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Canadian Journal of Anesthesia 49:427-433 (2002)
© Canadian Anesthesiologists' Society, 2002
Neuroanesthesia and Intensive Care

Isoflurane does not further impair microvascular vasomotion in a rat model of subarachnoid hemorrhage

[L'isoflurane ne produit pas d'altération subséquente sur la vasomotricité microvasculaire d'un modèle d'hémorragie sous-arachnoïdienne chez le rat]

Kyung W. Park, MD*, Hai B. Dai, MD{dagger}, Caroline Metais, MD{dagger}, Mark E. Comunale, MD* and Frank W. Sellke, MD{dagger}

* From the Departments of Anesthesia and Critical Care and
{dagger} Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusettes, USA.

Dr. Kyung W. Park, Department of Anesthesia and Critical Care Group, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Phone: 617-754-2678; Fax: 617-754-2677; E-mail: kpark{at}caregroup.harvard.edu


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: Since isoflurane is known to attenuate endothelium-dependent dilation (EDD) in normal cerebral arterioles, we examined whether the anesthetic has a similar effect and further impairs EDD in vessels exposed to SAH.

Methods: Autologous blood was introduced in the subarachnoid space and the parietal lobe harvested. Control animals were sacrificed without introduction of blood. The response of microvessles to the endothelium-dependent dilator adenosine diphosphate (ADP) 10-9–10-4 M, the endothelium-independent dilator nitroprusside 10-9–10-4 M, and ET-1 10-13–10-8 M was measured by videomicroscopy in the presence of 0–2 minimum alveolar concentration (MAC) of isoflurane.

Results: Isoflurane attenuated EDD to ADP in control vessels [66 ± 5% (control) vs 27 ± 11% (2 MAC) dilation to ADP 10-4 M, P < 0.05]. Although SAH was associated with reduced dilation to ADP, exposure to isoflurane did not further impair dilation to ADP after SAH [26 ± 3% (SAH) vs 21 ± 5% (SAH/2 MAC) dilation to ADP 10-4 M, P = NS]. Dilation to nitroprusside was not affected by isoflurane or SAH. Constriction to ET-1 was reduced by 2 MAC of isoflurane [21 ± 1% (control) vs 13 ± 5% (2 MAC) constriction to ET-1 10-8 M, P < 0.05], but not by 1 MAC of isoflurane in control vessels. Constriction to ET-1 was greatly attenuated by 1 or 2 MAC of isoflurane after SAH [32 ± 5% (SAH) vs 18 ± 4% (SAH/2 MAC) constriction to ET-1 10-8 M, P < 0.05].

Conclusion: In rats, isoflurane does not further impair EDD after SAH and modulates the constrictive response to ET-1. Such an effect of isoflurane would not predispose the SAH-exposed vessels to vasospasm.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
THE leading causes of mortality and morbidity after subarachnoid hemorrhage (SAH) are the immediate effects of SAH itself, rebleeding, and cerebral ischemia and infarction from cerebral vasospasm; and the one-month mortality rate from SAH approaches 50% in the U.S.1 In humans, cerebral vasospasm is believed to be biphasic, with both an acute phase occurring within hours and a delayed phase usually beginning two to four days after SAH and peaking on about day seven.2,3 SAH-associated vasospasm occurs not only in the large cerebral conduit arteries, but also in the cerebral microvessels. Cerebral microvascular vasospasm may actually be more important in producing cerebral ischemia than conduit vessel vasospasm.4 In our previous study using a rat model of SAH,5 we demonstrated that cerebral arterioles after SAH have endothelial dysfunction that could contribute to vasospasm. As a result, cerebral arterioles after SAH demonstrated attenuated response to the endothelium-dependent dilator adenosine diphosphate (ADP) and accentuated constriction to endothelin-1 (ET-1). We showed further that such a dysfunction might be based on reduced protein expression of endothelial nitric oxide synthase (eNOS).

Studies from multiple laboratories have shown previously that inhalational anesthetics cause attenuation of endothelium-dependent vasodilation in various non-diseased vascular beds including the cerebral microcirculation.6–9 In this study, therefore, we examined whether the inhalational anesthetic isoflurane may have an additive effect on endothelial dysfunction of cerebral microvessels after SAH.


   Methods
TOP
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With Institutional Animal Care and Use Committee approval, Wistar rats of either sex, weighing 250–300 g, were anesthetized by injecting 40 mg•kg-1 ketamine and 5 mg•kg-1 xylazine intraperitoneally. Our rat model of SAH has been previously described.5 Briefly, a polyethylene catheter (PE-10) was inserted percutaneously into the cisterna magna (CM) and was secured in place. After two days of recovery, lack of gross wound infection was noted and normal neurological function was verified. The animal was then re-anesthetized with ketamine and xylazine as before. A femoral arterial catheter was placed for blood sampling. SAH was modeled by withdrawing 0.3 mL of cerebrospinal fluid from the CM and injecting 0.3 mL of fresh non-heparinized autologous blood into the CM slowly over a ten-minute period with the animal in a 20° head-down position, as described by Cole et al.10 The animal was allowed to breathe spontaneously and kept in the head-down position. Twenty minutes after subarachnoid injection of blood, at a time known to coincide with maximal vasospasm,10 femoral arterial blood was sampled for blood gas analysis and the animal was euthanized for harvest of the brain tissue, which was quickly placed in a cold (4°C) modified Krebs solution (120 mM NaCl, 5.9 mM KCl, 11.1 mM dextrose, 25 mM NaHCO3, 1.2 mM NaH2PO4, 1.2 mM MgSO4, and 2.5 mM CaCl2). At necropsy, proper positioning of the polyethylene tubing in the CM and spread of the subarachnoid blood over the surface of the cerebral cortex were verified. Control animals received neither the percutaneous catheter into the CM nor subarachnoid blood injection.

Arterioles of diameters of about 100 µm were dissected from the parietal lobes of the SAH and control animals. Each vessel was placed in a vessel chamber, cannulated with dual micropipettes measuring 50–75 µm in diameter, and secured with a 10–0 suture. The vessel was continuously bathed with modified Krebs buffer, gassed with 95% O2–5% CO2 mixture, and maintained at 36.5–37.5°C and pH of 7.35–7.45. PO2 in the vessel chamber exceeded 400 mmHg. Because the vessel was studied in a no-flow state, pressure in the micropipettes was maintained at 40 mmHg to provide distention. The vessel was visualized and its internal lumen diameter was measured and recorded by videomicroscopy, as previously described.11 Stability of similarly prepared vessel preparations over at least 2.5 hr has been demonstrated previously.11

Each vessel was equilibrated at 37C for 30 min in the vessel chamber and the baseline internal diameter (Dbaseline) was measured. The vessel was then preconstricted with the thromboxane analogue U46619 1 µM for five minutes, since the response of the cerebral vessels to U46619 was previously demonstrated not to be influenced by SAH.5 The vessel was then subjected to isoflurane 0, 1, or 2 minimum alveolar concentration (MAC; 1 MAC = approximately 1.2% in rats)12 by adding the anesthetic to the 95% O2–5% CO2 mixture bubbling the Krebs buffer solution, using an in-line bubble-through vaporizer. In a preliminary experiment, using gas chromatography (GC), it took less than ten minutes for isoflurane to reach a steady state concentration after it was introduced in the vessel chamber.11 The anesthetic content in the gas mixture was monitored continuously using a Rascal II Gas Analyzer (Ohmeda, Salt Lake City, UT, USA.), calibrated with industrial standards. Previously we demonstrated by GC analysis that in our experimental preparation, the millimolar concentration and partial pressure of isoflurane in the vessel chamber reflected its concentration in the gas mixture bubbled into the buffer solution.11

The diameter obtained after U46619 and isoflurane (or U46619 alone in case of a vessel without isoflurane exposure) was considered as the constricted diameter (Dconst). At least 15 min after introduction of isoflurane, the vessel was subjected to increasing concentrations of (a) the endothelium-dependent dilator ADP 10-9–10-4 M or (b) the endothelium-independent dilator sodium nitroprusside (SNP) 10-9–10-4 M. At each concentration of the dilator, the internal diameter was measured (Ddil) and % dilation calculated as follows:

At the end of each experiment, the vessel chamber was flushed with fresh Krebs buffer and the vessel re-equilibrated at 37°C. Potassium chloride (KCl) was then added to a final concentration of 100 mM, and the internal lumen diameter was measured. Functional endothelium integrity was tested by measuring the response to ADP 10-5 M. Only those vessels that constricted by at least 15% to KCl and dilated at least 15% to ADP at the end of each experiment were considered viable and included for data analysis.

To examine the effect of isoflurane on ET-1-mediated vasoconstriction, additional SAH and control vessels were equilibrated at 37°C. Following exposure to isoflurane 0, 1, or 2 MAC for 15 min, the vessel diameter was measured and this value was taken as the Dbaseline. Each vessel was then subjected to ET-1 10-13–10-8 M. Vessel diameter was measured at each concentration of the constrictor (Dconst) and % constriction calculated from the Dbaseline:

Vessel viability was tested as above.

No animal contributed more than one vessel to any one experimental group. Therefore, n for each group represents the number of animals as well as the number of vessels. All data are presented as mean ± SD. Presence of a concentration-dependent vasomotion to a vasodilator or a constrictor was tested by one-way analysis of variance (ANOVA) (linear contrast). The effects of SAH or isoflurane on concentration response curves to the various vasomotor agents tested were analyzed by two-way ANOVA with a repeated measures factor, with posthoc multiple pairwise comparison (Neuman-Keuls) and stratified z tests to identify the concentrations where the differences in response were significant. Where appropriate, two-tailed Student's t test was used to compare the means of two groups. P < 0.05 was considered significant. All statistics were calculated using True Epistat software (Epistat Services, Richardson, TX, USA).


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Blood gases obtained just prior to harvest of the brain tissue demonstrated no significant respiratory depression, hypoxia, or acidosis.

To examine the dilatory response of the isolated cerebral microvessels, they were preconstricted with U46619 1 µM and then exposed to isoflurane 0–2 MAC, prior to subjecting them to increasing concentrations of selected dilators. No significant change in internal diameter of the U46619-preconstricted vessel was noted after steady state concentrations of isoflurane were obtained.

The dilatory response of the cerebral microvessels to the endothelium-dependent dilator ADP was attenuated by either 1 or 2 MAC of isoflurane (control with no isoflurane: n = 9, Dbaseline = 93 ± 6 µm; control with isoflurane 1 MAC: n = 8, Dbaseline = 102 ± 8 µm; control with isoflurane 2 MAC: n = 9, Dbaseline = 101 ± 6 µm; P < 0.001 for either 1 or 2 MAC vs 0 MAC; P = NS between 1 and 2 MAC; Figure 1aGo; Table IGo). Although vessels after SAH showed attenuated response to ADP compared to control (P < 0.001), there was no further attenuation of SAH vessels by either 1 or 2 MAC of isoflurane (P = NS) (SAH with no isoflurane: n = 7, Dbaseline = 96 ± 9 µm; SAH with isoflurane 1 MAC: n = 6, Dbaseline = 100 ± 7 µm; SAH with isoflurane 2 MAC: n = 8, Dbaseline = 103 ± 7 µm; Figure 1bGo; Table IGo).



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  		FIGURE 1 Percent dilation of U46619-preconstricted cortical microvessels vs logarithm of concentration of the endothelium-dependent dilator adenosine diphosphate (ADP). A) Dilation to ADP was significantly attenuated by 1 or 2 minimum alveolar concentration (MAC) of isoflurane in the control vessels. *P < 0.05 vs control. B) Dilation to ADP was significantly attenuated by exposure to subarachnoid hemorrhage (SAH), but there was no further significant attenuation by 1 or 2 MAC of isoflurane. *P < 0.05 vs SAH without isoflurane.

 

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  		TABLE I Percent dilation of rat cerebral microvessels to ADP
 
The dilatory response of the cerebral microvessels to the endothelium-independent dilator SNP was not affected by either 1 or 2 MAC of isoflurane with or without SAH (control with no isoflurane: n = 7, Dbaseline = 92 ± 6 µm; control with isoflurane 1 MAC: n = 9, Dbaseline = 96 ± 6 µm; control with isoflurane 2 MAC: n = 8, Dbaseline = 96 ± 8 µm; SAH with no isoflurane: n = 7, Dbaseline = 89 ± 8 µm; SAH with isoflurane 1 MAC: n = 6, Dbaseline = 100 ± 7 µm; SAH with isoflurane 2 MAC: n = 8, Dbaseline = 92 ± 6 µm; P = NS; Figures 2a and bGo; Table IIGo).



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  		FIGURE 2 Percent dilation of U46619-preconstricted cortical microvessels vs logarithm of concentration of the endothelium-independent dilator nitroprusside. Dilation to nitroprusside was not significantly affected by 1 or 2 minimum alveolar concentration (MAC) isoflurane either in the control vessels (a) or in vessels exposed to subarachnoid hemorrhage (SAH) (b).

 

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  		TABLE II Percent dilation of rat cerebral microvessels to nitroprusside
 
The constrictive response of the cerebral microvessels to ET-1 was not affected by 1 MAC of isoflurane (P = NS), but was attenuated by 2 MAC of isoflurane (P < 0.05; control with no isoflurane: n = 9, Dbaseline = 99 ± 9 µm; control with isoflurane 1 MAC: n = 9, Dbaseline = 90 ± 8 µm; control with isoflurane 2 MAC: n = 8, Dbaseline = 91 ± 9 µm; Figure 3aGo; Table IIIGo). Whereas constriction to ET-1 was increased after SAH compared to control (P < 0.001), constriction to ET-1 after SAH was attenuated by either 1 or 2 MAC of isoflurane (P < 0.001 each vs no isoflurane after SAH; SAH with no isoflurane: n = 6, Dbaseline = 104 ± 11 µm; SAH with isoflurane 1 MAC: n = 6, Dbaseline = 92 ± 7 µm; SAH with isoflurane 2 MAC: n = 7, Dbaseline = 91 ± 7 µm; Figure 3bGo; Table IIIGo).



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  		FIGURE 3 Percent constriction of cortical microvessels vs logarithm of concentration of endothelin-1. A) Constriction to endothelin-1 was significantly attenuated by 2 minimum alveolar concentration (MAC) of isoflurane, but not by 1 MAC of isoflurane in control vessels. *P < 0.05 vs control. B) Constriction to endothelin-1 was significantly increased in subarachnoid hemorrage (SAH)-exposed vessels compared to control, but isoflurane 1 or 2 MAC significantly modulated constriction to endothelin-1 in SAH-exposed vessels. *P < 0.05 vs control.

 

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  		TABLE III Percent constriction of rat cerebral microvessels to endothelin-1
 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main findings of the present study are that (a) although isoflurane causes attenuation of EDD in normal cerebral arterioles, it does not have a similar effect in the microvessels with endothelial dysfunction after SAH and (b) accentuation of constriction to ET-1 seen after SAH is attenuated by isoflurane. These effects of isoflurane might tend to have a protective effect against microvascular spasm following SAH.

There are both in vitro and in vivo studies that suggest that isoflurane is a cerebral vasodilator. Farber et al.13 found that, in preconstricted intraparenchymal cortical and hippocampal arterioles of rats, both isoflurane and halothane dilated the vessels in a dose-dependent manner, but that the vasodilatory effect of isoflurane was significantly less in the cortex than in the hippocampus. Clinically, systemic hypotension and consequent reduction in cerebral perfusion pressure (CPP) produced by isoflurane in patients undergoing craniotomy are not associated with any reduction in cerebral blood flow (CBF).14,15 Presumably, vasodilation produced by isoflurane compensates for the decrease in CPP to maintain CBF. This effect is present even following SAH.15 With isoflurane-induced vasodilation, there is a shift in the relationship between cerebral metabolic rate and CBF, so that for any given level of cerebral glucose metabolism16 or oxygen consumption,17 there is an increased level of CBF in the presence of isoflurane.

The role of endothelium in the observed vasomotor effects of isoflurane is complex and controversial. On the one hand, it has been shown that NOS inhibition can reduce CBF during isoflurane anesthesia18 and can block an increase in CBF by isoflurane,19 implying a role of NO in isoflurane-mediated vasodilation. On the other hand, Todd et al. have shown that NOS inhibition reduces CBF proportionately in both isoflurane-anesthetized and barbiturate-anesthetized rabbits, indicating that NO is not the primary mediator of the isoflurane-induced vasodilation, but acts to affect the background vasomotor tone.20 In addition, isoflurane has been shown to attenuate endothelium-dependent, NO-mediated dilation EDD in normal cerebral arteries9 and this has been corroborated in this study.

Our study examines the complex relationship between isoflurane and endothelium-mediated vasomotion of the cerebral arterioles in a rat model of SAH. The limitations of our model include the fact that we are only studying the acute phase after SAH, whereas cerebral vasospasm in humans is biphasic with both an acute and a delayed phase.2,3 However, acute-phase vasospasm is predictive of mortality after SAH21 and may be no less important than delayed-phase vasospasm. Secondly, we examined vasomotion in vitro and did not measure CBF per sec. Our findings will have to be interpreted in association with studies on CBF. Thirdly, in this study, we did not include a sham-operated control group. In our previous study,5 where we did include a sham-operated group, we found that the effect of SAH on endothelial dysfunction could be demonstrated over and above that of a sham surgery and therefore, we did not feel that we had to include a sham-operated group for the present study.

Our main findings about the relationship between isoflurane and endothelium-mediated vasomotion in cerebral arterioles after SAH are twofold. First, we previously reported that there is impairment of EDD after SAH and suggested that this may be a factor predisposing the cerebral vessels to vasospasm.5 If isoflurane, which causes attenuation of EDD in normal cerebral arterioles, were to cause a similar effect in vessels with endothelial dysfunction after SAH, the anesthetic might lead to a profound impairment of EDD and an increased disposition to vasospasm. However, we actually found that isoflurane caused no further impairment of EDD in vessels after SAH; cerebral arterioles showed similar degrees of EDD after SAH in the presence or absence of isoflurane.

Analogously, impairment of EDD has been observed in various pathological situations in addition to SAH. It has been noted in coronary artery disease,22 hypercholesterolemia,23 diabetes,24 proteinuria,25 and following cardiopulmonary bypass (CPB)9 - just to name a few. If isoflurane had an additive effect on impairment of EDD in these pathological conditions, then the anesthetic might contribute to end-organ ischemia in such situations. However, our studies in postCPB cerebral vessels9 and now in postSAH cerebral vessels demonstrate that there is no such additive effect. In humans after SAH, isoflurane has also been shown to maintain CBF.15

Previously, we found that, after SAH, there is an accentuation of ET-1 induced constriction of cerebral arteries and this may be another factor contributing to vasospasm after SAH. We suggested that this accentuation might be related to reduced endothelial modulation of ET-1 induced vasoconstriction.5 Although EDD after SAH is not impaired further by isoflurane, the endothelium is still dysfunctional due to the effect of SAH and ET-1 induced vasoconstriction might be expected to remain accentuated even in the presence of isoflurane. However, isoflurane also has a direct, endothelium-independent cerebral vasodilatory effect26–28 and this latter effect may be expected to counterbalance the accentuated constriction to ET-1. Indeed we found that, in the presence of isoflurane, accentuation of ET-1 effect was reduced. Interestingly, Ringaert et al.29 found that the increase in CBF produced by isoflurane is greater under hypocarbia when the background cerebral vessel tone is high than under hypercarbia when the tone is low. Similarly, attenuation of ET-1 induced vasoconstriction by isoflurane was greater in vessels after SAH than in control vessels, indicating that the cerebral vasodilatory effect of isoflurane depends on the pre-existing tone of the vessels.

In summary, using a rat model of the acute phase of SAH, we have found that the cortical microvessels have an attenuated EDD and accentuated response to ET-1 after SAH and that isoflurane does not further impair EDD, but modulates the accentuated response to ET-1 in these vessels. Such an effect of isoflurane would not predispose the vessels to vasospasm after SAH.


   Footnotes
 
Supported in part by United States Public Health Service grant HL-46716 and by a grant from the Beth Israel Anesthesia Foundation.

Revision received January 16, 2002. Accepted for publication November 5, 2001.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Sundt TM Jr, Whisnant JP. Subarachnoid hemorrhage from intracranial aneurysms. Surgical management and natural history of disease. N Engl J Med 1978; 299: 116–22.[Abstract]

2 Brawley BW, Strandness DE Jr, Kelly WA. The biphasic response of cerebral vasospasm in experimental subarachnoid hemorrhage. J Neurosurg 1968; 28: 1–8.[Medline]

3 Delgado TJ, Brismar J, Svendgaard NA. Subarachnoid haemorrhage in the rat: angiography and fluorescence microscopy of the major cerebral arteries. Stroke 1985; 16: 595–602.[Abstract/Free Full Text]

4 Ohkuma H, Manabe H, Tanaka M, Suzuki S. Impact of cerebral microcirculatory changes on cerebral blood flow during cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2000; 31: 1621–7.[Abstract/Free Full Text]

5 Park KW, Metais C, Dai HB, Comunale ME, Sellke FW. Microvascular endothelial dysfunction and its mechanism in a rat model of subarachnoid hemorrhage. Anesth Analg 2001; 92: 990–6.[Abstract/Free Full Text]

6 Zuo Z, Tichotsky A, Johns RA. Halothane and isoflurane inhibit vasodilation due to constitutive but not inducible nitric oxide synthase. Anesthesiology 1996; 84: 1156–65.[Medline]

7 Jing M, Bina S, Verma A, Hart JA, Muldoon SM. Effects of halothane and isoflurane on carbon monoxide-induced relaxations in the rat aorta. Anesthesiology 1996; 85: 347–54.[Medline]

8 Park KW, Dai HB, Lowenstein E, Darvish A, Sellke FW. Isoflurane and halothane attenuate endothelium-dependent vasodilation in rat coronary microvessels. Anesth Analg 1997; 84: 278–84.[Abstract]

9 Park KW, Dai HB, Lowenstein E, Stamler A, Sellke FW. Effect of isoflurane on the ß-adrenergic and endothelium-dependent relaxation of pig cerebral microvessels after cardiopulmonary bypass. Journal of Stroke and Cerebrovascular Diseases 1998; 7: 168–78.

10 Cole DJ, Nary JC, Reynolds LW, Patel PM, Drummond JC. Experimental subarachnoid hemorrhage in rats. Effect of intravenous - diaspirin crosslinked hemoglobin on hypoperfusion and neuronal death. Anesthesiology 1997; 87: 1486–93.[Medline]

11 Park KW, Dai HB, Lowenstein E, Sellke FW. Vasomotor responses of rat coronary arteries to isoflurane and halothane depend on preexposure tone and vessel size. Anesthesiology 1995; 82: 1323–30.

12 Vitez TS, White PF, Eger EI, II. Effects of hypothermia on halothane MAC and isoflurane MAC in the rat. Anesthesiology 1974; 41: 80–1.[Medline]

13 Farber NE, Harkin CP, Niedfeldt J, Hudetz AG, Kampine JP, Schmeling WT. Region-specific and agent-specific dilation of intracerebral microvessels by volatile anesthetics in rat brain slices. Anesthesiology 1997; 87: 1191–8.[Medline]

14 Newman B, Gelb AW, Lam AM. The effect of isoflurane-induced hypotension on cerebral blood flow and cerebral metabolic rate for oxygen in humans. Anesthesiology 1986; 64: 307–10.[Medline]

15 Madsen JB, Cold GE, Hansen ES, Bardrum B, Kruse-Larsen C. Cerebral blood flow and metabolism during isoflurane-induced hypotension in patients subjected to surgery for cerebral aneurysms. Br J Anaesth 1987; 59: 1204–7.[Abstract/Free Full Text]

16 Hansen TD, Warner DS, Todd MM, Vust LJ. The role of cerebral metabolism in determining the local cerebral blood flow effects of volatile anesthetics: evidence for persistent flow-metabolism coupling. J Cereb Blood Flow Metab 1989; 9: 323–8.[Medline]

17 Kuroda Y, Murakami M, Tsuruta J, Murakawa T, Sakabe T. Preservation of the ratio of cerebral blood flow/metabolic rate for oxygen during prolonged anesthesia with isoflurane, sevoflurane, and halothane in humans. Anesthesiology 1996; 84: 555–61.[Medline]

18 Wei HM, Weiss HR, Sinha AK, Chi OZ. Effects of nitric oxide synthase inhibition on regional cerebral blood flow and vascular resistance in conscious and isoflurane-anesthetized rats. Anesth Analg 1993; 77: 880–5.[Abstract/Free Full Text]

19 McPherson RW, Kirsch JR, Moore LE, Traystman RJ. N-nitro-L-arginine methyl ester prevents cerebral hyperemia by inhaled anesthetics in dogs. Anesth Analg 1993; 77: 891–7.[Abstract/Free Full Text]

20 Todd MM, Wu B, Warner DS, Maktabi M. The dose-related effects of nitric oxide synthase inhibition on cerebral blood flow during isoflurane and pentobarbital anesthesia. Anesthesiology 1994; 80: 1128–36.[Medline]

21 Bederson JB, Levy AL, Ding WH, et al. Acute vasoconstriction after subarachnoid hemorrhage. Neurosurgery 1998; 42: 352–62.[Medline]

22 Hambrecht R, Wolf A, Gielen S, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342: 454–60.[Abstract/Free Full Text]

23 Takahashi K, Ohyanagi M, Ikeoka K, Iwasaki T. Acetylcholine-induced response of coronary resistance arterioles in cholesterol-fed rabbits. Jpn J Pharmacol 1999; 81: 156–62.[Medline]

24 Vallejo S, Angulo J, Peiró C, et al. Highly glycated oxyhaemoglobin impairs nitric oxide relaxations in human mesenteric microvessels. Diabetologia 2000; 43: 83–90.[Medline]

25 Joles JA, Stroes ESG, Rabelink TJ. Endothelial function in proteinuric renal disease. Kidney Int 1999; 56(Suppl 71): S57–61.

26 Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology 1999; 91: 677–80.[Medline]

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28 Jensen NF, Todd MM, Kramer DJ, Leonard PA, Warner DS. A comparison of the vasodilating effects of halothane and isoflurane on the isolated rabbit basilar artery with and without intact endothelium. Anesthesiology 1992; 76: 624–34.[Medline]

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