Yukinaga Watanabe

Isoflurane and Sevoflurane Induce Vasodilation of Cerebral Vessels via ATP-sensitive K+Channel Activation

Background Activation of adenosine triphosphate‐sensitive K+ channels causes cerebral vasodilation. To assess their contribution to volatile anesthetic‐induced cerebral vasodilation, the effects of glibenclamide, an adenosine triphosphate‐sensitive K+ channel blocker, on the cerebral vasodilation induced by isoflurane and sevoflurane were studied. Methods Pentobarbital‐anesthetized dogs (n = 24) assigned to one of two groups were prepared for measurement of pial vessel diameter using a cranial window preparation. Each dog received three minimum alveolar concentrations (MAC; 0.5, 1, and 1.5 MAC) of either isoflurane or sevoflurane, and the pial arteriolar diameters were measured in the presence or absence of glibenclamide (10‐5 M) infused continuously into the window. Mean arterial pressure was maintained with phenylephrine. Furthermore, to assess the direct effect of isoflurane and sevoflurane on cerebral vessels, artificial cerebrospinal fluid was administered topically by being bubbled with isoflurane or sevoflurane. The blocking effect of glibenclamide on the vasoactive effects of these anesthetics also were evaluated. Results Isoflurane and sevoflurane both significantly dilated large (>or= to 100 [micro sign]m) and small (< 100 [micro sign]m) pial arterioles in a concentration‐dependent manner (6% and 10%, 3% and 8% for 0.5 MAC; 10% and 19%, 7% and 14% for 1 MAC; 17% and 28%, 13% and 25% for 1.5 MAC). Glibenclamide attenuated the arteriolar dilation induced by these anesthetics (not significant in isoflurane). Topical application of isoflurane or sevoflurane dilated large and small arterioles both in a concentration‐dependent manner. Such vasodilation was inhibited completely by glibenclamide. Conclusion The vasodilation of cerebral pial vessels induced by isoflurane and sevoflurane appears to be mediated, at least in part, via activation of adenosine triphosphate‐sensitive K+ channels.

Direct effects of ropivacaine and bupivacaine on spinal pial vessels in canine. Assessment with closed spinal window technique.

Background: Ropivacaine produces a vasoconstriction of cutaneous vessels in contrast to vasodilation produced by bupivacaine. To evaluate direct spinal microvascular actions of these local anesthetics, the authors investigated the concentration‐related effects of ropivacaine and bupivacaine on spinal pial vascular diameters using the spinal window technique. Methods: Anesthetized dogs (n = 14) divided into two groups (ropivacaine, n = 7; bupivacaine, n = 7) were prepared for measurement of spinal pial vessel diameters by intravital microscopy in a spinal window preparation. The authors administered six concentrations of each drug (10 sup ‐8 ‐10 sup ‐3 M) under the window and directly measured the spinal pial arteriolar and venular diameters at sequential times. Physiologic data including mean arterial blood pressure (MAP) and heart rate (HR) were determined before and after topical application of each concentration of the drugs. In additional experiments (n = 18), the action of topical ropivacaine and bupivacaine solution on spinal vessels was evaluated in the presence of yohimbine, prazosin, and propranolol. Results: Ropivacaine significantly constricted whereas bupivacaine dilated pial arterioles and venules, both in a concentration‐dependent manner. Microvascular alteration was not blocked with any of the adrenoceptor antagonists tested (yohimbine, prazosin, propranolol), each of which per se did not affect pial vessel diameters. Topical application of ropivacaine or bupivacaine did not induce any change in MAP or HR. Conclusions: The present results indicate that ropivacaine constricts and bupivacaine dilates the pial vessels of the spinal cord in a concentration‐dependent fashion, and the mechanisms involved in such actions do not seem to be mediated via alpha‐ or beta‐adrenoceptor of spinal vasculature.

Mechanisms of dexmedetomidine-induced cerebrovascular effects in canine in vivo experiments

Dexmedetomidine decreases cerebral blood flow without significantly affecting cerebral oxygen consumption in anesthetized dogs.To assess the direct cerebrovascular effects of dexmedetomidine, we investigated the responses of vasomotor tone to topical application of dexmedetomidine to pial vessels in vivo, using a parietal cranial window. Forty-one dogs were anesthetized with pentobarbital. In 20 dogs, we topically applied six concentrations of dexmedetomidine solution (10-8, 10-7, 10 (-6), 10-5, 10-4, 10-3 M) and directly measured pial arterial and venous diameters. In 10 dogs, the inhibitory effects of pretreatment of pial vessels with 10-5 M yohimbine were examined after the application of 10-5 M dexmedetomidine. In the remaining 11 dogs, the effects of 10-3 M dexmedetomidine were evaluated in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME), glibenclamide, or propranolol. Dexmedetomidine significantly constricted pial arteries and veins in a concentration-dependent manner (10-7 M to 10-4 M; P < 0.05). Yohimbine blocked dexmedetomidine-induced constriction of pial vessels (both large and small arteries and large veins P < 0.0001; small veins P < 0.005). However, when the highest concentration of dexmedetomidine (10-3 M) was administered under the window, pial vessel diameter was not significantly altered. In the presence of glibenclamide, 10-7 and 10-3 M dexmedetomidine induced a significant decrease in pial arterial diameter compared with 10-7 and 10-3 M dexmedetomidine solution alone, respectively (P < 0.05). L-NAME or propranolol did not affect the dexmedetomidine-induced constriction. Although yohimbine, glibenclamide, or propranolol did not change pial vascular diameter, L-NAME significantly constricted both pial arteries and veins (P < 0.05). Our study demonstrates that topical application of dexmedetomidine constricts both pial arterial and venous vessels in a concentration-dependent manner. The vasoconstrictor effects of dexmedetomidine appear to be mediated via activation of alpha2-adrenoceptors, although this action is accompanied by activation of adenosine triphosphate sensitive K+-channels as a counterbalancing vasodilatory effect. The present results also suggest that the resting tone of pial arteries and veins does not depend on alpha (2-and) beta-adrenergic control, but is influenced by nitric oxide. (Anesth Analg 1995;81:1208-15)

Intravenous dexmedetomidine inhibits cerebrovascular dilation induced by isoflurane and sevoflurane in dogs.

UNLABELLED Our aim in this study, performed using a closed cranial window preparation, was to investigate the effect of systemic pretreatment with dexmedetomidine on cerebrovascular response to isoflurane or sevoflurane. After instrumentation under pentobarbital anesthesia, 48 dogs were assigned to one of two groups: the isoflurane group or the sevoflurane group (n = 24 each). Twenty-four dogs received saline (n = 6) or one of three different doses of dexmedetomidine (0.5, 1.0, or 2.0 micrograms/kg) (n = 6 each) i.v. Animals were then exposed to three different minimum alveolar anesthetic concentrations (MACs; 0.5, 1.0, and 1.5) of either isoflurane or sevoflurane. Cerebrovascular diameters were measured at each stage. Pretreatment with dexmedetomidine decreased pial vessel diameters. Both isoflurane and sevoflurane significantly dilated both arterioles and venules in a concentration-dependent manner. Isoflurane- and sevoflurane-induced dilation of cerebral arterioles was significantly attenuated in the presence of dexmedetomidine. The dexmedetomidine-induced attenuation of the vascular responses was not dependent on the dose of dexmedetomidine and was not different between isoflurane and sevoflurane. The vasodilation of cerebral pial vessels induced by isoflurane and sevoflurane could be attenuated by the systemic administration of dexmedetomidine, and this interaction between dexmedetomidine and volatile anesthetics showed no evidence of dose-dependency. IMPLICATIONS The systemic administration of dexmedetomidine attenuates the dilation of cerebral vessels induced by isoflurane and sevoflurane in pentobarbital-anesthetized dogs. This interaction was not dependent on the clinical (0.5-2.0 micrograms/kg) dose of dexmedetomidine and was not different between isoflurane and sevoflurane anesthesia.

Direct effects of α1- and α2-adrenergic agonists on spinal and cerebral pial vessels in dogs

Background The effects of adrenergic agonists, often used as local anesthetic additives or spinal analgesics, on spinal vessels have not been firmly established. The authors investigated the effects of [Greek small letter alpha]2- and [Greek small letter alpha]1-adrenergic agonists on spinal and cerebral pial vessels in vivo. Methods Pentobarbital-anesthetized dogs (n = 28) were prepared for measurement of spinal pial-vessel diameter in a spinal-window preparation. The authors applied dexmedetomidine, clonidine, phenylephrine, or epinephrine in three different concentrations (0.5, 5.0, and 50 [micro sign]g/ml; [2.1, 1.9, 2.5, and 2.3] x [10-6, 10-5, and 10-4] M, respectively) under the window (one drug in each dog) and measured spinal pial arteriolar and venular diameters in a sequential manner. To enable the comparison of their effects on cerebral vessels, the authors also administered these drugs under a cranial window. Results On topical administration, each drug constricted spinal pial arterioles in a concentration-dependent manner. Phenylephrine and epinephrine induced a significantly larger arteriolar constriction than dexmedetomidine or clonidine at 5 [micro sign]g/ml (8%, 11%, 0%, and 1%, respectively). Spinal pial venules tended to be less constricted than arterioles. In cerebral arterioles, greater constrictions were induced by dexmedetomidine and clonidine than those induced by phenylephrine and epinephrine (14%, 8%, 0%, and 1%, respectively). Cerebral pial venules tended to exhibit larger constrictions than cerebral arterioles (unlike in spinal vessels). Conclusion Dexmedetomidine and clonidine constricted spinal vessels in a concentration-dependent manner, but such vasoconstrictions were smaller than those induced by phenylephrine and epinephrine.

Spinal conduction block by intrathecal ketamine in dogs

In addition to its use for intravenous (IV) anesthesia, ketamine can provide pain relief in humans when administered spinally.To elucidate the mechanisms of intrathecal (IT) ketamine analgesia, we observed differences in the effects of IV and IT ketamine on intraspinal evoked potentials (ISEPs) in 28 dogs anesthetized with pentobarbital. Bipolar extradural electrodes were inserted at the cervical and lumbar regions of the spinal cord for recording descending ISEPs represented by the two negative deflections, Waves I and II. IV ketamine 2 and 10 mg/kg did not affect the amplitude and latency of Wave I, whereas the large dose (10 mg/kg) significantly decreased the amplitude but not the latency of Wave II. IT ketamine 1 and 5 mg/kg caused significant dose-dependent decreases in both Wave I and II amplitudes and prolongations of both Wave I and II latencies. These IT effects on ISEPs are consistent with previous in vitro observations that ketamine blocks axonal conduction. We conclude that axonal conduction block may contribute to the analgesic mechanism of IT ketamine. (Anesth Analg 1997;85:106-10)

The effects of topical and intravenous ropivacaine on canine pial microcirculation

To assess the direct cerebrovascular effects of ropivacaine, we studied pharmacological responses to its topical and intravenous (IV) administration on vasomotor tone of pial vessels in in vivo experiments using a parietal cranial window in 24 dogs anesthetized with pentobarbital.We directly measured the diameters of pial arteries and veins after the administration of five different concentrations of ropivacaine solution (10-7 to 10-3 mol/L) randomly given into the window (n = 10). In six dogs, after pretreating the pial vessels with yohimbine (10-5 mol/L), the inhibitory action of yohimbine was examined after the application of ropivacaine (10-3 mol/L). The effects of IV ropivacaine (1 and 4 mg/kg) were also evaluated in the remaining eight dogs. Ropivacaine produced significant constriction of the pial arteries in a concentration-dependent manner (10-7 to 10-3 mol/L, P < 0.05) and only exerted a constrictive action on small veins (P < 0.05) at 10-3 mol/L. Yohimbine had no effect on ropivacaine-induced constriction of pial vessels. IV ropivacaine, 4 mg/kg but not 1 mg/kg, caused pial vascular constriction (large arteries P < 0.005, small arteries P < 0.0001, large veins P < 0.01, small veins P < 0.005) associated with decrease in heart rate (P < 0.001). The results indicate that topical application of ropivacaine constricts pial arterial vessels in a concentration-dependent manner. A large dose of IV ropivacaine produced pial vasoconstriction associated with a decrease in heart rate and no decrease in mean arterial blood pressure. These effects do not appear to be mediated via the mechanism that depends on the activation of alpha2-adrenoceptors. We conclude that ropivacaine in high concentrations could, perhaps directly, cause significant constriction of the central nervous system vasculature. (Anesth Analg 1997;85:75-81)

Clonidine premedication modifies responses to adrenoceptor agonists and baroreflex sensitivity

PurposeTo evaluate the effects of clonidine on responses to adrenoceptor agonists and baroreflex sensitivity, we examined arterial blood pressure (AP) responses to phenylephrine and heart rate (HR) responses to isoproterenol and baroreflex sensitivity (HR response to AP changes due to phenylephrine or nitroglycerin).MethodsWe studied 60 anaesthetized patients who either did or did not receive 5 μg·kg−1 clonidinepo before they were anaesthetized. After induction of general anaesthesia, the patients received 3 gmg·kg−1 phenylephrine, 0.02 μg·kg−1 isoproterenol, or 2–3 μg·kg−1 nitroglycerin, and haemodynamic measurements were taken. Baroreflex sensitivity was expressed as the slope of the linear regression line (msec·mmHg−1; in msec of R-R interval change vs mmHg change in systolic arterial pressure) following the administration of phenylephrine and nitroglycerin.ResultsPatients who received clonidine had greater augmented responses in AP to phenylephrine and in HR to isoproterenol (47.2 ± 15.6% vs 23.7 ± 11.9% for increase in systolic AP and 59.8 ± 22.6% vs 26.2 ± 11.0% for increase in HR,P < 0.05 respectively). There were no differences between the baroreflex sensitivities in the pressor (phenylephrine) test groups (3.77 ± 1.08 vs 4.41 ± 1.66 msec·mmHg−1). In contrast, the slopes of depressor (nitroglycerin) test groups were decreased in patients receiving clonidine (1.98 ± 0.73 vs 3.68 ± 1.72 msec mmHg−1,P < 0.05).ConclusionThe results suggest that premedication with clonidine might enhance critical hypotension during anaesthesia and surgery, but restoration both of AP and HR decrease can be achieved effectively by phenylephrine and isoproterenoliv, respectively.RésuméObjectifAfin d’évaluer les effets de la clonidine sur les réponses des récepteurs adrénergiques agonistes et sur la sensibilité baroréflexe, nous avons enregistré les changements de tension artérielle (TA) liés à la phényléphrine, les modifications de fréquence cardiaque (FC) liées à l’isoprotérénol et la sensibilité baroréflexe (les réactions de la FC aux changements de TA liées à la phényléphrine ou à la nitroglycérine).MéthodeNous avons étudié 60 patients qui avaient reçu ou non 5 μg·kg−1 de clonidinepo avant l’anesthésie. Après l’induction de l’anesthésie générale, les patients ont reçu 3 μg·kg−1 de phényléphrine, 0,02 μg·kg−1 d’isoprotérénol ou 2–3 μg·kg−1 de nitroglycérine, et on a procédé aux mesures hémodynamiques. La sensibilité baroréflexe était exprimée par la pente du tracé de régression linéaire (msec·mmHg−1; en msec de changement dans l’intervalle R-R vs en mmHg de changement dans la tension artérielle systolique) à la suite de l’administration de phényléphrine et de nitroglycérine.RésultatsLes patients qui ont reçu de la clonidine ont présenté des augmentations plus importantes de TA, en réaction à la phényléphrine, et de FC, en réaction à l’isoprotérénol (47,2 ± 15,6 % vs 23,7 ± 11,9 % concernant l’augmentation de la TA systolique et 59,8 ± 22,6 % vs 26,2 ± 11,0% concernant l’augmentation de FC,P < 0,05 respectivement). Il n’y a pas eu de différence de sensibilité baroréflexe entre les groupes testés pour les réactions au médicament stimulant, phényléphrine, (3,77 ± 1,08 vs 4,41 ± 1,66 msec·mmHg−1). En comparaison, les pentes des groupes du test hypotenseur (nitroglycérine) s’abaissaient chez les patients ayant reçu de la clonidine (1,98 ± 0,73 vs 3,68 ± 1,72 msec·mmHg−1,P < 0,05).ConclusionLes résultats laissent voir que la prémédication avec de la clonidine a pu favoriser une hypotension critique pendant l’anesthésie et la chirurgie, mais que le rétablissement de TA et de FC plus basses pouvait être réalisé efficacement avec de la phényléphrine et de l’isoprotérénoliv, respectivement.

The effects of bupivacaine and ropivacaine on baroreflex sensitivity with or without respiratory acidosis and alkalosis in rats.

Systemic toxicity of local anesthetics causes cardiac and central nervous system (CNS) depression that could be enhanced in the presence of respiratory acidosis.We examined a potential suppression of baroreflex function with bupivacaine and ropivacaine during hypercapnic acidosis or hypocapnic alkalosis. Baroreflex sensitivity (BRS) was randomly tested in rats with one of 13 conditions during intravenous administration of saline (control), bupivacaine 1, 2, or 3 mg/kg, or ropivacaine 2, 4, or 6 mg/kg. The effects of bupivacaine (3 mg/kg) or ropivacaine (6 mg/kg) on BRS were also examined during hypercapnic acidosis or hypocapnic alkalosis. The BRS was assessed using a value of Delta heart rate/Delta mean arterial pressure after infusion of phenylephrine (3 micro g/kg). Both bupivacaine and ropivacaine (at the largest dose) significantly suppressed BRS. Acute respiratory acidosis (pHa 7.24 +/- 0.04, PaCO2 63 +/- 4 mm Hg) enhanced BRS. The BRS enhanced during acidosis was also suppressed with bupivacaine and ropivacaine, but less so than in the absence of acidosis. The presence of hypocapnic alkalosis (pHa 7.55 +/- 0.03, PaCO2 25 +/- 2 mm Hg) did not affect BRS and reversed BRS suppression caused by both drugs. Thus, bupivacaine and ropivacaine affect neuronal control mechanisms for maintaining cardiovascular stability, and acute changes of respiration could significantly modify such suppression. (Anesth Analg 1997;84:398-404)

Attenuated additional hypocapnic constriction, but not hypercapnic dilation, of spinal pial arterioles during spinal ropivacaine.

UNLABELLED Ropivacaine constricts spinal vessels. Because the CO2 response of spinal vessels is similar to that of cerebral vessels, we tested to see if hypocapnia would cause further spinal vasoconstriction during ropivacaine administration. In 12 pentobarbital-anesthetized dogs, spinal pial arteriolar diameter was measured using a closed spinal window preparation. Either ropivacaine solution (0.1%; n = 6) or artificial cerebrospinal fluid (n = 6) was infused continuously into the spinal window. After a period of hypocapnia (Paco2, 20-25 mm Hg) had been induced, inspired CO2 levels were adjusted to produce normocapnia (35-40 mm Hg) followed by hypercapnia (55-60 mm Hg). When the desired Paco2 was reached, measurements were made of the arteriolar diameter and physiological variables. During normocapnia, ropivacaine infusion produced a significant constriction of pial arterioles, whereas artificial cerebrospinal fluid caused no change. Hypocapnia induced a much smaller (almost nonexistent) additional vasoconstriction in the ropivacaine group than in the control group (P < 0.01). The final hypercapnic vasodilation was somewhat greater during ropivacaine (P < 0.05 versus control group). Topical ropivacaine induced no change in hemodynamic variables. We conclude that hypocapnia of the magnitude tested did not cause further constriction in spinal vessels during spinal ropivacaine. IMPLICATIONS During topical application of the local anesthetic ropivacaine in dogs, hypocapnia (Paco2, 20-25 mm Hg) induced almost no additional constriction of spinal arterioles, and the hypercapnic vasodilation was maintained. These data suggest that an additional constriction in spinal vessels is unlikely when hypocapnia occurs during spinal ropivacaine.