Isoflurane produces endothelium-independent relaxation in canine middle cerebral arteries.

Although it is generally accepted that isoflurane can cause cerebral vasodilation, the sensitivity of the cerebral vessels to this anesthetic agent remains controversial. Furthermore, the mechanism by which isoflurane produces its direct effects on the cerebral vasculature remains unknown. The purpose of this study was to determine if isoflurane-induced relaxation of canine middle cerebral arteries is dose-dependent and/or endothelium-dependent. In an additional series of experiments, isoflurane-induced relaxation was studied in the presence of indomethacin to inhibit prostacyclin release, and endothelium-independent relaxation was examined with sodium nitroprusside. The response to isoflurane was examined in middle cerebral arteries prior to and following pretreatment with 300 microM NG-monomethyl-L-arginine (LnMMA), an inhibitor of endothelium-dependent vasodilation. Vascular rings (2.5 mm in length and 600-800 microns in diameter) were suspended in tissue baths and isometric tension recorded. The rings were constricted with either 0.2 microM 5-hydroxytryptamine or 5 microM prostaglandin F2 alpha and subsequently exposed to increasing concentrations of isoflurane (0.65-4.9%). In separate experiments the procedure was repeated in vessels with and without endothelium. Isoflurane produced a dose-dependent relaxation in all vessels. This relaxation was not inhibited by LnMMA and was unaffected by the absence of endothelium. The isoflurane response was independent of cyclooxygenase inhibition. These results demonstrate that isoflurane-induced relaxation of canine middle cerebral arteries: 1) is dose-dependent; 2) is not mediated by modulation of endothelium-derived relaxing factor or a release of prostacyclin; and 3) is endothelium-independent.     

Effects of isoflurane on K+ and Ca2+ conductance in isolated smooth muscle cells of canine cerebral arteries.

Although isoflurane is a known cerebral vasodilator, the mechanism of isoflurane-induced vasodilation is not clear. The purpose of this study was to investigate the effects of 2.6% isoflurane (1.2 mM) on macroscopic calcium and potassium channel currents in voltage-clamped canine middle cerebral artery cells. Cells were dialyzed with K(+)-glutamate solution and superfused with Tyrode's solution for measurement of potassium current (n = 20). Stepwise depolarization from a holding potential of -60 mV to beyond -30 mV elicited an outward, slowly inactivating potassium current that was reduced 50% +/- 2% and 81% +/- 3% (mean +/- SEM) in the presence of 1 mM 4-aminopyridine and 30 mM tetraethylammonium, respectively. Calcium ionophore (A23187, 10 microM) increased the potassium current by 76% +/- 3%, suggesting calcium dependency. Isoflurane reduced the amplitude of the potassium current by 35% +/- 4%. Calcium current was measured in cells dialyzed with solution containing 130 mM Cs(+)-glutamate and superfused with solution containing 10 mM BaCl2 and 135 mM tetraethylammonium to pharmacologically isolate the calcium current (n = 13). Under these conditions, progressive depolarizing steps from -60 mV elicited an inward current that was maximally activated at +20 mV and essentially eliminated by 1 microM nifedipine. This current, resembling a long-lasting (L-type) Ca2+ channel current, was reduced 40% +/- 4% by isoflurane. The results of this study suggest that isoflurane acts directly at the vascular muscle membrane to suppress transmembrane calcium and potassium currents. The decrease in calcium current would cause vasodilation; however, the concomitant decrease in potassium current may partially antagonize the depressant effect of isoflurane mediated through calcium current reduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hypoxia on endothelium-dependent relaxation of canine and rabbit basilar arteries

Summary An important role of endothelium-dependent relaxation in the local regulation of vascular tone has been suggested. In the present study, the effect of hypoxia on endothelium-dependent relaxation was investigated in canine and rabbit basilar and in rabbit common carotid arteriesin vitro, using an isometric tension recording method. Hypoxia was introduced by changing the gas mixture in thein vitro chamber from 95% O₂-5% CO₂ to 95% N₂-5% CO₂. Thrombin and acetylcholine were used to induce endothelium-dependent relaxation.Thrombin at 0.1 and 1.0U/ml, respectively, caused dose-dependent relaxation of the canine basilar artery precontracted by 10^–6M prostaglandin F₂. Acetylcholine also evoked dose-dependent relaxation of rabbit basilar and common carotid arteries precontracted by serotonin. Under hypoxic conditions, the relaxing effect of thrombin or acetylcholine decreased both in canine and in rabbit arteries, although it was not significant in rabbit basilar arteries.It has been postulated that following subarachnoid haemorrhage, diffusion of oxygen to the walls of the major cerebral arteries might be impaired by the subarachnoid clot. This could cause hypoxia of the arteries and contribute to vasospasm by suppressing endothelium-dependent relaxation, as well as by enhancing the contractile responses of the cerebral arteries to the vasoconstrictor agents in the bloody cerebrospinal fluid.     

Activation of the K+ channel BK(Ca) is involved in the relaxing effect of propofol on coronary arteries

BACKGROUND AND OBJECTIVE: Propofol may cause undesirable hypotension due to vasodilation. The underlying mechanisms are not completely understood. We investigated the mechanisms by which propofol relaxes vascular segments. METHODS: We studied the effect of propofol on isolated porcine coronary artery rings precontracted with potassium chloride or prostaglandin F2alpha. RESULTS: Propofol, in a concentration-dependent manner, relaxed all segments at concentrations of 5 microg mL(-1) and above. This relaxation was unaltered in the presence of N(omega)-nitro-L-arginine, indomethacin, diltiazem and glibenclamide. Tetraethylammonium chloride, an inhibitor of the BK(Ca) K+ channel (a high conductance Ca2+-sensitive K+ channel), dose-dependently attenuated the vasodilating effect of propofol (P < 0.001). CONCLUSIONS: Our results suggests that the activation of the BK(Ca) channel may contribute to the vasodilating effect of propofol, hereby causing hyperpolarization of the smooth muscle membrane and reduction of smooth muscle tone.     

Ca2+- and myosin phosphorylation-independent relaxation by halothane in K+-depolarized rat mesenteric arteries

BACKGROUND: Volatile anesthetics inhibit vascular smooth muscle contraction, but the mechanisms responsible are uncertain. In this study, the effects of halothane on Ca2+ signaling and Ca2+ activation of contractile proteins were examined in high K+-depolarized smooth muscle from rat mesenteric resistance arteries. METHODS: Vessels were cannulated and held at a constant transmural pressure (40 mmHg). Image analysis and microfluorimetry were used to simultaneously measure vessel diameter and smooth muscle intracellular [Ca2+] concentration ([Ca2+]i). Myosin light chain (MLC) phosphorylation was measured using the Western blotting technique. RESULTS: Step increases in extracellular [Ca2+] concentration (0-10 mM) in high K+ (40 mM)-depolarized smooth muscle produced incremental increases in [Ca2+]i, MLC phosphorylation, and contraction. Halothane (0.5-4.5%) inhibited contraction in a concentration-dependent manner, but the decrease in [Ca2+]i was small, and there was a marked shift in the [Ca2+]i-contraction relationship to the right, indicating an important Ca2+ desensitizing effect. Halothane (0.5-4.5%) did not affect MLC phosphorylation or the [Ca2+]-MLC phosphorylation relationship, but the MLC phosphorylation-contraction relationship was also shifted rightward, indicating an "MLC phosphorylation" desensitizing effect. In contrast, control relaxations produced by the Ca2+ channel blocker nifedipine were accompanied by decreases in both [Ca2+]i and MLC phosphorylation, and nifedipine had no affect on the [Ca2+]i-contraction, [Ca2+]i-MLC phosphorylation, and MLC phosphorylation-contraction relationships. CONCLUSIONS: In high K+-depolarized vascular smooth muscle, halothane relaxation is largely mediated by a Ca2+ and MLC phosphorylation desensitizing effect. These results suggest that the relaxing action of halothane is independent of the classic Ca2+-induced myosin phosphorylation contraction mechanism.     

Effects of aprotinin on endothelium-dependent relaxation of large coronary arteries

Objective: Aprotinin is widely used in heart surgery for reduction of intraoperative blood loss. But recent reports presenting results from rat aorta experiments claimed that aprotinin selectively impairs endothelium-dependent relaxation (EDR) as well as basal NO availability in concentrations similar to doses routinely used in cardiovascular surgery. An impairment of coronary EDR by aprotinin would be a great danger for any cardiothoracic intervention. We therefore tested the influence of aprotinin in the coronary arteries of a non-rodent species. Methods: Fresh coronary arteries of pigs were obtained from the local slaughterhouse and transported to our laboratory in cold oxygenated Krebs–Henseleit solution. Five-millimeter long rings were consecutively tested with or without aprotinin in concentrations of 500 KIU/ml (n = 7) or 1000 KIU/ml (n = 6) in oxygenated normothermic Krebs–Henseleit solution. PGF₂ (10 μmol/l) was used for inducing contraction and substance P (10 nmol/l) for inducing EDR, which was calculated in percentage of the precontraction. Indomethacin (10 μmol/l) was added in all measurements to eliminate the influence of prostaglandins. In additional similar experiments (n = 5), the influence of 1000 KIU/ml aprotinin on the EDR caused by the endothelium-derived hyperpolarizing factor (EDHF) was tested using l-NNA (300 μmol/l) to block all NO formation. Results: The EDR of pig coronaries (82 ± 5% or 80 ± 5% of the precontraction in the control tests before and after aprotinin exposure) was not significantly changed by 500 KIU/ml aprotinin (78 ± 7%). A small, but significant reduction of less than 1/10 of the EDR was induced by 1000 KIU/ml aprotinin (74 ± 5%). After accounting for l-NNA for NO blockage, no aprotinin-related difference remained (59 ± 6% vs 60 ± 6% in controls). Conclusion: For clinically relevant concentrations of aprotinin up to 500 KIU/ml, no significant reduction of the EDR can be found in epicardial coronary arteries of the pig. For higher doses of 1000 KIU/ml, a reduction in NO production seems to be the cause of the small but significant reduction of the EDR by aprotinin. Therefore, danger for impairment of coronary EDR by aprotinin at clinical dosage levels, as suggested by studies on rat aortas, seems to be absent in coronary arteries of a large mammalian model.     

Hypoxic preconditioning in coronary microarteries: role of EDHF and K+ channel openers

BACKGROUND: Hypoxic preconditioning may provide a useful method of myocardial protection in cardiac operations. The present study was designed to investigate the possible mechanisms of preconditioning regarding endothelium-derived hyperpolarizing factor (EDHF) and the effect of a potassium channel opener KRN4884 on the porcine coronary microartery in mimicking hypoxic preconditioning. METHODS: Porcine coronary microartery rings (diameter 200 to 500 microm) studied in a myograph were divided into seven groups: (1) control group; (2) hypoxia-reoxygenation group (hypoxia for 60 minutes followed by reoxygenation for 30 minutes); (3) preconditioning group (hypoxia for 5 minutes followed by reoxygenation for 10 minutes before hypoxia reoxygenation); (4) KRN4884 pretreatment group (KRN4884 was added into the myograph chamber 20 minutes before hypoxia reoxygenation); (5) 5-hydroxydecanoate + KRN group (5-hydroxydecanoate was given 20 minutes before KRN4884 pretreatetment); (6) glibenclamide (GBC) + KRN group (GBC was added 20 minutes before KRN4884 pretreatment); and (7) endothelium denuded group (the endothelium was removed). The endothelium-derived hyperpolarizing factor-mediated relaxation to bradykinin was studied in the rings precontracted with U46619 in the presence of N(omega)-nitro-L-arginine and indomethacin. RESULTS: The maximal relaxation induced by bradykinin was reduced in hypoxia reoxygenation (40.7% +/- 2.8% vs 66.9% +/- 2.5% in control, p = 0.000). This reduced relaxation was recovered in either preconditioning (64.6% +/- 4.6%, p = 0.002), or KRN4884 pretreatment (67.1% +/- 3.6%, p = 0.000). The 5-hydroxydecanoate, but not GBC pretreatment abolished the effect of KRN44884 pretreatment (67.1% +/- 3.6% vs 42.9% +/- 3%, p = 0.001). CONCLUSIONS: Hypoxia reoxygenation reduces the relaxation mediated by endothelium-derived hyperpolarizing factor in the coronary microartery. This function can be restored by either hypoxic preconditioning or the K(ATP) channel opener KRN4884, and therefore K(ATP) channel openers may provide similar effect as preconditioning. The mechanism is mainly related to the mitochondrial ATP-sensitive K+ channels.     

Role of guanylate cyclase-cGMP systems in halothane-induced vasodilation in canine cerebral arteries.

The cellular mechanisms through which halothane dilates blood vessels remain largely unknown. The present studies were designed to determine the effects of 0.59 and 0.9 mM halothane (equivalent to 2.0% and 3.0%, respectively) on tissue cyclic guanosine 3,5-monophosphate (cGMP) level and guanylate cyclase enzyme activity in canine middle cerebral arteries. Rings of cerebral arteries preconstricted with 5-hydroxytryptamine (0.2 microM) were exposed for 15 min to low or high concentrations of halothane or for 5 min to sodium nitroprusside (50 microM). The vessels were instantaneously frozen by immersing them in liquid N2; they then were homogenized, and the tissue cGMP levels were determined using radioimmunoassay. Halothane produced 2.23 +/- 0.44- and 4.47 +/- 0.87-fold increases in tissue cGMP levels over control at 0.59 and 0.9 mM, respectively. Sodium nitroprusside, a nitrovasodilator, also increased the tissue cGMP level 7.80 +/- 1.36-fold over the control value. To understand better the mechanisms of halothane-induced increase of tissue cGMP level, the effects of this anesthetic agent on guanylate cyclase enzyme activity were examined. Halothane, unlike sodium nitroprusside, did not modulate the activity of the soluble guanylate cyclase enzyme. However, halothane (1.0 mM), like atrial natriuretic factor (5 microM), stimulated the particulate guanylate cyclase enzyme activity. LY-83583 (6-anilino-5,8-quinolinedione, 10 microM), an agent that inhibits soluble guanylate cyclase activity, significantly reduced the response of the vessels to calcium ionophore (A23187, 0.4 microM), an endothelium-dependent vasodilator, without producing a significant effect on halothane-induced vasodilation. These results suggest that halothane-induced vasodilation of cerebral blood vessels is partly mediated by an increase in tissue cGMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological comparison of endothelium-dependent relaxation in isolated cerebral and extracerebral arteries

Endothelium-dependent relaxation was induced by acetylcholine (ACh), adenosine triphosphate (ATP), and thrombin in isolated cerebral and extracerebral arteries obtained from rabbits and dogs. Using an isometric tension-recording method, the authors then examined the difference in the extent of relaxation between the cerebral and extracerebral arteries. In rabbits, the dose-response curve of the basilar artery for ACh was significantly different (p less than 0.05) from curves of the femoral and common carotid arteries. The IC50 value (the concentration inducing a one-half inhibition of the initial contractile tone) for the basilar artery in ACh-induced relaxation was significantly higher (p less than 0.05) than for the common carotid artery, although the mean maximum relaxation of the basilar artery to ACh was not significantly different from that seen in extracerebral arteries. The relaxing effect of ACh in dogs was much less in the middle cerebral and basilar arteries than in the common carotid, vertebral, and femoral arteries. On the other hand, both ATP (in rabbits and dogs) and thrombin (in dogs) induced significantly more (p less than 0.05) relaxation in the cerebral arteries than in the extracerebral arteries. Endothelium-dependent relaxation induced by ACh or ATP has been demonstrated in a wide range of arteries from a variety of animals. The present results suggest that ATP has a more important role than ACh in the regulation of the vascular tone of the major cerebral arteries in these two species.     

Pharmacological studies on relaxation of spastic primate cerebral arteries in subarachnoid hemorrhage

Chronic cerebral vasospasm was induced in 16 monkeys by direct placement of a clot of autologous blood over the arteries of the circle of Willis on the right side. The middle cerebral arteries (MCA's) on the clot side all showed angiographic vasospasm, which was maximal 7 days after subarachnoid hemorrhage. Animals were sacrificed at this time and vascular responses to acetylcholine (ACh), histamine, and the calcium ionophore A23187 were studied in MCA rings from the clot (spastic) side and the non-clot (control) side. In control preparations with an intact endothelium, which had been precontracted by prostaglandin F2 alpha (PGF2 alpha), histamine and A23187 produced significant relaxation. The same concentrations of histamine and A23187 did not relax vascular tissues in which the endothelium had been mechanically removed. Acetylcholine did not produce a significant endothelium-dependent relaxation of primate MCA rings, but did relax rings of primate common carotid artery. Pretreatment with chlorpheniramine (an H1-receptor antagonist) prevented histamine-induced relaxation; however, cimetidine (an H2-receptor antagonist) had no inhibitory action. It thus seems that histamine mediates relaxation of intact MCA's mostly by an H1-receptor-mediated release of endothelium-derived relaxing factor (EDRF). Relaxations induced by histamine and A23187 in MCA's from the clot side were substantially reduced. Moreover, the small component of ACh-induced relaxation was also abolished. Endothelium-independent relaxation induced by glyceryl trinitrate (GTN) occurred in arteries from both the control and the clot sides. Constrictions induced by KC1 and PGF2 alpha were reduced on the clot side of the MCA's. These results suggest that subarachnoid hemorrhage influences both the generation of EDRF and the constriction of affected arteries. The small contraction which was elicited in spastic arteries was fully relaxed by GTN.     

Effect of bilirubin on rabbit cerebral arteries in vivo and in vitro.

The effect of bilirubin on vasoreactivity was examined in the exposed rabbit basilar artery (diameter, 1045 +/- 17 microns; n = 18) and its cortical branches (diameter, 265 +/- 11 microns; n = 43) in vivo. Vasoconstriction induced by uridine triphosphate (UTP; 10(-5) to 10(-3) mol/L) was observed in vivo before and after a 60-minute application of supersaturated bilirubin (10(-4) mol/L). Bilirubin was dissolved in modified artificial cerebrospinal fluid (pH 7.4) or in physiological salt solution (pH 7.6). The latter was spectrophotometrically estimated to contain a higher concentration of free bilirubin because of the formation of less colloid. After treatment with bilirubin in artificial cerebrospinal fluid, the effect was minimal in the basilar arteries (n = 7), whereas the diameter of the branches was reduced by 9.6 +/- 1.5% (n = 23) and UTP-induced vasoconstriction was potentiated. After application of bilirubin in physiological salt solution, the basilar arteries contracted slightly (-2.1 +/- 0.9%; n = 6) and the UTP-induced vasoconstriction in the branches was attenuated (n = 12). After a 60-minute incubation of basilar artery with bilirubin in physiological salt solution in vitro, isometric tension recordings showed a diminution in KCl- and UTP-induced vasoconstrictions. Acetylcholine- and sodium nitroprusside-induced relaxations were also attenuated. It is suggested that bilirubin may exert different effects depending on the size of arteries and the concentration of free bilirubin. The constrictor and potentiating effects of bilirubin could be caused by the impairment of the relaxation mechanism. When the toxic effect of bilirubin becomes severe, the constrictor mechanism is also damaged.     

Effects of halothane and isoflurane on calcium and potassium channel currents in canine coronary arterial cells.

The effects of halothane (0.75% and 1.5%) and isoflurane (2.6%) on macroscopic Ca2+ and K+ channel currents (ICa and IK, respectively) were investigated in voltage-clamped vascular muscle cells from the canine coronary artery. Single coronary arterial cells were dialyzed with K+ glutamate solution and superfused with Tyrode's solution for measurement of IK (n = 45). Stepwise depolarization from a holding potential of -60 mV to beyond -30 mV elicited an outward, slowly inactivating IK that had a macroscopic slope conductance of 18 nS. IK was reduced 75% by 10 mM 4-aminopyridine, a K+ channel antagonist. Compared to 4-aminopyridine, halothane at 0.75% and 1.5% reduced peak IK amplitude only by 14 +/- 2% and 36 +/- 3%, respectively. At approximately equianesthetic concentrations, 2.6% isoflurane suppressed IK less than did 1.5% halothane, reducing peak amplitude by 15 +/- 3%. In other sets of experiments, cells were dialyzed with 120 Cs(+)-glutamate solution and superfused with 10 mM BaCl2 or CaCl2 solutions to isolate ICa (n = 39) pharmacologically. Under these conditions, progressive depolarizing steps from -60 mV elicited a small inward current, which was potentiated 3.4-fold by equimolar substitution of Ba2+ for Ca2+ in the external solution and was blocked by 1 microM nifedipine. This inward current, which resembled L-type ICa, was blocked 37 +/- 4% and 70 +/- 4% in the presence of 0.75% and 1.5% halothane, respectively. Isoflurane (2.6%) also decreased ICa by 55 +/- 5%. It appears that while halothane and isoflurane suppress both IK and ICa, these anesthetics preferentially reduce ICa.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of potassium channel inhibitors on the relaxation induced by the nitric oxide donor diethylamine nitric oxide in isolated human cerebral arteries

OBJECT: The goal of this study was to investigate whether K+ channels are involved in nitric oxide (NO)-induced relaxation of isolated human cerebral arteries. METHODS: Successive concentration-response curves relating to the use of the NO donor diethylamine NO (DEA/NO) were established in the absence and presence of different K+ channel inhibitors after mounting human cerebral arteries onto a wire myograph. The arteries were obtained from macroscopically intact tissue that had been removed during brain tumor operations. A high K+ concentration partially inhibited the relaxant effects of DEA/NO. Different K+ channel inhibitors (tetraethylammonium [TEA], 10(-3) M; charybdotoxin, 10(-7) M; glibenclamide, 10(-6) M; 4-aminopyridine [4-AP], 10(-3) M; BaCl2, 5 x 10(-5) M; and apamin, 10(-6) M) alone failed to affect the responses to DEA/NO. However, a combination of TEA, glibenclamide, 4-AP, and BaCl2 partially blocked the relaxant effects of DEA/NO. In addition, the effects of DEA/NO were inhibited by the thromboxane A2 analog U46619 (3 x 10(-7) M). CONCLUSIONS: Inhibitors of the large-conductance or small-conductance Ca++-activated K+ channels, the adenosine triphosphate-sensitive K+ channels, and the delayed-rectifier or inward-rectifier K+ channels failed to alter the effects of DEA/NO when only one K+ channel blocker was used. However, a regimen of a combination of K+ channel blockers that possess selectivity for different channels demonstrated that different K+ channel types are involved; these channels may function in a redundant manner and compensate for each other. Selective thromboxane A2 agonists are capable of inhibiting the relaxant response to the NO donor.     

普鲁卡因对鼠大脑皮层锥体神经元延迟整流型钾离子通道电流的影响

目的　观察不同浓度普鲁卡因对新生鼠大脑皮层锥体神经元延迟整流型K+ 通道电流的影响 ,以探讨其中枢作用机理。方法　采取神经元急性分离法分离SD大鼠皮层锥体细胞 ,运用膜片钳内面向外式记录技术 ,记录不同浓度普鲁卡因对延迟整流型K+ 通道电流参数。根据普鲁卡因浓度不同分为 8个组 ,其浓度分别为 0、0 2、0 4、0 8、1 6、2 4、3 2和 4 0mmol/L ,每组以 7个不同钳制电压观测 1 1个样本。结果　当普鲁卡因浓度增至 0 4mmol/L时 ,其Ⅰ Ⅴ关系线斜率最小 ,通道的电导减至最低 [(36± 1 4) pS] ;此后随药物浓度的增加 ,Ⅰ Ⅴ关系线斜率增大 ,电导增加 ,并在2 4mmol/L增至最高 [(60± 2 0 )pS]。结论　普鲁卡因对鼠大脑皮层锥体神经元延迟整流型K+ 离子通道电流、电导的影响随其浓度不同表现为抑制与兴奋双相作用     

Hemodynamic effect of calcium channel blockade during anesthesia for coronary artery surgery.

Because the choice of anesthetic technique does not influence the incidence of perioperative myocardial ischemia, reduction of ischemic risk may require specific antianginal therapy. Calcium entry blockers are effective drugs in antianginal therapy. Diltiazem reduces myocardial oxygen demand through decreases in heart rate, inotropy, and systolic function, while increasing myocardial oxygen delivery through coronary vasodilation. These potentially beneficial effects of diltiazem were evaluated in 15 of 29 patients (diltiazem v placebo, double-blind study) scheduled for coronary artery bypass graft surgery. Continuous infusion of diltiazem (0.15 mg/kg bolus followed by 2 micrograms/kg/min), during anesthesia and surgery before cardiopulmonary bypass, significantly reduced the major MVO2 determinants during anesthesia with moderate doses of fentanyl and a benzodiazepine (midazolam in 8 of 14 control patients and 9 of 15 treated patients, or flunitrazepam in the others). Heart rate, mean arterial pressure, and inotropy were decreased during the most stressful events of surgery when plasma diltiazem concentrations were in the therapeutic range (greater than 96 ng/mL). The number of patients with perioperative ischemia was 2 of 15 in the treated group and 4 of 14 in the control group. Provided that diltiazem plasma concentrations are sufficient, it can contribute to lowering the ischemic burden during anesthesia for coronary artery surgery.     

Inhibitory effects of etomidate and ketamine on adenosine triphosphate-sensitive potassium channel relaxation in canine pulmonary artery

BACKGROUND: The authors recently demonstrated that etomidate and ketamine attenuated endothelium-dependent pulmonary vasorelaxation mediated by nitric oxide and Ca -activated K + channels. In the current study, they tested the hypothesis that these intravenous anesthetics inhibit pulmonary vasorelaxation mediated by adenosine triphosphate-sensitive potassium (K + ATP ) channel activation. METHODS: Endothelium intact and denuded pulmonary arterial rings were suspended in organ chambers for isometric tension recording. The effects of etomidate (5 x 10(-6) and 5 x 10(-5) m) and ketamine (5 x 10(-5) and 10(-4) m) on vasorelaxation responses to lemakalim (K + ATP channel activator), prostacyclin, and papaverine were assessed in phenylephrine-precontracted rings. The effect of cyclooxygenase inhibition with indomethacin was assessed in some protocols. RESULTS: Etomidate (5 x 10(-6) m) only inhibited the vasorelaxant response to lemakalim in endothelium intact rings, whereas a higher concentration of etomidate (5 x 10(-5) m) inhibited relaxation in both intact and endothelium-denuded rings. Pretreatment with indomethacin abolished the endothelium-dependent attenuation of lemakalim-induced relaxation caused by etomidate. Ketamine (5 x 10(-5) and 10(-5) m) inhibited the relaxation response to lemakalim to the same extent in both endothelium-intact and -denuded rings, and this effect was not prevented by indomethacin pretreatment. Etomidate and ketamine had no effect on the relaxation responses to prostacyclin or papaverine. CONCLUSIONS: These results indicate that etomidate, but not ketamine, attenuates the endothelium-dependent component of lemakalim-induced pulmonary vasorelaxation an inhibitory effect on the cyclooxygenase pathway. Both anesthetics inhibit K + ATP -mediated pulmonary vasorelaxation a direct effect on pulmonary vascular smooth muscle.     

Attenuation of contraction of isolated canine coronary arteries by enflurane and halothane

Contraction of vascular smooth muscle such as that existing in coronary arteries is regulated in part by Ca++ entry into cells via Ca++ channels. Volatile anaesthetics are known to attenuate agonist-induced coronary artery constriction. The purpose of this experiment was to determine if 1.5 MAC concentrations of halothane or enflurane attenuated contractions evoked by activation of one type of Ca++ channel--the potential operator channel. In the current experiment, potential operator channels were activated by depolarizing isolated canine coronary artery rings with high concentration of K+, causing Ca++ entry and vessel contraction. Rings without endothelium were suspended for isometric force measurement in organ chambers containing aerated Krebs-Ringer solution. Maximum response to Ca++ in rings depolarized with K+ was 120 +/- 5 per cent in untreated versus 101 +/- 3 per cent in rings treated with enflurane (P less than 0.01). The maximum response was 123 +/- 6 per cent in untreated versus 111 +/- 5 per cent during halothane administration (P less than 0.05). In contrast, nifedipine 10(-9) M depressed maximum contractions from 114 +/- 5 per cent to 37 +/- 4 per cent (P less than 0.01) and nifedipine 10(-8) M depressed contractions to 30 +/- 4 per cent (P less than 0.01). In a further series of experiments, sustained contractions were depressed by continued administration of the anaesthetics, indicating no loss of anaesthetic effect with time. The results indicate that 1.5 MAC halothane and enflurane attenuate contractions of canine coronary arteries evoked by depolarization and Ca++ entry through potential operated channels. However, neither halothane nor enflurane exhibited the marked depressant effect exerted by nifedipine.     

Morphological changes of cerebral penetrating arteries in a canine double hemorrhage model

BACKGROUND: Morphological presentations of cerebral vasospasm, such as dystrophy and desquamation of endothelial cells, corrugation of the internal elastic layer, and necrotic changes in smooth muscle cells, are well defined in large cerebral arteries. This study was undertaken to examine pathological changes in cerebral penetrating arteries in a canine double hemorrhage model. METHODS: Eighteen mongrel dogs were subjected to an autologous arterial blood (0.4 mL/kg) injection into the cisterna magna on day 0 and day 2 after withdrawal of an equivalent amount of cerebrospinal fluid. Angiogram was performed on day 0 before the blood injection and on the day the dogs were sacrificed. The dogs were divided into four groups: control (day 0) (n = 4), hemorrhage and sacrificed on day 3 (n = 4), day 5 (n = 5), and day 7 (n = 5). The penetrating arteries were removed and found to be spastic on days 3, 5, and 7, but not in the control group. RESULTS: Endothelial dystrophy and partial desquamation were recorded in all dogs sacrificed on days 5 and 7. Condensation of chromatin, blebbing of the membrane, and condensation of cytoplasm were identified in many endothelial cells, features that are consistent with apoptosis. The morphological changes in the penetrating arteries were more pronounced on days 5 and 7. CONCLUSIONS: Vasospasm occurred in cerebral penetrating arteries in a canine double hemorrhage model. The morphological change in penetrating arteries, especially apoptosis in endothelial cells, is consistent with an early phase of vasospasm. Vasospasm in a penetrating artery may contribute to the cerebral ischemia that occurs during vasospasm.     

Differential relaxant effect of high concentrations of intravenous anesthetics on endothelin-constricted proximal and distal canine coronary arteries.

This study determined the direct effect of three intravenous anesthetics on isolated canine coronary arteries constricted with the potent endogenous vasoconstrictor endothelin. Arteries were divided into groups of large (1.3-2.5 mm) and small (250-500 microns) vessels, and arterial rings were suspended in tissue baths. The rings were stretched to an optimal resting tension and then preconstricted with an EC50 concentration of endothelin that was equivalent for both groups. Incremental concentrations (5 x 10(-6) M to 1.6 x 10(-2) M) of thiopental, ketamine, and propofol were added to the baths, and the relaxant responses were recorded. Small arteries demonstrated greater vasodilation at equivalent drug concentrations than did large arteries. These results demonstrate antagonism of the vasoconstrictor endothelin by intravenous anesthetics. Distal vessels are more sensitive than proximal vessels to the relaxant effects of the intravenous anesthetics studied. Direct effects on coronary vascular tone, however, are only apparent at concentrations above those seen clinically. Despite the potential for a differential effect on proximal and distal coronary arteries, we conclude that thiopental, ketamine, and propofol do not possess a direct effect on the tone of large or small canine coronary arteries at concentrations seen in routine clinical practice.