(Circulation. 1995;92:423-427.)
© 1995 American Heart Association, Inc.
Articles |
Isoflurane Attenuates cAMP-Mediated Vasodilation in Rat Microvessels
From the Department of Anesthesia and Critical Care and the Department of Surgery, Beth Israel Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Frank W. Sellke, Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Hospital, Dana 905, 330 Brookline Ave, Boston, MA 02215.
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Abstract |
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Background Endothelium-dependent vasodilation mediated by cGMP is known to be attenuated by the inhalational anesthetic isoflurane. The present study examines the effect of isoflurane on ß-adrenergic and cAMP-mediated vasodilation.
Methods and Results Fifty-three subepicardial coronary arteries (diameter, 103±13 µm) from Wistar rats were studied in vitro in a pressurized (40 mm Hg), no-flow state with use of optical density video detection system. After preconstriction of vessels with the thromboxane A2 analogue U46619 10-6 mol/L, concentration response curves to the nonselective ß-adrenergic agonist isoproterenol, the GS protein activator sodium fluoride, the adenylate cyclase activator forskolin, the cAMP analogue 8-Br-cAMP, or the phosphodiesterase inhibitor RO20-1724 were obtained either in the presence or absence (control) of 2% isoflurane. Relaxations to all the agents tested were significantly reduced in the presence of isoflurane compared with controls.
Conclusions Isoflurane attenuates cAMP-mediated vasodilation. The impairment appears to be distal to adenylate cyclase and is not due to enhancement of cAMP phosphodiesterase.
Key Words: vasodilation • receptors, adrenergic, beta • anesthesia • microcirculation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The inhalational anesthetic isoflurane is classically described as a dilator of both the systemic and the coronary vasculature.1 However, some recent data cast doubt on this classic notion. Park et al2 have demonstrated in rabbits that large epicardial coronary arteries dilate in an endothelium-dependent manner in response to increasing concentrations of isoflurane, whereas small subepicardial arteries constrict. The latter action was found to be endothelium dependent and mediated by a cyclooxygenase product.
Furthermore, Muldoon et al3 demonstrated that the inhalational anesthetic halothane attenuates endothelium-dependent vasodilation. Similar findings have been reported not only for halothane4 5 6 7 but also for isoflurane4 5 and enflurane.5 Endothelium-dependent vasodilation is produced largely by endothelial production of nitric oxide, leading to activation of smooth muscle soluble guanylate cyclase and synthesis of cGMP.8 9 The increase in cGMP produces relaxation of vascular smooth muscle.10 The site of impairment in inhalational anesthetic–induced attenuation of endothelium-dependent vasodilation is a matter of controversy.4 5 6 7 However, it is generally agreed that the site(s) is distal to the endothelial receptor of endothelium-dependent vasodilating agonist but proximal to the action of cGMP.3 4 5 6 7
Two cyclic nucleotides, namely cGMP and cAMP, are known to be involved in vascular smooth muscle relaxation.10 Whereas the effect of inhalational anesthetics on endothelium-dependent vasodilation has been investigated, the effect of isoflurane on cAMP-mediated vasodilation has not been examined. The present study was undertaken to define the effect of isoflurane on ß-adrenergic and cAMP-mediated vasodilation and the mechanism of the observed action.
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Methods |
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Vessel Preparation
In accordance with institutional Animal Care Committee standards, Wistar rats of either sex, weighing 100 to 150 g, were anesthetized by injection of ketamine 40 mg/kg and xylazine 5 mg/kg IP. Subepicardial microvessels were prepared as described previously.2 Each vessel was placed in an isolated vessel chamber cannulated with dual micropipettes measuring 50 to 100 µm in diameter and secured with a 10-0 nylon monofilament suture. The vessel was continuously bathed with modified Krebs buffer,2 gassed with 95% O2–5% CO2 mixture, and maintained at 37°C and pH of 7.4. PO2 in the vessel chamber exceeded 400 mm Hg. Because the vessel was studied in a no-flow state, the pressure in the micropipettes was maintained at 40 mm Hg to provide distension. The vessel was visualized with an inverted microscope (Olympus IMT-2) connected to a video camera (Burle Security Products). The vessel image was projected onto a video screen (Panasonic). The vessel internal lumen diameter was measured with the use of an optical density video detection system (Living Systems Instrumentation) as previously described.11 Measurements of the lumen diameter were recorded with a Western Graphtec Multicorder. A schematic of the experimental setup has been published previously.2
Stability of the Preparation
To test for the stability of the
vessel preparation over time,
the internal diameters of 8 microvessels (baseline diameter, 103.9±8.4
µm) were studied over 2.5 hours. The vessels were found to reach an
equilibration point within the first 5 minutes. No spontaneous
vasodilation or vasoconstriction occurred over the 2.5-hour time
period.
To test for the stability of vasomotor response over time, 7 microvessels (baseline diameter, 103.0±8.1 µm) were equilibrated in the vessel chamber for 30 minutes and then subjected successively to KCl (100 mmol/L), acetylcholine (10-5 mol/L), and U46619 (10-6 mol/L), with rinsing and reequilibration for 5 minutes between interventions. After subjection to U46619, the vessel was subjected to isoproterenol (10-7 mol/L) and the percentage of relaxation from U46619-induced constriction was calculated. The vessels were again subjected to the same set of interventions after 1.5 hours in the vessel chamber. Magnitudes and direction of vasomotor responses were compared.
Study Protocol
After a minimum of 20 to 30 minutes of
equilibration in the
vessel chamber, a baseline measurement of the vessel lumen internal
diameter was obtained. The vessel then was preconstricted with U46619
10-6 mol/L. Only vessels that constricted by 20% to 40%
to U46619 were studied further. The vessel then was either subjected to
isoflurane 2% (study group) or to continued aeration with 95%
O2–5% CO2 alone (control). Isoflurane was
administered by adding the anesthetic to the 95% O2–5%
CO2 mixture bubbled into the Krebs buffer solution with use
of an in-line Vernitrol bubble-through vaporizer (Ohio Medical
Products). In a preliminary experiment, it was determined by gas
chromatography that it took less than 10 minutes for
isoflurane to reach a steady state concentration in the solution after
it was introduced into the vessel chamber. The anesthetic content in
the gas mixture was continuously monitored with the use of a Rascal II
gas analyzer (Ohmeda) that had been calibrated with industrial
standards. Gas chromatography analysis of
selected samples from the vessel chamber showed that the millimolar
concentration and partial pressure of isoflurane in the vessel chamber
(0.70±0.07 mmol/L and 13.44±1.43 mm Hg) consistently
reflected its concentration in the gas mixture bubbled into the buffer
solution. No significant change in internal diameter of the
U46619-preconstricted vessel was noted after subjection to isoflurane
2%.
At least 15 minutes after introduction of isoflurane 2% or 0% (control), the vessel was subjected to increasing concentrations of isoproterenol (10-12 to 10-4 mol/L), the GS protein activator NaF (10-9 to 10-2 mol/L), the adenylate cyclase activator forskolin (10-9 to 10-5 mol/L), the cAMP analogue 8-Br-cAMP (10-12 to 10-5 mol/L), or the cAMP-specific phosphodiesterase inhibitor RO20-1724 (4-[(3-Butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone)12 (10-8 to 10-5 mol/L). Another set of vessels was preincubated with RO20-1724 5x10-7 mol/L, and concentration response curves to forskolin (10-9 to 10-5 mol/L) were obtained in the presence and absence of isoflurane 2%. At each concentration, the internal diameter was measured, and percentage of relaxation from U46619-induced preconstriction was calculated. Concentration response curves for up to two experimental conditions were generated per vessel. At the end of each experiment, the anesthetic was discontinued. The vessel chamber then was flushed with fresh Krebs buffer and the vessel reequilibrated at 37°C. KCl then was added to a final concentration of 100 mmol/L, and the internal lumen diamter was measured. Only vessels that constricted by at least 15% to KCl at the end of each experiment were considered still viable and included for data analysis. This represented exclusion of any vessel that constricted less than the average by approximately 1 SD, as determined in the study on the stability of vessel preparation and vasomotor responses. Fifty-three vessels from 23 Wistar rats, not counting the vessels used to test the stability of vessel preparation, met this criterion and are the subject of the present study.
Statistical Analysis
Comparison of vessel sizes in different
experimental groups was
made by Student's t test. Comparison of the vasomotor
responses to KCl, acetylcholine, U46619, or isoproterenol after 30
minutes of equilibration versus after 1.5 hours also was performed
using the Student's t test. The effects of isoflurane on
concentration response curves to the various vasodilators tested were
analyzed by multiway ANOVA (ANOVA-blocked design) to test the
null hypothesis that isoflurane had no effect on the response of the
vessels to the vasodilators. Significance was considered at
P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Stability of Vessel Preparation
There was no significant difference in the magnitude of vasomotor responses of rat subepicardial arteries to KCl, acetylcholine, U46619, or isoproterenol after 1.5 hours of equilibration versus after 30 minutes (see Fig 1
).
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Exclusion of Vessels
Seventy-nine coronary microvessels of
apparent
anatomic integrity, not counting the vessels used for time control
studies, were harvested from 23 rats. Of these, 8 vessels were
discarded because of technical problems with mounting onto
micropipettes, such as inadvertent introduction of air
bubbles. Fourteen vessels did not have adequate response to
preconstriction with U46619 10-6 mol/L, defined as 20% to
40% constriction from the baseline diameter. Of the remaining 57
vessels, 4 failed to have 15% or greater constriction response to KCl
at the end of the study and were also excluded. Exclusive of the
vessels discarded because of technical problems, approximately 25% of
the vessels were excluded from data analysis because of
inadequate response to U46619 or KCl. The remaining 53 vessels are the
subject of the present investigation.
Effect of Isoflurane on cAMP-Mediated Vasodilation
Isoflurane
2% significantly (P<.001) attenuated
vasodilation of rat subepicardial arteries to the ß-adrenergic
agonist isoproterenol (Fig 2) (control: n=7; size,
102.3±7.9 µm; isoflurane-exposed: n=6, size,
102.8±8.5 µm).
The two study groups were not significantly different from each other
in baseline diameter.
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Likewise, isoflurane 2% significantly
(P<.01) attenuated
vasodilation of the coronary microvessels to the GS
protein activator NaF (Fig 3) (control: n=7;
size, 103.1±7.4 µm; isoflurane-exposed: n=6; size,
93.8±10.9
µm). The two groups of vessels were not signficantly different from
each other in baseline diameter.
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Furthermore, isoflurane 2%
significantly (P<.01)
attenuated vasodilation of the vessels to the adenylate
cyclase activator forskolin (Fig 4)
(control: n=6; size, 95.8±14.0 µm; isoflurane-exposed:
n=5;
size, 90.0±11.5 µm). The two groups of vessels were not
significantly different from each other in baseline diameter.
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Additionally, isoflurane significantly (P<.001) attenuated
vasodilation to the stable cAMP analogue 8-Br-cAMP (Fig 5)
(control: n=7; size, 105.6±7.5 µm;
isoflurane-exposed: n=10; size, 103.9±4.6 µm). The two
groups of
vessels were not significantly different from each other in baseline
diameter.
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Finally, isoflurane significantly attenuated vasodilation to
the
phosphodiesterase inhibitor RO20-1724 (P<.001)
(Fig 6) (control: n=8; size, 114.8±6.2 µm;
isoflurane-exposed: n=7; size, 109.8±13.2 µm) or to
forskolin in
the presence of RO20-1724 (P<.001) (Fig 7)
(control: n=5; size, 100.2±7.6 µm; isoflurane-exposed:
n=5;
size, 100.2±7.0 µm). The baseline diameters of the study groups did
not differ significantly from those of the respective control
groups.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study examines the effect of an inhalational anesthetic on ß-adrenergic and cAMP-mediated smooth muscle relaxation. The vasodilators studied were the ß-adrenergic receptor agonist isoproterenol, the GS protein activator NaF, the adenylate cyclase activator forskolin, the cAMP analogue 8-Br-cAMP, and the cAMP-specific phosphodiesterase inhibitor RO20-1724. The most important findings of the study are (1) isoflurane attenuates ß-adrenergic, cAMP-mediated vasodilation and (2) the impairment appears to be distal to adenylate cyclase and is not due to enhancement of cAMP phosphodiesterase.
Because isoflurane attenuated vasodilation to all the dilators used in this study, it is not possible to pinpoint the site of action other than to postulate where, distal to cAMP production, isoflurane may be interfering. Several mechanisms whereby an increase in vascular smooth muscle intracellular cAMP leads to vasodilation have been proposed. First, an increase in cAMP increases the activity of the cAMP-dependent protein kinase.13 14 The cAMP-dependent protein kinase in turn phosphorylates and thereby decreases the activity of the myosin light chain kinase. Decreased myosin phosphorylation leads to a decrease in actin-myosin interaction. Second, cAMP-mediated vasodilation may result from activation of the cGMP-dependent protein kinase.15 16 The cGMP-dependent protein kinase may phosphorylate phospholamban,10 17 a regulator of sarcoplasmic reticulum Ca2+-ATPase.18 Phosphorylation of phospholamban activates the sarcoplasmic reticulum Ca2+-ATPase, enhancing sarcoplasmic reticulum Ca2+ uptake. The resulting decrease in Ca2+ then will bring about vasodilation by (1) deactivation of myosin light chain kinase and (2) deactivation of an unidentified Ca2+-dependent regulatory site that maintains myosin-actin crossbridge attachment even after myosin is dephosphorylated.19 20 Third, cAMP may affect the sensitivity of myofilaments to Ca2+. Morgan and Morgan21 measured intracellular Ca2+ in ferret portal vein smooth muscles by using the Ca2+ indicator aequorin. They reported that isoprenaline and forskolin produced vasodilation even when there was no concurrent decrease in intracellular Ca2+. They suggested that the vasodilators caused an uncoupling between calcium and myofilaments. Different mechanisms of cAMP-mediated vascular smooth muscle relaxation may be in effect in different tissues in different species of animals.
In this study, we have shown that isoflurane attenuates cAMP-mediated vasodilation by acting at a step distal to adenylate cyclase but not by enhancing the activity of the phosphodiesterase. Previous studies4 5 22 of the effect of isoflurane on cGMP-mediated vasodilation agree that endothelium receptor–mediated increase in endothelium-derived nitric oxide (and subsequent increase in smooth muscle cGMP) is attenuated by isoflurane. Although they do not agree where isoflurane is interfering distal to the endothelial receptor, they agree that the site is not distal to cGMP and thus not at or distal to cGMP-dependent protein kinase. Therefore, it may be surmised that while the site of action of isoflurane on cAMP-mediated vasodilation is distal to cAMP production, it probably is not by deactivation of cGMP-dependent protein kinase. It may, however, be through the deactivation of cAMP-dependent protein kinase or by affecting the action of cAMP on the sensitivity of the myofilaments to Ca2+. Further studies will be required to address these potential mechanisms of attenuation.
Clinical Implications
Any clinical implications of this
investigation must be tempered
by the fact that this study was conducted in vitro in a single species.
Given this limitation, however, our finding adds to the complexity of
the relationship between isoflurane and the adrenergic system in the
clinical situation. First, in general, surgical stimulation under
anesthesia leads to variable activation of the
endogenous adrenergic system. This is associated with a
variable decrease in the ß-adrenergic receptor density and
receptor affinity for its agonist isoproterenol.23
Anesthetics such as isoflurane may blunt activation of the adrenergic
system to surgical stress24 and thus may be expected to
lessen receptor downregulation and preserve adrenergic responsiveness.
Second, the direct effect of isoflurane on the sympathetic nervous
system is to decrease its efferent traffic, with depression of the
postganglionic activity greater than the preganglionic
activity.25 Our study demonstrates that isoflurane
attenuates the dilatory response to ß-adrenergic agents at the
vascular effector level. Isoflurane also attenuates ß-adrenergic
response at another effector, namely the sinoatrial
node.25 26 However, vasoconstrictive
response to 
-adrenergic stimulation is maintained during
isoflurane anesthesia.27 Third, despite the
depressant effect on the sympathetic system and attenuation of the
ß-adrenergic vasodilation by isoflurane, ß-adrenergic
blockade with propranolol is well tolerated during
isoflurane anesthesia.28 One explanation of
this observation may be that because of systemic vasodilation,
isoflurane may reflexively activate the sympathetic
chronotropic response.
We have reported previously2 that isoflurane constricts coronary resistance arteries in the absence of preconstriction. In this study, we observed that after preconstriction of the vessels with U46619, application of isoflurane resulted in no significant vasodilation or vasoconstriction. The constrictive effect of isoflurane may have been masked in the present study because of preconstriction. Taken together, these studies suggest a variable vasoconstrictive effect of isoflurane, depending on the preexisting tone of the arteries. This variable effect raises the possibility that isoflurane may have a less constrictive effect in normal resistance arteries with greater tone and autoregulatory reserve than in postocclusion, collateral-dependent arteries with less tone and autoregulatory reserve. Such an effect may result in an unfavorable redistribution of blood flow away from the collateral-dependent region, ie, coronary steal. Isoflurane-associated coronary steal has been described in several situations.29 30 In other situations, studies have failed to confirm maldistribution.31 32 The disparity in these findings may be due to the confounding effects of autoregulation, metabolism-flow coupling, and changes in compressive resistance caused by changes in myocardial contractility.
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Acknowledgments |
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This study was supported in part by USPHS HL-46716, by a Grant-in-Aid from the American Heart Association, Massachusetts Affiliate, and by Beth Israel Anesthesia Foundation.
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