(Stroke. 1996;27:311-316.)
© 1996 American Heart Association, Inc.
Articles |
Relaxation of Subarachnoid HemorrhageInduced Spasm of Rabbit Basilar Artery by the K+ Channel Activator Cromakalim
From the Departments of Neurosurgery (M.Z., C.L.B., A.I.L.), Molecular and Cellular Physiology (N.S.), and Pharmacology and Cell Biophysics (R.M.R.), University of Cincinnati College of Medicine, and Veterans Affairs Medical Center (M.Z., R.M.R.), Cincinnati, Ohio.
Correspondence to Robert M. Rapoport, PhD, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Bethesda Ave, Cincinnati, OH 45267-0575.
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Abstract |
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 Top Abstract IntroductionMaterials and Methods Results Discussion References |
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Background and Purpose Cerebral vasospasm resulting from subarachnoid hemorrhage (SAH) is refractory to most vasodilators. However, despite evidence that a mechanism underlying the vasospasm may be smooth muscle cell membrane depolarization resulting from decreased K+ conductance, the ability of K+ channel activators to relax the spasm has not been thoroughly investigated. The purpose of this study, therefore, was to investigate whether K+ channel activation selectively relaxes SAH-induced vasospasm.
Methods Three days after SAH in the rabbit, relaxation of the basilar artery in response to the K+ channel activator cromakalim as well as to staurosporine (protein kinase C antagonist), forskolin (adenylate cyclase activator), and sodium nitroprusside (guanylate cyclase activator) was measured in situ with the use of a cranial window. Relaxation in response to these agents was also investigated in control vessels contracted with serotonin. Membrane potential of the smooth muscle cells of the basilar artery from SAH and control rabbit was measured in vitro with the use of intracellular microelectrodes.
Results Cromakalim completely relaxed the SAH-induced spastic basilar artery, while staurosporine, forskolin, and sodium nitroprusside were significantly less efficacious. In contrast, sodium nitroprusside and forskolin were more efficacious relaxants in serotonin-contracted control vessels than in SAH vessels. The K+ channel blocker glyburide and high [K+] prevented cromakalim-induced relaxation. Glyburide did not inhibit forskolin-induced relaxation of serotonin-contracted control vessels. Cromakalim concentration-dependently repolarized spastic basilar artery smooth muscle cells, and the repolarization was prevented by glyburide.
Conclusions These results suggest that K+ channel activation selectively relaxes SAH-induced vasospasm. We speculate that the ability of K+ channel activators to selectively relax the spasm may be due, at least in part, to the underlying inhibition of K+ channels after SAH.
Key Words: vasodilatation • rabbits • potassium channels • basilar artery • vasospasm • cerebral arteries
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in humans is generally resistant to drug-induced dilatation.1 2 3 The lack of drug-induced dilatation of SAH-induced spastic vessels in humans is well reproduced in animal models, as the spasm after SAH in animals is also resistant to reversal in vivo in response to numerous vasodilators, including aminophylline, papaverine, nifedipine, nicardipine, and nitroglycerin.4 5 6 7 8 9 10 11
Despite evidence that K+ channel activation may relax SAH-induced vasospasm, the ability of K+ channel activators to relax spastic vessels has not been thoroughly investigated. Evidence in support of the potential effectiveness of K+ channel activators to relax spastic vessels includes the observations that (1) nicorandil, a K+ channel activator, partially reversed SAH-induced spasm of the canine basilar artery12 13 14 (it should be noted, however, that nicorandil may induce relaxation through both K+ channel activation and additional mechanisms15–18);(2) spastic vessels are depolarized12 19 20 21 ; and (3) this depolarization of spastic vessels may be due to decreased K+ conductance.12
The purpose of this study, therefore, was to investigate whether the K+ channel activator cromakalim selectively relaxes SAH-induced spasm of the rabbit basilar artery in situ. Some of these results have appeared in preliminary communications.22 23
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Animal Preparation
General Procedures
Procedures were approved by the Institutional Animal Care and Use Committee. Ninety-three immunized and conditioned New Zealand White male rabbits (weight, 3 to 4 kg) were anesthetized with ketamine HCl (30 mg/kg IM) and xylazine (6 mg/kg IM), intubated, and mechanically ventilated with room air supplemented with O2. The respiratory rate and volume were adjusted to maintain expiratory PCO2 between 35 and 37 mm Hg. Heart rate and systemic pressure were measured with the use of a femoral artery catheter. Arterial PO2 and PCO2 were monitored and maintained within normal levels by adjusting the respiratory rate and/or tidal volume. Supplemental anesthesia and fluids were administered through a cannulated femoral vein. Core body temperature was monitored rectally and maintained at 37°C with a heating pad.
SAH
Rabbits were immobilized in a
stereotaxic frame and the cisterna magna punctured
percutaneously with a 21-gauge butterfly needle.
Autologous arterial blood (1 mL/kg) was then injected over
3 minutes. After the hemorrhage, the animals were housed flat
in animal incubators and allowed to recover. The animals were monitored
postoperatively for infections, hydration, and signs of postoperative
pain. Antibiotics and fluids were administered as appropriate and
nursing care delivered in accordance with good veterinary practice and
in consultation with the Veterinary Medical Officer.
Controls were injected with artificial cerebrospinal fluid (CSF) (mmol/L: NaCl 121.8, KCl 3.2, CaCl2 2.5, MgCl2 1.26, NaHCO3 25.0, D-glucose 3.7, urea 6.0) or were not injected. Similar results were observed in injected and noninjected controls, and the results were combined.
Basilar Artery Cranial Window
Three days after SAH,
rabbits were anesthetized, placed
in a head holder in the supine position, and the clivus exposed by
blunt dissection between the carotid sheath and trachea. After division
of the superficial transverse vein and the hyoid bone, the trachea and
esophagus were retracted laterally. Compression of the carotid arteries
and the descending vagus nerves was avoided. The muscle covering the
basioccipital bone was removed by electrocautery. A rectangular
osteotomy (4 to 5 mm wide) was then made at the base of the skull
between the tympanic bullae with the use of a microdrill and
microrongeur under an operating microscope. After perfect hemostasis
was achieved, the dura was opened and excised with microscissors, the
basilar artery exposed, and the arachnoid membrane around the basilar
artery opened. The blood clot present in SAH animals was gently
removed with microforceps, and although any mechanical stimulation was
avoided, a transient (less than 2 minutes) increase in magnitude of the
underlying vasospasm was observed in 9 of 21 animals.
Contractility Studies
The surgical field was illuminated with
a 100-W halogen lamp,
which was fitted with a heat filter to avoid warming the cranial
window, and was visualized through a trinocular microscope (Zeiss
OPMI-1). Basilar artery diameter was measured with a PC image
analysis system (Image Analyzer, Magiscan) with the use
of a video camera mounted on the phototube of the microscope. Head
temperature was monitored with a needle inserted in the residual longus
colli muscle and was maintained at 37°C to 38°C.
The cranial window was suffused (1 mL/min) with artificial CSF, maintained at 37°C, and gassed with 7% O2/6% CO2/87% N2. The pH and CO2 values of CSF samples obtained from the cranial window were 7.4±0.1 and 40±3 mmol/L, respectively (mean±SE; n=15 in each case). Vessel diameter, blood pressure, heart rate, and arterial PO2 and PCO2 stabilized within 45 minutes after CSF suffusion, and agents were then suffused over the craniotomy. Vessel diameter was recorded at the time of the plateau response to each agent. Each value of vessel diameter was the mean of 13 consecutive measurements (1/10 s). Spontaneous vasomotion of approximately two cycles per minute along the entire length of basilar artery was observed in 4 of 10 vessels from control rabbits and 2 of 10 vessels from SAH rabbits. The amplitude of vasomotion in basilar artery from control and SAH rabbits was 6±1% (mean±SE) and 3% (mean) of baseline diameter, respectively. The vehicle for cromakalim, glyburide, and forskolin (ethanol) and the vehicle for staurosporine (dimethyl sulfoxide) did not alter basal, SAH-, and serotonin-induced tone.
Electrophysiological Studies
Basilar artery was pinned to the
bottom of a tissue chamber and
superfused with Krebs-Ringer bicarbonate solution (mmol/L: NaCl 118.5,
KCl 4.74, MgSO4 1.18, KH2PO4 1.18,
CaCl2 2.5, NaHCO3 24.9, glucose 10, EDTA 0.03)
maintained at 37°C and gassed with 95% O2/5%
CO2. Intracellular electrical activity was recorded
after 90 minutes of equilibration. Glass microelectrodes (tip
resistance, 60 to 80 M
) were filled with 3 mmol/L KCl. Cell
impalement from the adventitial side of the artery was made with the
help of a sliding micrometer. Successful impalement was
indicated by a sharp drop in voltage from baseline on entry of the
microelectrode into the cell and a sharp return to baseline on exit of
the microelectrode. Membrane potential was monitored continuously with
an oscilloscope and recorded from a voltmeter. Ethanol vehicle did
not alter membrane potential.
Statistical Methods
Statistical significance between multiple
and two means was
determined with the use of the Bonferroni procedure and Student's
unpaired t test, as appropriate. Student's paired
t test was used as indicated. Significance was accepted at
the .05 level of probability. The magnitude of contraction was
expressed as a percentage of basal diameter, measured in
micrometers. The magnitude of relaxation was expressed as a
percentage of the contraction, measured as the difference in
micrometers between basal and agonist-induced tone. The
contraction (in micrometers) due to SAH was calculated with
the use of the mean basal diameter of all control vessels. Values are
expressed as mean±SE.
Materials
Reagent sources were as follows: Calbiochem,
forskolin; Kamiya,
staurosporine; Sigma, serotonin maleate and
sodium nitroprusside; Smith Kline/Beecham, cromakalim (gift); and
Hoechst-Roussel, glyburide (gift).
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Results |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Contractility
Resting (control) basilar artery diameter was 916±8.9 µm (n=38). SAH contracted the vessel by 36.9±2.1% (n=8; Fig 1
).
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significantly greater than SAH.
Cromakalim relaxed spastic vessels in a
concentration-dependent manner, and 10 µmol/L cromakalim induced
complete relaxation (Fig 2). Cromakalim also relaxed
control vessel basal diameter in a concentration-dependent manner
and induced a maximal relaxation of 27.7±2.2% (n=3; Fig
3).
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), forskolin (
), staurosporine
(
), and sodium nitroprusside (
). Mean±SE values are
shown;
n=3 to 4. *Significantly less than cromakalim at the same
concentration.
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;
30-minute exposure). Mean±SE values are shown; n=3 in each case.
*Significantly less than the same concentration of cromakalim in the
absence of glyburide.
In contrast to the ability of cromakalim to
completely relax spastic
vessels, 1 µmol/L staurosporine induced only 6.5±1.2%
relaxation (n=3), and 10 µmol/L forskolin relaxed spastic vessels
by
only 17.8±3.3% (n=4; Fig 2
). In addition, 1
µmol/L sodium
nitroprusside, which was a maximally effective relaxant concentration,
relaxed spastic vessels by only 19.6±7.8% (n=3; Fig
2).
To test whether SAH prevented forskolin-,
staurosporine-,
and sodium nitroprusside–induced relaxation, SAH-induced spastic
vessels were contracted with 1 µmol/L serotonin and then
challenged with vasodilator. Serotonin (1 µmol/L)
contracted spastic vessels by an additional 30% over that induced by
SAH (Fig 1). Forskolin, staurosporine, and sodium
nitroprusside relaxed spastic vessels contracted with
serotonin, although the magnitude of relaxation was only
the amount of the serotonin-induced contraction (Fig 4). In
contrast, cromakalim completely relaxed
serotonin-contracted spastic vessels in a
concentration-dependent manner (Fig 4).
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To test whether
the relatively small magnitude of sodium nitroprusside-
and forskolin-induced relaxation of spastic vessels was due to the
mechanism underlying the spasm and not the result of contraction per
se, control vessels were contracted with 1 µmol/L
serotonin and then challenged with vasodilator.
Serotonin contracted control vessels by approximately 80%
of SAH vessels (Fig 1). Sodium nitroprusside (10 nmol/L)
relaxed
serotonin-contracted control vessels by 58.6±5.8%
(n=3; Fig 5), which was significantly greater than the
magnitude of 10 nmol/L sodium nitroprusside-induced relaxation in
SAH-induced spastic vessels (13.1±3.9%; n=4; Fig
2). In addition, 1
and 10 µmol/L forskolin relaxed serotonin-contracted
vessels by 27.5±1.4% and 74.2±2.3%, respectively (n=3 in
each
case), which were significantly greater than the respective magnitudes
of relaxation to 1 and 10 µmol/L forskolin in SAH-induced spastic
vessels (5.4±2.2% and 17.8±3.3%, respectively; n=4 in
each case;
Fig 2). Cromakalim (10 µmol/L) completely relaxed
serotonin-contracted control vessels (Fig 5).
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), with 10 nmol/L
sodium nitroprusside (
To test
whether cromakalim induced relaxation through a mechanism
independent of K+ channel activation, control basilar
arteries were contracted with 40 mmol/L KCl (43.2 mmol/L KCl final) or
with 125 mmol/L KCl (substituted for NaCl) and then challenged with
cromakalim. We found that 10 µmol/L cromakalim, but not 1 µmol/L,
relaxed 43.2 mmol/L KCl–contracted vessels, while 10
µmol/L cromakalim relaxed 125 mmol/L KCl–contracted
vessels by only 10.3±3.9% (n=3; Fig 6). KCl (43.2
and
125 mmol/L) contracted control vessels by 27.2±1.6% and
62.0±7.2%,
respectively (n=3 in each case; Fig 1).
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Glyburide
(10 µmol/L), a K+ channel blocker, also
prevented cromakalim-induced relaxation of spastic vessels at
cromakalim concentrations less than 10 µmol/L (Fig 7).
Glyburide also prevented cromakalim-induced relaxation of resting
control vessels (Fig 3). Glyburide contracted control vessels
by
6.0±1.4% (n=7; Fig 1) and contracted SAH vessels
by 3.0±0.3% (n=3;
P<.01 using Student's paired t test).
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To
test whether the inhibition of cromakalim-induced relaxation by
glyburide was due to a nonselective action of glyburide, control
vessels were contracted with 1 µmol/L serotonin in the
presence of 10 µmol/L glyburide and then challenged with forskolin.
The magnitude of contraction due to serotonin in the
presence of glyburide, 40.4±3.2% (n=4), was significantly
greater
than that due to serotonin in the absence of glyburide (Fig 1).
Glyburide did not inhibit forskolin-induced relaxation of
serotonin-contracted vessels (Fig 5).
Membrane Potential
Smooth muscle cells of spastic vessels
were depolarized by 10 mV
compared with control vessels (Fig 8). Cromakalim
repolarized the cells in a concentration-dependent manner (Fig
9) and at concentrations that relaxed the spasm (Figs
2 and 4).
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Glyburide (10 µmol/L)
completely prevented the 0.1 µmol/L and
partially prevented the 1 and 10 µmol/L cromakalim–induced
repolarization of the smooth muscle cells of spastic vessels (Fig
10). Glyburide further depolarized the cells of spastic
vessels (Fig 10 compared with Fig 8).
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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The present study demonstrates that the K+ channel activator cromakalim selectively relaxed the SAH-induced spastic basilar artery. The mechanism underlying the cromakalim-induced relaxation is likely due to K+ channel activation since (1) the relaxation was associated with repolarization of the smooth muscle cells; (2) glyburide, a K+ channel blocker, selectively prevented the relaxation, as well as the associated smooth muscle cell repolarization; and (3) high [K+] prevented the relaxant effects of cromakalim. Although 10 µmol/L glyburide did not prevent the 10 µmol/L cromakalim–induced relaxation and hyperpolarization of spastic vessels, the lack of inhibition may reflect the ability of high cromakalim concentrations to overcome the inhibitory effects of glyburide.24 It should be noted that it is difficult to conclude which K+ channel(s) is/are activated by cromakalim because of possible lack of selectivity of cromakalim and glyburide for specific K+ channels.25
In contrast to the relative lack of relaxant efficacy of staurosporine and sodium nitroprusside in spastic vessels (present results), efficacious in situ relaxations in response to staurosporine and to another protein kinase C antagonist, H7, were observed in the spastic basilar artery from dogs11 26 and in response to sodium nitroprusside in spastic pial arterioles from newborn pigs.27 An explanation for these apparently contrasting results may be related to differences between vessels as well as models of SAH-induced vasospasm.
An additional contrast is that while 10 µmol/L glyburide increased basilar artery basal tone (present results), albeit of relatively small magnitude, glyburide did not alter the basal tone of rat basilar artery and rat and rabbit pial arterioles in situ (1 µmol/L glyburide28 29 30 31 ) and rabbit basilar artery in vitro (10 µmol/L glyburide32 ). The explanation for these apparently contrasting results may be due to the different concentrations of glyburide tested as well as to differences between species, vessels, and preparations.
Whether the ability of K+ channel activation to selectively relax spastic vessels is related to SAH-induced inhibition of K+ channels cannot be concluded from this study. In support of this suggestion, however, is the observation that SAH-induced depolarization of the canine basilar artery was the result of decreased K+ conductance.12
Along these lines, there is increasing evidence in support of a role for endothelin-1 in SAH-induced cerebral vasospasm.33 34 Furthermore, endothelin-1 blocked K+ATP and K+-Ca2+ channels and depolarized and contracted smooth muscle cells of porcine coronary artery.35 36 37 The selective relaxation of the SAH-induced vasospasm by cromakalim may result, therefore, from the greater efficacy of cromakalim at reversing endothelin-1–induced K+ channel inactivation and the resulting signal transduction mechanisms compared with the other vasodilators presently tested.
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Acknowledgments |
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This study was supported by grants from the Department of Veterans Affairs and the Department of Neurosurgery, University of Cincinnati College of Medicine (Ohio). The technical support provided by Gerald M. Schmitt, Sharada Upputuri, and Dr Chandrasekhar Upputuri is gratefully acknowledged. We thank Rita Eveleigh for help in manuscript preparation.
Received August 4, 1995; revision received September 25, 1995; accepted October 17, 1995.
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