alpha2-Adrenoceptor agonists, such as clonidine and dexmedetomidine, reduce blood pressure as well as decrease sympathetic nervous activity and transmission of pain information . Dexmedetomidine, the dextro enantiomer of medetomidine, is a potent and highly selective alpha2-adrenoceptor agonist [1,2], which reduces requirements for intravenous drugs [3,4], volatile anesthetics [5,6], and narcotics , and exerts hypnotic , sedative , analgesic , and opioid-induced muscle rigidity relaxing  effects. As indicated in animal experiments [12,13], the intrathecal administration of dexmedetomidine offers promise of clinical utility in the perioperative interval. An examination of the effects of dexmedetomidine when administered topically to the brain and spinal cord is necessary.
The alpha2 receptors in cerebral arteries play an important role in cerebrovascular constriction . Clonidine, also an alpha2-adrenoceptor agonist, exerted cerebrovascular constrictive effects in vivo  and in vitro . Because of dexmedetomidine's high potency and selectivity for alpha2 adrenoceptors, it also should affect the cerebral vasculature. Indeed, dexmedetomidine decreased cerebral blood flow in isoflurane-anesthetized dogs . However, a direct cerebrovascular effect of dexmedetomidine and its mechanism has not been established.
To investigate the direct effects of topical application of dexmedetomidine on pial vascular tone, we performed the present study in anesthetized dogs using cranial window and intravital microscopy techniques. After demonstrating that dexmedetomidine produced concentration-dependent pial vasoconstriction, we studied the effects of yohimbine, an alpha2-adrenoceptor antagonist, Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase , glibenclamide, an adenosine triphosphate (ATP)-sensitive K+-channel blocker, and propranolol, a beta-adrenergic antagonist, on pial vasoconstriction induced with dexmedetomidine.
The experimental protocols were approved by our Institutional Committee for Animal Care. Forty-one dogs weighing 6-10 kg were anesthetized with pentobarbital sodium (20 mg/kg) intravenously [IV] and vecuronium (4 mg IV) and subsequently maintained with a continuous infusion of pentobarbital sodium (2 mg mg centered dot kg-1 centered dot h-1). After tracheal intubation, each dog was mechanically ventilated. The tidal volume and respiratory rate were adjusted to maintain a PaCO2 of 35-42 mm Hg, and supplemental oxygen was used to maintain PaO2 between 120 and 160 mm Hg. Catheters were inserted into the left femoral vein to administer fluid and drugs and into the left femoral artery to measure mean arterial blood pressure (MAP) and to provide blood samples for arterial blood gas analysis. Rectal temperature was maintained between 36.5 and 37.5 degrees C by a water-circulating warming blanket.
A closed cranial window was used to visualize the pial microcirculation . The scalp was retracted and the temporalis muscle was removed. A hole 2 cm in diameter was made in the parietal bone. After the coagulation of dural vessels with a bipolar electrocoagulator, the dura was cut and retracted over the bone. A stainless steel ring with a cover glass was placed over the hole and secured with bone wax and dental acrylic. The space under the window was filled with artificial cerebrospinal fluid (aCSF), and four polyethylene catheters were inserted into the ring. One catheter was attached to a reservoir bottle containing aCSF to maintain a constant intracranial pressure of 7 cm H2 O. Three other catheters served as an inlet and an outlet for aCSF and study drug solutions, and for continuous monitoring of intracranial pressure. The volume of fluid below the window was between 0.5 and 1 mL. The compositions of aCSF were Na+, 151 mEq/L; K+, 4 mEq/L; Ca2+, 3 mEq/L; Cl-, 110 mEq/L; and glucose, 100 mg/dL; pH was adjusted to 7.48, and the solution was bubbled with mixture of 5% CO2, 20% O2, and 75% N (2) at 37.0 degrees C.
The diameters of pial arteries and veins were measured by videomicrometer (Olympus Flovel videomicrometer, Model VM-20; Flovel, Tokyo, Japan) on a television monitor which was attached to a microscope (Model OMK-1; Olympus, Tokyo, Japan).
The study was divided into three stages, the first to investigate the effects of dexmedetomidine on pial vessels (n = 20), the second to investigate the effects of yohimbine (n = 10), and the third to investigate the effects of L-NAME, glibenclamide, and propranolol (n = 11).
In the first set of experiments, dexmedetomidine (Farmos, Turku, Finland) was freshly dissolved in aCSF and six different concentrations (10-8, 10-7, 10-6, 10-5, 10-4, and 10-3 M solutions) were used for the study. After 30 min of stabilization, the measurements of pial arterial and venous diameters and various laboratory data including MAP, heart rate, rectal temperature, arterial pH and gas tensions, serum electrolytes, and glucose concentration were performed before and after sequential, topical application of six different concentrations of dexmedetomidine into the cranial window. To establish the baseline vessel size, the window was flushed continuously with aCSF for 40 min after each measurement. After 40 min from the last administration, the pial vascular diameters had returned to control values.
In the second set of experiments, we evaluated the effects of yohimbine (Wako, Osaka, Japan), an alpha2-adrenoceptor antagonist, on the constrictive action of topical 10-5 M dexmedetomidine. The concentration of yohimbine was 10-5 M dissolved in aCSF. After the completion of baseline measurements after topical application of 10-5 M yohimbine, 10-5 M dexmedetomidine solution was applied and the measurements were repeated.
In the third set of experiments, we examined the effects of L-NAME (Sigma, St. Louis, MO), glibenclamide (Sigma), and propranolol (Wako) on 10-3 M dexmedetomidine-induced pial vascular alteration. Glibenclamide was dissolved in 100% dimethyl sulfoxide and then diluted to a concentration of 10-5 M solution in aCSF. The concentration of dimethyl sulfoxide in the 10-5 M glibenclamide solution was 0.1%. Upon completion of baseline measurements after topical use of 10-3 M L-NAME, 10-5 M glibenclamide, or 10-3 M propranolol, dexmedetomidine 10-3 M solution was applied and the measurements were repeated.
Since we found that glibenclamide influenced the 10-3 M dexmedetomidine-induced pial vascular alteration, we tested the effects of glibenclamide on 10-7 and 10-5 M dexmedetomidine-induced pial vascular constriction (n = 5).
Comparisons of MAP, heart rate, body temperature, pH, PaCO2, PaO (2), Na+, K+, and blood sugar among all experimental groups were performed using one-way analysis of variance (ANOVA) with post hoc Scheffe's F-testing. Intergroup differences in MAP, heart rate, and body temperature were determined by paired t-test.
The sizes of blood vessels were divided on the basis of initial diameter into two subgroups, >200 and <200 micro meter. Concentration-dependent effects of dexmedetomidine and the effects of L-NAME, glibenclamide, and propranolol against dexmedetomidine were examined via ANOVA and Bonferroni's corrections for post hoc comparisons. Inhibitory effects of yohimbine for dexmedetomidine-induced pial vasoconstriction were determined by ANOVA with post hoc Scheffe's F-testing. A P value less than 0.05 was considered statistically significant. Values were represented as mean +/- SEM.
There was no difference in rectal temperature, arterial pH, PaCO2, PaO2, and electrolytes among each experimental application period; topical application of dexmedetomidine did not induce any changes in MAP and heart rate, except at a concentration of 10-3 M Table 1. The application of 10-3 M was associated with an increase in MAP (P < 0.0005) and a decrease in heart rate (P < 0.005). Those changes in MAP and heart rate were also observed after dexmedetomidine in the presence of L-NAME (MAP P < 0.001; heart rate P < 0.05), glibenclamide (MAP P < 0.0005; heart rate P < 0.01), and propranolol (MAP P < 0.05; heart rate P < 0.05). No alteration in MAP or heart rate was detected after the infusion period of propranolol alone Table 1.
Dexmedetomidine at 10-8 to 10-4 M produced significant concentration-dependent constriction in pial large and small arteries and large veins (10-8 M, 10-7 M < 10-5 M, 10-4 M, P < 0.05; Figure 1). The topical pretreatment of 10-5 M yohimbine abolished the 10-5 M dexmedetomidine-induced pial arterial (large and small, P < 0.0001) and venous constriction (large, P < 0.0001; small, P < 0.005; Figure 2), but yohimbine per se had no effect on pial vascular diameter.
The highest concentration of dexmedetomidine (10-3 M) produced no significant change in pial arterial diameter Figure 1. The presence of topical L-NAME and propranolol did not modulate the alteration of 10-3 M dexmedetomidine-induced pial vascular responses Figure 3. Topically applied 10-5 M glibenclamide or 10-3 M propranolol had no effect on pial vascular diameters but L-NAME at 10 (-3) M caused pial arterial and venous constriction (P < 0.05; Table 2). In the presence of glibenclamide, dexmedetomidine at 10-7, 10-5, and 10-3 M constricted large and small arteries; the changes in vessel diameters were statistically significant as compared with topical 10-7 and 10-3 M dexmedetomidine solution alone (P < 0.05; Figure 4).
The present study demonstrates that the topical application of dexmedetomidine (10-8, 10-7, 10-6, 10-5, and 10-4 M) dissolved in aCSF produced the concentration-dependent constriction of pial arteries and veins in dogs. Since the effects were blocked by yohimbine, an alpha2 antagonist, the dexmedetomidine-induced vasoconstriction appears to involve the activation of alpha2 adrenoceptors. This supports results of previous studies of isolated cerebral vessels [16,20]. However, the highest concentration of dexmedetomidine (10-3 M) did not cause constriction in pial vessels. Glibenclamide, but not L-NAME or propranolol, was associated with a significant constriction after the subsequent application of 10-3 M dexmedetomidine in large and small pial arteries. Topical application of 10-3 M dexmedetomidine also induced systemic or central cardiovascular effects (increased MAP and decreased heart rate), perhaps alpha2-adrenoceptor-mediated responses via central or an unknown mechanism.
The circumstances of the present study differ from previous in vitro  or in vivo studies [17,21]. Topical application evaluates the direct effect on cerebral vessels in situ and avoids the confounding effect of dexmedetomidine-induced systemic cardiovascular effects, such as an increase in MAP and a decrease in heart rate . The cranial window technique used in the present study is feasible, allows reproducible measurements of "topical" parietal pial vessels with a reasonable degree of accuracy, and does not impair vascular reactivity. Once the window is fixed in place, the pial vessels can be directly studied for several hours and changes in the pial vessels due to topical application of vasoactive agents or drugs can be studied . The invasive nature of the preparation requires anesthetic maintenance. Depression of the responsiveness of cerebral arteries  caused by anesthetics is an unavoidable problem inherent in this in vivo methodology in contrast to in vitro studies. Although anesthetics in concentrations used in surgical anesthesia appear to affect only the magnitude, and not the direction, of the vascular responses , the effects of anesthetics must be taken into account. Pentobarbital, used in the present study, seems to have no effect on isolated cerebral vessels . Furthermore, the other factors that might affect cerebral vessels, such as pHa, PaCO2, PaO2, electrolytes, and glucose, were similar during experiments as shown in Table 1. Therefore, we can exclude the possibility that pentobarbital anesthesia or other physiologic factors affected the present results obtained with dexmedetomidine at 10-8 M to 10-4 M.
It is possible that the constriction of pial vessels induced by dexmedetomidine might be attributable to decreased metabolic demands, perhaps secondary to decreased neuronal activity . Clonidine-induced reduction in spinal cord blood flow was apparently due, in part, to a decrease in metabolism, as measured by glucose metabolism . In a previous study, pial vasodilation associated with topical cocaine, which is thought to increase cerebral metabolism, could not be separated from vasodilation secondary to increased cerebral metabolism . However, since dexmedetomidine-induced pial arterial and venous constriction was blocked with yohimbine, which is 60 times more selective for the alpha2 than the alpha1 receptors , the contribution of decreased cerebral metabolism, if any, should be minimal. It is likely that alpha (2) adrenoceptors exist and are physiologically important both in large and small arteries in dogs. Although alpha2 adrenoceptors are located in the canine isolated saphenous vein , no data are available regarding canine pial veins. In our previous canine study using the cranial window technique, we reported that nicorandil, a K+-channel opener, produced a concentration-dependent dilation of pial veins similar to pial arteries . In the present study, dexmedetomidine constricts pial veins relatively more than pial arteries. Since dexmedetomidine-induced pial venous constriction diminished in the presence of yohimbine, the results indicate that alpha2 adrenoceptors exist both on large and small veins, and play a role in venous constriction. Thus the present results confirm the involvement of alpha (2-adrenoceptor-mediated) dexmedetomidine-induced pial arterial and venous constriction.
The results of the application of 10-3 M dexmedetomidine appear to be complex. When we administered 10-3 M dexmedetomidine into the cranial window, large and small arteries and small veins did not constrict, despite a 15%-25% increase in MAP. The increase in MAP could cause some constriction of pial arteries as a function of normal autoregulation; however, one may assume that the presence of dexmedetomidine could affect the autoregulation of pial arteries.
To investigate these surprising results, we have tested whether other mechanisms could be involved at a higher concentration. These include the NO, ATP-sensitive K+ channel, and the other adrenoceptor mechanisms. First, data suggest that alpha1 adrenoceptors do not mediate 10-3 M dexmedetomidine-induced changes in cerebrovascular tone. In rats, dexmedetomidine in high concentrations stimulated alpha1 adrenoceptors . In canine pial arteries, alpha1 adrenoceptors were not detected . Second, ATP-sensitive K+ channels reportedly are present in cerebrovascular smooth muscle cells [31-33], and play an important role in modulating cerebrovascular tone . Activation of these channels markedly dilates pial arteries . We have also reported that ATP-sensitive K+ channel openers, nicorandil and cromakalim, dilated pial arteries and veins in a concentration-dependent manner . Because glibenclamide, an ATP-sensitive K+ channel blocker, altered the responses of small arteries and veins induced by dexmedetomidine Figure 3, Figure 4, the lack of vasoconstriction in response to its 10-3 M concentration appears to be related to activation of ATP-sensitive K+ channels; a vasodilative effects via which might, to some extent, counteract dexmedetomidine-induced vasoconstriction via alpha2 adrenoceptors. Third, vasoconstrictive responses to alpha2 adrenergic stimulation could be influenced by release of NO . However, pretreatment with L-NAME, an inhibitor of NO synthase, failed to influence the response to 10-3 M dexmedetomidine. Coughlan et al.  reported in a recent in vitro study that L-NAME was associated with an exaggerated constrictor response to dexmedetomidine in coronary but not in cerebral arteries. In vivo, inhibition of NO synthase induced by systemic L-NAME did not affect dexmedetomidine-induced decreases in cerebral blood flow .
Although the cranial window technique primarily demonstrates the topical response of pial vessels to topically applied vasoactive drugs, higher concentrations of drugs could produce systemic actions or neuronally mediated cardiovascular effects. The former is well known in spinally as well as epidurally administered drugs in clinical anesthesia. In the present study, topical application of 10-3 M dexmedetomidine also increased MAP and decreased heart rate, changes associated with systemic IV administration . The hypertensive effect of IV dexmedetomidine is mediated by activation of alpha2 adrenoceptors in peripheral vascular smooth muscle . Alternatively, 10-3 M dexmedetomidine could stimulate intracranial vasomotor centers such as the nucleus tractus solitarius which is activated by alpha2 agonists .
In the present study, topical application of yohimbine, an alpha2 antagonist, and propranolol, a beta antagonist, did not affect the resting tone of canine pial vessels, but topical L-NAME per se significantly constricted pial vessels. Propranolol given IV has also been reported not to affect the diameters of large and small pial arteries . Busija and Leffler  have shown that norepinephrine constricts pial vessels via stimulation of alpha2 adrenoceptors in newborn pigs, and that IV prazosin, an alpha1 antagonist, did not affect the resting tone of pial vessels. Therefore, we speculate that the resting tone of pial vessels is unlikely to be dependent on alpha and beta adrenoceptors. Since systemic L-NAME profoundly decreased cerebral blood flow in isoflurane-anesthetized dogs without reducing cerebral oxygen consumption , the resting tone of pial vessels is likely, at least in part, mediated by NO. Recent in vitro  and in vivo data  support our speculation that NO influences basal cerebrovascular tone.
IV administration of 10 micro gram/kg of dexmedetomidine reduced cerebral blood flow 45%  or 37%  without changing cerebral metabolism in isoflurane-anesthetized dogs, and decreased cerebral blood flow 34% in halothane-anesthetized dogs . Volatile anesthetics such as isoflurane and halothane are potent direct cerebral vasodilators; their action is potentiated by K+ channel blockade induced by tetraethylammonium . The pial vascular effects of high concentrations of dexmedetomidine are related to K+ channel activation. Further, although the results were obtained in vitro, not in cerebral vessels, volatile anesthetics can induce a vascular effect via NO-dependent mechanisms , and halothane-induced vasodilation seems to be, in part, mediated by opening K+ channels . Therefore, a significant interaction between dexmedetomidine and anesthetics could possibly occur in the vascular reactivities as well as the neuronal functions of the central nervous system. Since anesthetic-induced flow changes appear to be mediated by changes in cerebro- vascular resistance, it is possible that dexmedetomidine counteracts an anesthetic-induced dilation of the cerebral vessels. However, whether dexmedetomidine-induced cerebral vasoconstriction could be modulated by volatile or IV anesthetics awaits further in vivo studies.
In summary, the present study demonstrates that topical application of dexmedetomidine produced pial arterial and venous constriction in a concentration-dependent manner (10-8 M to 10-4 M) in an in vivo canine model with a cranial window. The mechanism of such action is mediated by the activation of alpha2 adrenoceptors. High concentrations of dexmedetomidine also may activate ATP-sensitive K+ channels, thus counteracting the constrictive action.
The authors thank Drs. S. Ohta and S. Akamatsu, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, for their help to performing the experiments. The authors would like to acknowledge the generous donation of dexmedetomidine by Farmos, Turku, Finland.
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