24 h. The digestion of tissue samples with a very low specific weight (e.g., air-dried lung tissue) can be a problem, because the samples float in aqueous KOH. This was solved by using ethanolic KOH (Raab et al., 1999). Fluorescence was determined with a PerkinElmer LS50B luminescence spectrophotometer (PerkinElmer Life and Analytical Sciences, Beaconsfield, UK). The fluorescence intensity of each dye/solvent sample was measured at the optimal excitation/emission wavelength pair of each dye (blue, 360 and 423 nm; blue-green, 420 and 467 nm).
The blood flow for each tissue piece in ml/min was processed manually. A reference blood flow sample must be obtained at the time of microsphere injection. If the fluorescence of each organ piece is denoted by fli, where i is the sample number, flref is the fluorescence of the reference blood flow sample, and R is the withdrawal rate of the reference blood flow sample in milliliters per minute, then flow to piece i, Qi, is given by the equation Qi (milliliters per minute) = (fli/flref) x R (milliliters per minute).
The fluorescence in the lungs represents the microspheres entering via the bronchial artery flow, those not trapped in the capillary bed, and those from the arterial side after escaping via carotid arteriovenous anastomoses (AVAs). Therefore, the amount of fluorescence in the lungs can be used as an index of the AVA fraction of blood flow (Saxena and Verdouw, 1982).
Drugs. Donitriptan, GR 127935, and sumatriptan hydrochloride were synthesized by the Department of Analytical Chemistry and Division of Medicinal Chemistry IV at the Centre de Recherche Pierre Fabre (Perez and John, 1999). Donitriptan and sumatriptan were dissolved in 40% polyethylene glycol 300 in sterile saline (0.9%), whereas GR 127935 was dissolved in 0.9% sterile saline. Drugs were weighed as base taking into account the salt to base ratio.
Parameters Measured or Calculated and Statistical Analysis. Parameters measured were systolic and diastolic arterial pressure in mm Hg; mean arterial pressure (MAP) in mm Hg was calculated as MAP = (SAP + 2DAP)/3, where SAP is systolic arterial pressure and DAP is diastolic arterial pressure; and heart rate (HR) in beats/min was derived from the arterial pressure signal and the mean right carotid blood flow (CaBF) in milliliters per minute. Carotid vascular resistance (CaVR) in mm Hg · min/ml was determined as the ratio of MAP to CaBF.
These parameters are the average of all successive determinations taken during a 4-s recording period. Analog arterial pressure signals were digitized (500 Hz), simultaneously recorded and analyzed on line by interactive software (Notocord-hem 3.4; Notocord Systems, Croissy sur Seine, France).
All data are presented as means ± S.E.M. Intergroup comparisons were analyzed by one-way analysis of variance (ANOVA) followed by Dunnett's test. After ANOVA, if data were unsuitable (i.e., unequal variance), for parametric analysis a Kruskal-Wallis one-way analysis of variance on ranks was performed followed by the Dunn post hoc test. Statistical comparisons for regional blood flow between baseline and postinfusion data were performed using the paired Student's t test (Sigma Stat; SPSS Inc., Chicago, IL). A P < 0.05 level was chosen for significance.
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Results |
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Effects of Donitriptan and Sumatriptan on Arterial Blood Gas Parameters. Baseline values and maximal effects of donitriptan and sumatriptan on arterial blood gas parameters are presented in Table 1. The PaO2, PaCO2, arterial pH, and arterial oxygen saturation (AOS) values were comparable among groups (P = N.S.; Table 1), except for initial PaO2 and PaCO2 values in the donitriptan (2.5 µg/kg) group, which were slightly but significantly lower than in vehicle. As in vehicle-treated rats, in donitriptan- and in sumatriptan-treated animals, no significant changes in PaO2, PaCO2, or arterial pH occurred (Table 1).
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Effects of Donitriptan and Sumatriptan on Venous Blood Gas Parameters. Baseline values and maximal effects of donitriptan and sumatriptan on venous blood gas parameters are summarized in Table 2. The initial values of PvCO2, venous pH, venous oxygen saturation (VOS), and arteriovenous oxygen saturation difference (AVOSD) were comparable among the five groups (P = N.S.). On the other hand, initial PvO2 values in donitriptan (2.5 and 10 µg/kg) and in sumatriptan groups were significantly lower than in vehicle.
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Donitriptan significantly reduced PvO2 (P < 0.05, compared with vehicle; Table 2; Fig. 1A). At 40 µg/kg, donitriptan induced a maximal variation of -24.7 ± 3.4% (P < 0.05) compared with vehicle (-6.9 ± 4.4%). Sumatriptan statistically significantly decreased PvO2 with a maximal reduction of -19.0 ± 5.0%.
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In the vehicle group, VOS remained unchanged throughout the experiment, 68.9 ± 3.4 and 64.6 ± 3.9%, initial and end experiment values, respectively; P = N.S.). In donitriptan-treated animals, compared with baseline, VOS significantly decreased from 2.5 µg/kg, with a maximal variation of -32.9 ± 8.0% (P < 0.01; Fig. 1C). Sumatriptan (630 µg/kg) induced similar decreases in VOS with a maximal variation of -25.7 ± 7.3% (P < 0.05; Fig. 1C). Because AOS remained unchanged throughout the experiment, the AVOSD significantly increased in donitriptan- and sumatriptan-treated rats (Table 2).
Effects of Donitriptan and Sumatriptan on Hemodynamic Parameters. Baseline values of MAP, HR, CaBF, and CaVR are presented in Table 3. Under baseline conditions, these cardiovascular parameters were not significantly different from those in the vehicle group, with the exception of CaBF, lower in sumatriptan group and CaBF and its corresponding resistance, which was significantly lower in the donitriptan (2.5 µg/kg) than in the vehicle group (P < 0.05; Table 3). In vehicle-treated animals, MAP and HR did not undergo notable changes throughout the experiment, the maximal variation for MAP and HR were -0.4 ± 7.3 and -0.9 ± 2.4%, respectively (data not shown). CaBF and associated resistance were not significantly affected by vehicle when compared with initial values (maximal changes in CaVR, -6.4 ± 3.8%; P = N.S.).
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MAP and HR were not significantly affected by triptans; for example, at 40 µg/kg donitriptan, maximal variations for MAP and HR were -1.7 ± 7.0 and -4.0 ± 2.7%, respectively (P = N.S., compared with vehicle group). Interestingly, Fig. 1D shows that in this model, donitriptan and sumatriptan were devoid of significant vasoconstrictor effects.
Effects of GR 127935. In an additional series of experiments, donitriptan (10 µg/kg) was reevaluated in animals pretreated by GR 127935 (0.63 mg/kg), a relatively selective 5-HT1B/1D receptor antagonist (Skingle et al., 1996). Under these conditions, baseline PaO2, PvO2, PaCO2, PvCO2, AOS, VOS, and AVOSD values were similar in animals about to be treated with vehicle or donitriptan (data not shown).
GR 127935 per se did not significantly modify these parameters. The maximal variation in VOS induced by GR 127935 alone was -13.9 ± 5.7% (P = 0.38 versus vehicle without GR 127935). GR 127935 fully inhibited the donitriptan-induced increase in PvCO2 (P = N.S. versus vehicle; Fig. 3A), and the maximal changes in vehicle- and donitriptan-treated rats were 4.5 ± 2.4 and 6.3 ± 6.5%, respectively (P = N.S.). Furthermore, in the presence of GR 127935 the fall in VOS induced by donitriptan (10 µg/kg) was abolished (Fig. 3B).
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Figure 4 shows percentage of changes from baseline values in AVA blood flow after vehicle or donitriptan (10 µg/kg) administration. Donitriptan failed to affect AVA blood flow (-26.4 ± 4.1 versus -21.9 ± 4.9% in the presence of vehicle; P = N.S.).
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Discussion |
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,b), but this time in a model in which the triptans are devoid of known cranial vasoconstrictor effects. In the anesthetized rat, donitriptan, from 10 µg/kg, decreased jugular venous hemoglobin oxygen saturation without affecting systemic arterial oxygen saturation, leading to increases in cephalic AVOSD. Sumatriptan investigated at 630 µg/kg produced similar effects. Both triptans also increased carbon dioxide partial pressure in jugular venous blood. Interestingly, the 5-HT1B/1D receptor antagonist GR 127935 (Skingle et al., 1996) significantly reduced both donitriptan-induced decreases in VOS and increases in PvCO2, indicating the involvement of 5-HT1B/1D receptors. Donitriptan and sumatriptan did not significantly affect carotid or regional cranial blood flow, demonstrating that these effects on blood gases occurred independently of vasoconstriction. Furthermore, in this model donitriptan failed to affect AVA blood flow.
Donitriptan-Induced Increases in AVOSD and PvCO2. Donitriptan (from 10 µg/kg) and sumatriptan (630 µg/kg) reduced VOS and PvO2 without significantly affecting systemic AOS or PaO2. Consequently, triptan-induced increases in AVOSD can be explained by the selective decreases in jugular VOS. In our study, the 5-HT1B/1D receptor antagonist GR 127935 abolished donitriptan-induced increases in AVOSD, indicating the involvement of 5-HT1B/1D receptors. Such effects have been previously described for triptans in anesthetized pigs (Létienne et al., 2003a,b). Furthermore, donitriptan and sumatriptan significantly increased jugular PvCO2, suggesting an enhancement of cerebral metabolism (Dejours, 1963). It is noteworthy that this latter effect is probably mediated by 5-HT1B/1D receptors since it was abolished by GR 127935. As described previously (Létienne et al., 2003a,b), changes in PvCO2 seem somewhat smaller than those occurring for other blood gas parameters, but contrary to PvO2, a small, statistically significant increase in venous PCO2 reflects marked increases in tissue CO2 reserve and metabolism (Dejours, 1963). Because systemic AOS or PaO2 remained unaffected by donitriptan and sumatriptan, effects on hemoglobin oxygen affinity or on pulmonary blood oxygenation can be excluded. Since none of the triptans investigated significantly affected arterial or venous pH or PaCO2, metabolic acidosis can also be ruled out.
Absence of Vasoconstrictor Responses of Donitriptan. One of the main observations of the present investigation was the absence of effects of donitriptan and sumatriptan on carotid blood flow. Indeed, donitriptan and sumatriptan produce selective carotid vasoconstriction in several animal species, including dogs (Parsons et al., 1997; De Vries et al., 1998a; Centurion et al., 2001), rabbits (Choppin and O'Connor, 1996; Akin et al., 2002), and pigs (De Vries et al., 1998b, 1999; John et al., 1999, 2000; Tom et al., 2002; Létienne et al., 2003a,b). The poor functional evidence of 5-HT1B receptors in this vascular bed in rats (Pagniez et al., 1998) could parsimoniously explain our results. A second major finding in the present study is that donitriptan was devoid of significant vasoconstrictor effects in any of the cranial regional vascular beds investigated. This observation is corroborated by a report from another group, in which similar results on cerebral blood flow were described in rats after intracarotid administration of sumatriptan (Fukuda et al., 2002). In our study, the fluorescent microsphere technique was chosen for the determination of regional blood flow. In each tissue investigated, donitriptan failed to affect regional blood flow. We found no evidence to suggest that donitriptan closed cephalic arteriovenous anastomoses.
An Overlooked Mechanism of Action of Triptans? Donitriptan and sumatriptan elicited decreases in jugular VOS in anesthetized rats without carotid vasoconstriction. In addition, in this model, the decrease in VOS and the increase in PvCO2 induced by triptans reached remarkably similar levels to those observed in anesthetized pigs (Létienne et al., 2003a,b).
Our previous observations and present results in anesthetized rats, indicate that enhancement of cerebral oxygen utilization and augmented tissue metabolism via 5-HT1B/1D receptor activation may be an important mechanism of triptan action, and even possibly the principal mechanism relevant to acute headache relief. In the present model, it seems that this mechanism occurs independently of vasoconstriction. It is tempting to speculate that donitriptan and sumatriptan could activate 5-HT1B receptors on endothelial cells of brain arteries and microvessels (Riad et al., 1998). Because endothelial cells are regulators of oxygen consumption (Clementi et al., 1999), 5-HT1B receptor activation might lead to enhanced oxygen extraction from blood with increased subsequent metabolism. Further studies are warranted to define the precise mechanisms that mediate the enhancement of tissue metabolism by triptans. Consequently, it is possible that novel drugs (selective of endothelial 5-HT1B receptors) may be identified for the acute treatment of migraine headache that selectively increase cranial oxygen extraction and metabolism in the absence of vasoconstriction.
Interestingly, our data might insinuate a possible link with migraine pathophysiology. Oxygen consumption increases in colocalized manner with neuronal activity after sensory stimulation (Vanzetta and Grinvald, 1999; Sheth et al., 2004), leading to local decreases in tissue oxygenation (Thompson et al., 2003). Because migraineurs can present cortical hyperexcitability (Aurora et al., 1999) and/or meningeal sensitization (Strassman et al., 1996), an investigation of whether exacerbated decreases in localized tissue oxygenation occur in these patients upon sensory stimulation would merit consideration.
Limitations and Caveats. In the present study, GR 127935 significantly reduced both donitriptan-induced decreases in VOS and increase in PvCO2, indicating the involvement of 5-HT1B/1D receptors. However, it will be interesting to consider the utility of selective 5-HT1B and 5-HT1D receptors antagonists. Nowadays, one would expect that pharmacological responses mediated by 5-HT1B receptors will be blocked by a selective 5-HT1B receptor antagonist (e.g., SB 224289) and resistant by a selective 5-HT1D receptor antagonist (e.g., BRL 15572).
In this study, the dose of sumatriptan used to observe the effects on jugular VOS and PvCO2 is supratherapeutic; therefore, the findings may not have any clinical relevance. As prospects, the augmented tissue metabolism could be evaluated by direct measures using either autoradiographic or 2-deoxyglucose methods (Sokoloff et al., 1977; Sakurada et al., 1978), allowing a best quantification of tissue metabolism changes.
In summary, donitriptan and sumatriptan elicited increases in arteriovenous oxygen saturation difference accompanied by increases in PvCO2. For donitriptan, both actions were inhibited by GR 127935, indicating mediation by 5-HT1B/1D receptors. In this model, donitriptan and sumatriptan were devoid of significant carotid vasoconstrictor effects and donitriptan failed to significantly affect regional cranial blood flow. In rats, donitriptan and sumatriptan increase cerebral oxygen consumption and tissue metabolism independently of cranial vasoconstriction, suggestive of an important and possibly overlooked mechanism of triptan action relevant to clinical headache relief.
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Footnotes |
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ABBREVIATIONS: 5-HT 5-hydroxytryptamine; GR 127935, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2[-methyl-4(5-methyl-1,2,4)-oxadiazol-3-yl]-(1,1 biphenyl)-4-carboxamide dihydrochloride; AVA, arteriovenous anastomosis; donitriptan, 4-[4-[2-[3-(2 amino-ethyl)-1H-indol-5-yloxy]-acetyl]-piperazin-1-yl]-benzonitrile hydrochloride; MAP, mean arterial pressure; HR, heart rate; CaBF, carotid blood flow; CaVR, carotid vascular resistance; ANOVA, analysis of variance; PaO2, oxygen partial pressure in arterial blood; PaCO2, carbon dioxide partial pressure in arterial blood; AOS, oxygen saturation in systemic arterial blood; VOS, jugular venous oxygen saturation; AVOSD, arterial-jugular venous oxygen saturation difference; PvO2, oxygen partial pressure in venous blood; PvCO2, carbon dioxide partial pressure in venous blood; SB 224289, 1'-methyl-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4;carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]; BRL 15572, 3-[4-(4-chlorophenyl)piperazin-1-yl]-1,1-diphenyl-2-propanol.HCL.
Address correspondence to: Dr. Robert Létienne, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres Cedex, France. E-mail: robert.letienne{at}pierre-fabre.com
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