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CARDIOVASCULAR
Centre de Recherche Pierre Fabre, Castres, France
Received May 26, 2003; accepted June 24, 2003.
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Abstract |
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, 2000; Dukat, 2001), via 5-HT1B receptor activation, decreased the hemoglobin oxygen saturation of venous blood draining the head concomitantly with cranial vasoconstriction (Létienne et al., 2003). These effects explain the observed increases in arteriovenous oxygen saturation difference with donitriptan, and are associated with closure of cephalic arteriovenous anastomoses (AVAs; Tom et al., 2002). However, the donitriptan-induced decreases in jugular venous oxygen saturation were unexpectedly accompanied by increases in jugular venous carbon dioxide partial pressure (Létienne et al., 2003), suggesting that in addition to closure of cephalic AVAs, donitriptan increases cerebral oxygen extraction and tissue metabolism (Létienne et al., 2003).
The current mechanisms of action of 5-HT1B/1D receptor agonists (triptans) in the acute relief of migraine headache are considered to comprise cranial vasoconstriction (Humphrey and Feniuk, 1991), 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). The observation that donitriptan promotes cerebral oxygen utilization and tissue metabolism (Létienne et al., 2003) implies that this additional mechanism of action may be relevant to the acute headache-relieving effects of donitriptan, and possibly other triptans.
The aim of the present investigation was therefore to examine whether other triptans produced similar effects to those of donitriptan in the anesthetized pig model. The effects of naratriptan (Connor et al., 1997), rizatriptan (Street et al., 1995), and sumatriptan (Humphrey and Feniuk, 1991), which are currently in routine clinical use, were investigated on cephalic arteriovenous oxygen saturation difference and hemodynamics in carotid, coronary, and systemic vascular beds. The data suggest that in addition to carotid vasoconstriction, enhancement of cephalic oxygen extraction and tissue metabolism is a class effect of triptans.
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Materials and Methods |
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Before thoracotomy, catheters were placed in the inferior vena cava via the left saphenous vein for drug/vehicle administration and in the right saphenous vein for anesthesia. A femoral artery was cannulated for aortic blood pressure measurements. Blood was withdrawn through this arterial line, and the right external jugular vein was catheterized for venous blood sampling to obtain measurements of arterial and venous blood gases. Blood flows were measured in left and right common carotid arteries by means of appropriately sized flow probes connected to a pulsed Doppler flow amplifier (VF1; Crystal Biotech, Northborough MA). The mean total carotid blood flow was calculated as the sum of left and right mean carotid blood flows. A left thoracotomy was performed in the 4th intercostal space. Aortic blood flow was measured with an electromagnetic flow probe (SP 2202; Gould Instrument Systems Inc., Cleveland, OH) placed around the thoracic aorta. The left anterior descending coronary artery was isolated and a pulsed Doppler flow probe was placed at its proximal level. Sterile saline was infused i.v. throughout the experiment to compensate for fluid loss (0.5–1 liter total volume).
Analog phasic pressure and flow outputs were fed simultaneously to an amplifier-recorder (Gould Instrument Systems Inc.) and to a personal computer equipped with an analog-to-digital converter board. Using Data flow software (Crystal Biotech), the sampling frequency for all analog signals was 200 Hz for high resolution. Calculated parameters were as follows: systemic vascular resistance was derived from mean arterial pressure (MAP) divided by aortic blood flow, total carotid vascular resistance was derived from MAP divided by total carotid blood flow, and coronary vascular resistance was derived from coronary perfusion pressure divided by left anterior descending coronary blood flow. Coronary perfusion pressure was determined as the difference between diastolic aortic pressure and left ventricular end-diastolic pressure.
Several blood gas parameters were determined: the oxygen and carbon dioxide partial pressure values in arterial and venous blood, PaO2, PaCO2, PvO2, and PvCO2, respectively, and arterial and venous pH. The arterial and venous oxygen saturation and the arteriovenous oxygen saturation difference (AVOSD) were calculated as described previously (Létienne et al., 2003).
Experimental Protocol. After completion of surgical procedures, a stabilization period at least 30 min was observed. Subsequently, animals received an i.v. infusion of either vehicle 1 (40% polyethylene glycol 300 in sterile saline; n = 9) or vehicle 2 (sterile saline; n = 10), or cumulative doses of naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 µg/kg; n = 7). Each dose of drug was infused over 15 min. Similarly, seven 15-min cumulative administrations of vehicle were infused in the vehicle groups.
Drugs. Azaperone was purchased from Janssen Pharmaceutica (Beerse, Belgium). Naratriptan, rizatriptan, and sumatriptan were synthesized by the Department of Analytical Chemistry (Centre de Recherche PierreFabre, Castres, France). Naratriptan was dissolved in 40% polyethyleneglycol 300 in sterile saline (0.9%), whereas rizatriptan and sumatriptan were dissolved in saline (0.9%). Drugs were weighed as base taking into account the salt-to-base ratio.
Data and Statistical Analysis. Dose-response curves were fitted using an operational sigmoid model (Origin; Microcal Software, Northampton, MA) from relative maximal effects induced by agonists. From the results of these analyses, the geometric mean dose of agonist producing 50% of the maximal response (ED50) was calculated with 95% confidence intervals (Black and Leff, 1983). To evaluate the area under a curve from values of the ordinate and the abscissa, the trapezoidal rule was used (Tallarida and Murray, 1987). One-factor analysis of variance (ANOVA) with repeated measurements followed by Dunnett's test (SigmaStat; Jandel, Erkrath, Germany) was used to assess significance among and between groups, and the unpaired Student`s t test as an additional post hoc test was used when appropriate (SigmaStat).
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Results |
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Effects of Naratriptan, Rizatriptan, and Sumatriptan on Arterial Blood Gas Parameters. Baseline values and maximal effects of sumatriptan, naratriptan, and rizatriptan on arterial blood gas parameters are presented in Table 1. The PaO2, PaCO2, arterial oxygen saturation (AOS) and arterial pH (apH) values were comparable among groups (P = N.S.; Table 1). As in vehicle-treated pigs, in rizatriptan- and sumatriptan-treated animals, a comparable significant decrease in PaO2 occurred with time, whereas with naratriptan, a slight but nonstatistically significant decrease in PaO2 was observed (P = 0.086). PaCO2, AOS, and apH were not significantly affected by different treatments, the maximal variations in PaCO2 induced by naratriptan, rizatriptan, and sumatriptan were 1.5 ± 1.6, 1.2 ± 0.7, and 1.1 ± 1.3 mm Hg, respectively (P = N.S. compared with vehicle group).
Effects of Naratriptan, Rizatriptan, and Sumatriptan on Venous Blood Oxygen Status. Baseline values and maximal effects of naratriptan, rizatriptan, and sumatriptan on venous blood oxygen status are summarized in Table 2. The initial PvO2 values were comparable among the four groups (P = N.S.). Naratriptan and sumatriptan slightly but significantly decreased PvO2, with maximal variations of –4.8 ± 1.4 mm Hg (P < 0.05) and –6.2 ± 3.2 mm Hg (P < 0.05), respectively, compared with vehicle (Table 2). Rizatriptan dose dependently and significantly reduced PvO2 (P < 0.01), compared with vehicle (Table 2). In the vehicle group, venous oxygen saturation (VOS) remained unchanged throughout the experiment (69.0 ± 3.6 and 68.4 ± 3.4%, initial and end-experiment values, respectively; P = N.S.). In naratriptan-, rizatriptan-, and sumatriptan-treated animals, VOS decreased dose dependently [geometric mean ED50 values: 3.1 µg/kg and 95% confidence limits ND-19.1 µg/kg; 17.9 (ND-59.4), and 16.0 (ND-67.5) µg/kg, respectively]. Animals did not systematically decrease VOS in response to a triptan. Table 3 shows the number of responders in naratriptan, rizatriptan and sumatriptan groups with overall 11/21 responders with 
10% decreases from baseline VOS values and 9/21 with changes 25%. Figure 1A shows that rizatriptan-induced decreases in VOS were more pronounced than for naratriptan (P = 0.149) or sumatriptan (P = 0.304). For VOS, the area under the curve (arbitrary values) calculated for naratriptan, rizatriptan, and sumatriptan were –34,216 ± 9,057 (P < 0.01), –59,440 ± 19,100 (P < 0.001), and –27,695 ± 16,584 (P < 0.05), respectively, compared with vehicle (–1,223 ± 5,575). Consequently, because AOS remained unchanged throughout the experiment, the AVOSD significantly increased from 10 or 40 µg/kg naratriptan, rizatriptan, or sumatriptan [maximal variation 10.2 ± 3.2 (P < 0.05), 16.5 ± 6.0 (P < 0.05), and 9.3 ± 4.6 mm Hg (P < 0.05), respectively, compared with vehicle; Table 2). No significant variations in pH were found in the venous blood analyses (Table 1).
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Effects of Naratriptan, Rizatriptan, and Sumatriptan on PvCO2. The initial values of PvCO2 measured in the triptan-treated groups were similar to those of the vehicle group (Table 2). Vehicle was devoid of significant effects per se on PvCO2 as indicated in Table 2 (maximal effect –0.8 ± 1.3 mm Hg; P = 0.522). Rizatriptan significantly and dose dependently from 160 µg/kg increased PvCO2 (P < 0.05 versus vehicle group). Figure 1B shows that sumatriptan also tended to increase PvCO2. As observed for changes in VOS, animals did not systematically increase PvCO2 in response to a triptan, with 10% increases in PvCO2 over baseline observed in 3/7, 5/7, and 4/7 animals in the naratriptan, rizatriptan, and sumatriptan groups, respectively (overall 12/21 responders; Table 3), which are similar to the VOS response rates, but only 4/21 animals responded with 25% increases in PvCO2 (Table 3). The areas under the curve for increases in PvCO2 in the presence of naratriptan, rizatriptan, and sumatriptan were 8,250 ± 8,139 (P = 0.37), 56,189 ± 19,384 (P < 0.05), and 16,408 ± 13,480 (P = 0.26) compared with vehicle (2,605 ± 9,728). Figure 1B clearly shows that for PvCO2 the profile of rizatriptan is different, the maximal variation in PvCO2 was 24.9 ± 8.9% (P = 0.078 compared with naratriptan, 6.1 ± 4.0% and P = 0.127 compared with sumatriptan, 7.6 ± 5.7%). Thus, overall response rates corresponding to 10 or 25% changes from baseline were, respectively, 95.2 and 85.7% for carotid resistance, 52.4 and 42.5% for VOS, and 57.1 and 19.0% for PvCO2. The data indicate that as percent changes from baseline increase from 10 to 25%, the parameter most affected is PvCO2 (Table 3). A highly statistically significant linear correlation exists between PvO2 and PvCO2 (R = –0.50, P = 0.002, n = 40; Fig. 2A), but not between total carotid vascular resistance and PvO2 (Fig. 2B) or PvCO2 (Fig. 2C). In Fig. 2, data are pooled from the 40 animals used in the present investigation.
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Effects of Naratriptan, Rizatriptan, and Sumatriptan on Hemodynamic Parameters. Baseline values of hemodynamic parameters for the four groups are summarized in Table 4. Under baseline conditions, in triptan-treated groups, MAP, heart rate (HR), systemic vascular resistance (SVR), and coronary vascular resistance (LADVR) values were not significantly different to those of the vehicle group. Initial total carotid vascular resistance (TCVR) was significantly lower in rizatriptan than in the other groups (P < 0.05; Table 4). In vehicle-treated pigs, MAP did not undergo notable variations throughout the experiment, but HR gradually decreased with time. Vascular resistances (SVR, TCVR, and LADVR) were not significantly affected by vehicle compared with initial values (maximal variations in SVR, TCVR, and LADVR reached 12 ± 5%, P = 0.58; 8 ± 6%, P = 0.59; and 15 ± 6%, P = 0.61, respectively). Similar gradual decreases in HR were observed in triptan-treated animals. Naratriptan and sumatriptan significantly increased MAP0 (maximal changes 16.6 ± 4.5, P < 0.05; 13.9 ± 7.4%, P < 0.05 compared with the vehicle group). Rizatriptan elicited no significant increases in MAP (maximal effect 7.0 ± 3.2%, P = 0.128). Sumatriptan and rizatriptan tended to increase SVR (maximal increase 31 ± 16%, P = 0.11; and 27 ± 10%, P = 0.16, respectively, compared with vehicle), but only naratriptan significantly increased SVR (P < 0.05). Naratriptan, rizatriptan, and sumatriptan evoked dose-dependent increases in TCVR, leading to 53 ± 14, 61 ± 8, and 61 ± 14% maximal increases (P < 0.05, compared with vehicle; Fig. 1C), with geometric mean ED50 values of 7.1 µg/kg [95% confidence limits 4.1–12.1 µg/kg, 15.6 (12.8–17.9), and 17.9 (8.2–59.4 µg/kg), respectively]. Figure 1C shows that for TCVR, contrary to VOS or PvCO2, naratriptan, rizatriptan, and sumatriptan effects are comparable. Indeed, of the 21 animals that received a triptan, only one (in the sumatriptan group) failed to generate 10% increases in TCVR (overall 20/21 responders) and only two animals failed to produce 20% increases in TCVR (Table 3). Naratriptan, rizatriptan, and sumatriptan produced no significant changes in LADVR.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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) in the anesthetized pig. The three triptans investigated dose dependently decreased jugular venous hemoglobin oxygen saturation without affecting systemic arterial oxygen saturation, leading to increases in cephalic AVOSD. Although both naratriptan and sumatriptan tended to increase carbon dioxide partial pressure in jugular venous blood, statistically significant increases were observed only with rizatriptan. In contrast, quantitatively similar increases in carotid vascular resistance were produced by the three triptans. Response rates for triptan-induced decreases in jugular VOS and increases in jugular PvCO2 were approximately 2-fold lower than those for triptan-induced carotid vasoconstriction. The data strongly suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.
Triptan-Induced Increases in AVOSD. Naratriptan, rizatriptan, and sumatriptan dose dependently reduced VOS without significantly affecting systemic AOS or PaO2. The increases in AVOSD evoked by these drugs can therefore be explained by selective decreases in jugular VOS, which in turn can plausibly be explained by closure of cephalic AVAs (Den Boer et al., 1991; Tom et al., 2002; Létienne et al., 2003). Donitriptan, in addition to decreasing jugular hemoglobin oxygen saturation was unexpectedly found to increase PvCO2 (Létienne et al., 2003), indicating augmented cephalic oxygen consumption and metabolism. These effects occur concomitantly with carotid vasoconstriction and both vascular and blood gas effects are 5-HT1B receptor-mediated (Létienne et al., 2003). Because naratriptan, rizatriptan, and sumatriptan are also relatively selective 5-HT1B/1D receptor agonists (Goadsby, 1998; De Vries et al., 1999), but behave as partial agonists (John et al., 1999, 2000), similar but possibly less efficacious (i.e., lower magnitude and less consistent) actions to those described for donitriptan might be expected. The results of the present investigation show that this is indeed the case. Naratriptan, rizatriptan, and sumatriptan dose dependently and significantly increased carotid resistance to a similar extent (53 to 61% maximum increase). However, the three triptans did not evoke identical changes in blood gas parameters. Indeed, these drugs significantly decreased jugular hemoglobin oxygen saturation, with the greatest maximal decrease being elicited by rizatriptan, whereas only the latter produced statistically significant increases in jugular PvCO2, with naratriptan and sumatriptan showing a moderate propensity to increase the parameter. Increases in PvCO2 associated with decreases in PvO2 are indices of augmented tissue metabolism (Dejours, 1963). Because systemic AOS or PaO2 remained unaffected by naratriptan, rizatriptan, or sumatriptan, effects on hemoglobin oxygen affinity or on pulmonary blood oxygenation can be excluded. Because none of the triptans investigated affected arterial or venous pH or PaCO2, metabolic acidosis can also be ruled out. Changes in PvCO2 are "not readily apparent" due to the low resolution and sensitivity of this parameter to changes in tissue metabolism. This is because physiological arteriovenous differences are relatively small (5–7 mm Hg) and tissue reserves of dissolved CO2 are around 17-fold larger than those of oxygen (Farhi and Rahn, 1960). Thus, a small increase in venous PCO2 reflects marked increases in tissue reserve and metabolism (Dejours, 1963). This implies that naratriptan and sumatriptan, despite increasing PvCO2, albeit nonstatistically significantly, nevertheless enhance cerebral metabolism. This is supported by the decreases in jugular oxygen saturation evoked by both triptans, and the significant correlation observed between jugular venous oxygen saturation and PvCO2. Because naratriptan, rizatriptan, and sumatriptan produced qualitatively similar changes in carotid resistance but not in jugular oxygen saturation or PvCO2, the possibility is raised that such events may occur independently. This tenet is supported by a significant linear correlation observed between PvCO2 and PvO2 (P = 0.002), but not between PvCO2 or PvO2 and carotid resistance (P = 0.76 and 0.28, respectively). Carotid vasoconstriction occurred in practically all triptan-treated animals (lowest response rate 85.7%), but not decreases in jugular venous oxygen saturation or increases in PvCO2 (lowest response rate 19.0%) with nonresponders occurring in each group. This latter observation is intriguing, because it is well established that fewer than one-half the migraine patients treated with naratriptan, rizatriptan, or sumatriptan, or indeed other currently available triptans, are pain-free 2 h later (Goadsby et al., 2002). The 57.1 and 19.0% PvCO2 response rates (i.e., corresponding to 10 and 25% changes over baseline) observed in the present study for naratriptan, rizatriptan, and sumatriptan are, respectively, reminiscent of the 55 to 60% of patients that show a headache response and the 30% that become pain free with these drugs given orally (Goadsby et al., 2002). After subcutaneous sumatriptan, headache response rates are higher, with 76% patients showing improvement and 48% pain free (Ferrari, 1991). Consequently, determining whether the clinical headache response to a triptan occurs concomitantly with changes in jugular venous PCO2 levels might shed further light on this issue, despite the practical difficulties involved.
A Further Mechanism of Action of Triptans. The main mechanisms currently thought to underlie the therapeutic action of triptans in the acute relief of migraine include cranial vasoconstriction (Humphrey and Feniuk, 1991), peripheral neuronal inhibition associated with reduced release of sensory neuropeptide vasodilators (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). Our previous observation with donitriptan (Létienne et al., 2003) and present results with other triptans indicating augmented cerebral oxygen utilization and tissue metabolism implies that this additional mechanism of action may also be relevant to the acute headache-relieving effects of triptans as a whole. Interestingly, if the latter mechanism does indeed prove to be relevant to the acute antimigraine effects of triptans, the corollary might provide a clue as to the nature of the hitherto elusive migraine trigger. In this respect, it is tempting to speculate that cerebral focal hypo-oxygenation may be involved, as suggested previously (Amery, 1982). The availability of analytically powerful techniques such as blood oxygen level-dependent functional magnetic resonance imaging (Thompson et al., 2003) may encourage future investigation in this direction. Further studies are warranted to define the precise cellular and molecular mechanisms that mediate the enhancement of tissue metabolism by triptans.
In conclusion, naratriptan, rizatriptan, and sumatriptan robustly produced vasoconstriction of equivalent magnitude in the carotid vascular bed, but evoked decreases in jugular oxygen saturation and particularly increases in PvCO2 in a less consistent manner, possibly implying distinct mechanisms. Collectively, the data indicate that triptan-induced increases in AVOSD and PCO2 in venous blood draining the head are class effects.
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Footnotes |
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; AVA, arteriovenous anastomosis; MAP, mean arterial pressure; AVOSD, arterial-jugular venous oxygen saturation difference; ANOVA, analysis of variance; AOS, oxygen saturation in systemic arterial blood; apH, arterial pH; VOS, jugular venous oxygen saturation; HR, heart rate; SVR, systemic vascular resistance; LADVR, left anterior descending vascular resistance; TCVR total carotid vascular resistance; ND, not determined.
Address correspondence to: Dr. G. W. John, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres Cedex, France. E-mail: gareth.john{at}pierre-fabre.com
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) ± S.E.M. in arterial blood gas parameters after vehicle, naratriptan, rizatriptan, or sumatriptan administration.
