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1 Department of Clinical Pharmacology, 3 Institute of Medical Physics, and 2 Department of Ophthalmology, University of Vienna School of Medicine, A-1090 Vienna, Austria
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Carbon dioxide is an important regulator of vascular
tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (KATP) activation, significantly blunts vasodilation in
response to hypercapnic acidosis in animals. We investigated whether
glibenclamide also alters the cerebral and ocular vasodilator response
to hypercapnia in humans. Ten healthy male subjects were studied in a
controlled, randomized, double-blind two-way crossover study under
normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU · kg
1 · min1
iv) were administered with glucose to achieve comparable plasma insulin
levels. In control experiments, five healthy volunteers received
glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and
nicorandil in a randomized, three-way crossover study. Mean blood flow
velocity and resistive index in the middle cerebral artery (MCA) and in
the ophthalmic artery (OA) were measured with Doppler sonography.
Pulsatile choroidal blood flow was assessed with laser interferometric
measurement of fundus pulsation. Forearm blood flow was measured with
venous occlusion plethysmography. Hypercapnia increased ocular fundus
pulsation amplitude by +18.2-22.3% (P < 0.001) and mean
flow velocity in the MCA by +27.4-33.3% (P < 0.001),
but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow
increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes
in cerebral or ocular hemodynamics and did not affect systemic
hemodynamics or forearm blood flow but significantly increased glucose
utilization and blunted the nicorandil-induced vasodilation in the
forearm. This suggests that hypercapnia-induced changes in the vascular
beds under study are not mediated by activation of KATP
channels in humans.
cerebral blood flow; ocular blood flow; adenosine 5'-triphosphate-sensitive potassium channels
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ARTERIAL CARBON DIOXIDE tension is an important regulator of cerebral and ocular blood flow (1, 6, 22). Hypercapnia is associated with decreased extracellular pH, activation of potassium channels, and membrane hyperpolarization (14, 17, 28). Four different potassium channels have been described in cerebral blood vessels: 1) ATP-sensitive potassium channels (KATP channels), 2) calcium-activated potassium channels, 3) delayed rectifier potassium channels, and 4) inward rectifier potassium channels. Activation of ATP-sensitive and calcium-activated potassium channels appears to have a major role in relaxation of cerebral arteries and arterioles in response to several stimuli, including receptor-mediated agonists, intracellular second messengers, and hypoxia. The influence of ATP-sensitive and calcium-activated potassium channels is altered in states of disease but does not appear to influence resting tone in the cerebral circulation (13).
Data from several animal studies suggest that hypercapnia-induced vasodilation could be blunted by KATP channel blockade (6, 15). It therefore was the aim of the present study to investigate whether inhibition of KATP channel activation using glibenclamide alters the cerebral and ocular vasodilator response to hypercapnia in humans in vivo. This was tested in a randomized controlled two-way crossover design. Because blockade of pancreatic KATP channels dose dependently stimulates insulin secretion (7), glucose was coadministered in an effort to achieve euglycemic conditions. To maintain double-blind conditions and control for hyperinsulinemia, a low-dose insulin clamp (5) was performed on the other trial. To investigate whether glibenclamide has effects on basal tone of other vascular beds and is effective in blocking vascular KATP channels, the effect of nicorandil, a KATP channel opening drug, was studied on forearm blood flow in the absence and presence of glibenclamide.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
The study protocol was approved by the Ethics Committee of the Vienna University School of Medicine. The investigation conforms with the principles outlined in the Declaration of Helsinki. The nature of the study was explained, and all subjects gave written consent to participate. Fifteen male healthy volunteers were studied (age range, 20-35 yr; mean ± SD, 27 ± 4 yr). Each subject passed a screening examination that included medical history and physical examination, 12-lead electrocardiogram, complete blood count, activated partial thromboplastin time, thrombin time, fibrinogen, clinical chemistry (sodium, potassium, creatinine, uric acid, glucose, cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase,
-glutamyltransferase, alkaline phosphatase, total
bilirubin, total protein), standardized oral glucose tolerance test,
hepatitis A, B, C, and HIV serology, urine analysis, and a urine drug
screen. Subjects were excluded if any abnormality was found as part of
the screening unless the investigators considered an abnormality
clinically irrelevant. Furthermore an ophthalmic examination, including
slit-lamp biomicroscopy and indirect funduscopy, was performed in each
subject before the first study day. Inclusion criteria were normal
ophthalmic findings and a refractive error of less than 3 diopters.
Subjects did not take any nontrial medication, including
over-the-counter drugs, throughout the study and were asked to abstain
from alcohol and beverages containing xanthine derivatives for 12 h
before drug administration. On each trial day subjects arrived after an
overnight fast. Washout periods between study days were at least 5 days.
Study Protocols
Protocol 1.
Ten healthy subjects were studied according to a randomized,
double-masked, balanced, two-way crossover study design. After resting
for at least 20 min in the sitting position to establish stable
hemodynamic conditions, baseline measurements of fundus pulsation
amplitude (FPA), sonography of the cerebral and the ophthalmic artery
(OA), and a blood gas analysis were performed. Thereafter a 12-min
inhalation period of 5% CO2-95% air was started and the
measurements were repeated. After a resting period of 18 min, drug
treatment was started and subjects received either glibenclamide (5 mg
po; Glyburid Euglucon, 5 mg, Hoechst) and placebo intravenously or oral
placebo and intravenous insulin (0.3 mU · kg1 · min1;
Lilly Huminsulin, Lilly; Fegersheim, France). To maintain euglycemic conditions, venous blood glucose was measured at regular intervals in
arterialized venous blood from the heated contralateral arm and glucose
(20% glucose, Leopold Infusionsflaschen, Leopold Pharma; Linz,
Austria) was infused to achieve a blood glucose concentration of
between 80 and 120 mg/dl. Every 30 min measurements of blood velocities
with ultrasound sonography and FPA with laser interferometry were
undertaken, and every 60 min a 12-min inhalation period of 5%
CO2-95% air was repeated. Blood gas analysis was performed at baseline and during every inhalation period after 5 min of CO2 inhalation (Fig. 1).
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Protocol 2, control experiments. To investigate whether glibenclamide exerts an effect on vascular KATP channels, a control experiment in five healthy subjects was performed. The study design was randomized, three-way crossover. After subjects rested for at least 20 min in the supine position to establish stable hemodynamic conditions, baseline measurements of forearm blood flow using a plethysmographic method were performed.
Volunteers then received either nicorandil (40 mg po, Dancor, Merck; Darmstadt, Germany) or vehicle in the presence of glibenclamide (5 mg po, Glyburid Euglucon 5) or nicorandil alone on the three different trial days: day A, glibenclamide and nicorandil; day B, glibenclamide and vehicle; and day C, nicorandil. If glibenclamide was administered subjects also received glucose intravenously (20% glucose, Leopold Infusionsflaschen, Leopold Pharma) to maintain euglycemic conditions. Nicorandil or vehicle was administered 120 min after glibenclamide administration. On trial day C nicorandil alone was administered after an equivalent resting period. Forearm blood flow was measured in 15-min intervals during the study; blood pressure and pulse rate were measured every 5 min. Blood samples for the determination of insulin plasma levels were drawn at baseline and 90 and 210 min after glibenclamide administration.Measurements
Blood pressure and pulse rate. Systolic, diastolic, and mean blood pressures (MAP) were measured on the upper arm by an automated oscillometric device (HP-CMS patient monitor, Hewlett Packard; Palo Alto, CA). Pulse rate was automatically recorded from a finger pulse-oxymetric device (HP-CMS patient monitor).
Fundus pulsations.
Pulse synchronous pulsations of the eye fundus were assessed by laser
interferometry on the subject's right eye. The method is described in
detail by Schmetterer and Lexer (23). Briefly, the eye is illuminated
by the beam of a single mode laser diode with a wavelength (
) of 783 nm. The light is reflected at both the surface of the cornea and the
retina. The two reemitted waves produce interference fringes from which
the distance changes between cornea and retina during a cardiac cycle
can be calculated. Distance changes between cornea and retina lead to a
corresponding variation of the interference order
[
N(t)]. This change in interference order can be
evaluated by counting the fringes moving inward and outward during the
cardiac cycle. Changes in optical distance [L(t)], corresponding to the
cornea-retina distance changes, can then be calculated by
L(t) = N(t) · /2. The maximum
distance change is called the FPA and estimates the local pulsatile
blood flow (21). FPA was calculated as the mean of at least five
cardiac cycles. The short-term and day-to-day variability of the method is small, which allows detection of even small changes in local pulsatile blood flow following pharmacological stimulation (25). To
obtain information on the choroidal blood flow, the macula, where
the retina lacks vasculature, was chosen for measurements (27).
Color Doppler ultrasound.
Mean blood flow velocity (MFV), peak-systolic flow velocity (PSV), and
end-diastolic flow velocity (EDV) were determined in the right OA with
color Doppler ultrasound (8) and in the middle cerebral artery (MCA)
with transcranial ultrasound. MFV was measured manually as the time
mean of the spectral outline. Measurements were performed with a
7.5-MHz probe in the OA and with a 2-MHz probe in the MCA (CFM 750, Vingmed Sound; Horten, Norway). The OA was measured anteriorly, at the
point where it crosses the optic nerve. The sample volume marker was
placed ~25 mm posterior to the globe. The resistive index was
calculated for both arteries as resistive index equals PSV 
EDV/PSV. All parameters were determined as mean values over
at least three cardiac cycles.
Blood gas analysis. Blood gas values were determined from capillary blood samples of the earlobe. After the earlobe was covered with ointment containing nicotinate and nonylvanillamid (Finalgon, Tomae; Biberach, Germany) to induce capillary vasodilation, a lancet incision was made. The arterialized blood was drawn into a thin-glass capillary tube. Arterial pH, PCO2, and PO2 were determined with an automatic blood gas analysis system (AVL 995-Hb; Graz, Austria).
Glucose utilization. The amount of glucose necessary to maintain euglycemic conditions from minute 60 to minute 90, from minute 120 to minute 150, and from minute 180 to minute 210 was calculated as a measure of drug-induced glucose utilization.
Determination of glucose and insulin plasma levels. Glucose concentration was determined by using the glucose oxidase method (Beckman, Glucose Analyzer II Beckman Instruments; Fullerton, CA). Plasma insulin concentrations were determined by using a double antibody RIA (Diagnostic Systems Laboratories; Webster, TX).
Forearm blood flow. Forearm blood flow was measured by venous occlusion plethysmography, using a mercury-filled Silastic strain-gauge plethysmograph (EC-6, Hokanson; Washington, DC) (9). The forearm under study was placed above the level of the right atrium. Venous blood return from the arm was obstructed by inflating a cuff placed around the upper arm to 50 mmHg for 10 s. This inflated cuff caused swelling of the forearm at a rate proportional to the rate of arterial inflow. The rate of swelling of the forearm in milliliters per minute is calculated from changes of forearm circumference by a strain gauge placed around the forearm. The hands were excluded from the circulation by inflating a wrist-cuff to suprasystolic pressures. This method has been used repeatedly to assess effects of vasoactive drugs in human pharmacology studies (2).
Data Analysis
All statistical analyses were done using the Statistica software package (Release 4.5, StatSoft; Tulsa, OK). Reactivity of cerebral blood flow (CBF) to changes in PCO2 has been calculated asln CBF/ln
PCO2 × 100 (30). MFV and FPA
are not direct measures of total blood flow. Nevertheless we calculated
the reactivity to changes in PCO2 as
ln MFV/ln PCO2 × 100 and
ln FPA/ln PCO2 × 100 (22)
for each subject after glibenclamide administration and after insulin
infusion for better comparison with other published data. Reactivity of
hemodynamic parameters to changes in
PCO2 were analyzed with repeated
measures ANOVA during the different treatments. Data are presented as
means ± SE. The effect of hypercapnia was expressed as percent change
of the corresponding values preceding the breathing periods. Post hoc
analysis was done with paired t-tests. P < 0.05 was
considered the level of significance. In protocol 2 changes in
forearm blood flow were analyzed with repeated measures ANOVA during
the different treatments. Plasma levels of insulin were compared by
using the Wilcoxon signed ranks test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Protocol 1
Baseline values of the measured parameters are presented in Table 1. There were no significant differences between the 2 study days at baseline.
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Effects of CO2 Inhalation
CO2 breathing significantly increased FPA and MFV in the MCA under baseline conditions (Fig. 2 and Table 2). The increase in FPA was 18.2 ± 2.8% (P < 0.001) and 22.3 ± 3.4% (P < 0.001) on the 2 trial days, respectively (Fig. 2). The increase in MFV in the MCA was 27.4 ± 4.1% (P < 0.001) and 33.3 ± 5.0% (P < 0.001). The reactivity to hypercapnia was higher in the MCA and in the choroid than in the OA (Table 2), where no significant increase in MFV was seen during baseline measurements (2.1 ± 3.5%, P = 0.6, and 6.5 ± 4.5%, P = 0.2, Fig. 2). As expected, breathing of 5% CO2-95% air significantly increased PCO2 and PO2 and caused a significant decrease in pH (Table 3).
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Effects of CO2 Inhalation During Low-Dose Insulin
Insulin alone did not exert any effects on outcome parameters under study (Fig. 2). During the three CO2 inhalation periods, FPA increased by 18.8 ± 3.5, 21.1 ± 4.3, and 21.1 ± 2.7%, respectively (P < 0.001 vs. preceding value, Fig. 2). This increase was not different from baseline responsiveness to hypercapnia as indicated by a comparable reactivity index (Table 2). The effect in the MCA was stronger with an increase in MFV of 27.7 ± 6.1% (P < 0.001 vs. preceding value), 27.9 ± 6.7% (P < 0.001 vs. preceding value), and 29.9 ± 5.4% (P = 0.004 vs. preceding value) during the three breathing periods. Again, reactivity was not different from baseline conditions (Table 2). In contrast, MFV in the OA was enhanced significantly only at single time points during insulin administration, resulting in a maximal increase of 7.8 ± 2.9% (P = 0.02 vs. preceding value, Fig. 2). PCO2, PO2, and pH changed significantly vs. preinhalation period (Table 3). Glucose utilization during the three observation periods increased significantly over time (Fig. 3).Effects of CO2 Inhalation During Glibenclamide Administration
Glibenclamide alone did not exert any effects on outcome parameters under study (Fig. 2). During the three inhalation periods, FPA increased by 26.6 ± 5.5, 25.0 ± 4.0, and 27.5 ± 3.9%, respectively (P < 0.001 vs. preceding value, Fig. 2). The reactivity to hypercapnia was comparable with baseline conditions (Table 2). The increase of MFV in the MCA during the three inhalation periods was 33.7 ± 5.6, 32.7 ± 5.6, and 33.6 ± 4.1% (P < 0.001 vs. preceding value, Fig. 2). Again, reactivity to hypercapnia was not different from baseline conditions (Table 2). No significant effect on baseline measurements was observed in the OA after glibenclamide administration (maximum change 8.9 ± 5.0%, P = 0.1, Fig. 2). Although there was a slightly more pronounced effect of hypercapnia in the MCA and in the choriod during glibenclamide administration, no significant differences in FPA and MFV between treatment groups were detectable. Again, the changes in PCO2, PO2, and pH were in the same range as during the baseline inhalation period and significantly different from individual preceding values (Table 3). Glucose utilization during the different 30-min observation periods increased significantly and was comparable to the increase induced by insulin (Fig. 3).
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Systemic Hemodynamic Effects
Systemic hemodynamics did not change under insulin or glibenclamide (Table 3). Hypercapnia caused a small increase in MAP and pulse rate during some breathing periods. However, these changes were small and not consistently observed.Protocol 2, Control Experiments
Baseline values of the outcome parameters did not differ between the 3 study days (data not shown).Forearm blood flow was unchanged during glibenclamide, but
significantly increased following nicorandil alone by a maximum of 78.2 ± 42.8% vs. baseline (P = 0.041, ANOVA). By contrast, preceding administration of glibenclamide abrogated the effect of
nicorandil on forearm flow (Fig. 4). As
expected from protocol 1, glibenclamide alone did not exert any
effect on systemic hemodynamic parameters. Administration of nicorandil
slightly decreased mean arterial pressure by 14.6 ± 2.7% and
increased pulse rate by 13.5 ± 12.5% vs. baseline (P = 0.03 and P = 0.66, ANOVA). This was also seen after glibenclamide
with nicorandil, which resulted in a decrease of mean arterial
pressure by 13.4 ± 3.8% vs. baseline, and an increase of pulse rate
by 13.8 ± 8.9% vs. baseline (P = 0.16 and
P = 0.43, ANOVA).
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Insulin plasma levels markedly increased from 7.1 to a maximum of 35.2 µU/ml and from 8.5 to 41.7 µU/ml at 210 min after glibenclamide and glibenclamide with nicorandil coadministration, respectively (P = 0.04, Wilcoxon matched-pairs test). Nicorandil alone had no effect on plasma insulin.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to examine whether inhibition of KATP channel activation with glibenclamide influences the effects of hypercapnia on cerebral and ocular hemodynamics. In the present experiments the cerebral and ocular vascular bed was studied because the choriod and the MCA showed a high reactivity to increased PCO2 in previous experiments (20, 22, 29). As expected, CO2 inhalation caused a significant increase in FPA and MFV in the MCA. The increase in MFV in the OA during hypercapnia was much smaller and reached the level of significance only during some inhalation periods. The main finding of our experiments is that glibenclamide had no effect on hypercapnia-induced hemodynamic responses in healthy subjects.
KATP channels are not only found in blood vessels but also
in pancreatic 
-cells, where insulin secretion is stimulated by blockade of KATP channels (4). Thus our experimental setup had to be controlled for hyperinsulinemia, because we have previously shown that insulin itself can increase ocular blood flow (24). Our
results demonstrate that 1) indeed, a marked increase in plasma insulin was measurable after glibenclamide and that 2) the dose of exogenous insulin administered did not alter blood flow in the
vascular beds under study. Our study design was therefore not affected
by different baseline conditions. Although the profile of
hyperinsulinemia in response to glibenclamide is different from the
continuous insulin administration regimen, the glibenclamide-increased glucose requirement was comparable with that of insulin, at least at
selected time points. Furthermore, measurements of reactivity to
hypercapnia over time demonstrate that the inhalation stimuli were also
robust against minor changes in circulating insulin levels.
It has been demonstrated previously that therapeutic concentrations of glibenclamide affect vascular KATP channels in the human forearm (3) after intra-arterial infusion. Because estimation of glibenclamide concentration in the cerebral and ocular beds is not possible, we investigated whether inhibition of KATP channel activation has an impact on blood flow in a different vascular bed and can be influenced by a potassium channel opening drug. Whereas nicorandil alone significantly increased forearm blood flow over baseline, no changes in forearm blood flow were observed after preceding administration of glibenclamide. This is of interest because we would have expected that the nitric oxide (NO) donor properties of nicorandil could still be detectable under glibenclamide conditions in the forearm. However, it is well known that NO donor drugs differ in their arteriovenous selectivity (16), and our results therefore argue that the contribution of NO release to the effect of nicorandil on the forearm vasculture is small, at least following systemic administration.
It may, however, be speculated that the release of vasoactive NO from nicorandil was responsible for the systemic hypotensive response, which was noted in the presence and absence of glibenclamide to a similar degree. Nevertheless, our data are in agreement with results from other vascular beds, showing that the effects of nicorandil, but not of nitroglycerin, were blunted by blockade of KATP channels in isolated canine coronary arteries (11, 31). It is therefore likely that the abrogation of nicorandil's effects by glibenclamide in the forearm is due to inhibition of potassium channel activation rather than to other mechanisms. This suggests that the dose of glibenclamide in our experiment was also appropriate to inhibit activation of vascular KATP channel in other vascular beds in humans, even if drug levels are not accessible in these tissues.
In the present study PCO2 increased from ~38 to 44.5 mmHg and elicited a significant effect on cerebral and ocular blood flow on both study days. One limitation of the study is that for ethical reasons only a moderate increase in PCO2 can be studied, and we have not obtained a dose-response relationship to hypercapnia. It was demonstrated in animal experiments that application of glibenclamide significantly reduced the vasodilation of feline pial arterioles in response to hypercapnia (15). This was also observed in rabbit cerebral arterioles (6). Of note are the differences in PCO2 achieved during hypercapnic inhalation. For example, the blunted response of blood vessels during glibenclamide was observed at a PCO2 of 54 mmHg, but not at a PCO2 of 66 mmHg in rabbits. This suggests that vasodilation to high levels of hypercapnia may not be mediated by KATP channels but rather involve other mechanisms. Nevertheless, the vasodilatory changes observed in the subjects under study are of a physiologically relevant magnitude, and an important effect of KATP channel blockade should have been detectable in the present cohort.
In addition, pH decreased significantly during all inhalation periods, resulting in extracellular acidosis. It is known that acidosis causes vascular relaxation, which has already been demonstrated in isolated canine basilar artery rings (12). This effect is also reversible with glibenclamide, suggesting a stimulatory function of the metabolic status on KATP channels. Again, the changes in pH in response to CO2 inhalation were consistent throughout the trial days and not affected by the drugs under study. Although we cannot discriminate whether extracellular acidosis is primarily responsible for vasodilation in the present study, animal experiments have postulated that glibenclamide could influence vascular effects from extracellular acidosis as well as from hypercapnia.
Limited reproducibility or sensitivity of the methods employed are unlikely to contribute to the negative findings of the present study. Laser interferometric measurement of fundus pulsations is highly reproducible and subject to a very small short-term intraindividual variability (26). Even though the reproducibility of MFV in the OA and in the MCA is smaller, the sensitivity of the methods used should have been appropriate to detect even minor hemodynamic changes by glibenclamide during hypercapnic vasodilation.
How can our negative findings be reconciled with previous results from animal and human studies? Species differences could account for our unexpected results because the KATP channel inhibitor tolbutamide had no significant effect on cerebral blood flow during hypoxia and hypercapnia in rats (19) and glibenclamide attenuated cerebral blood flow during hypoxia but not during hypercapnia in rat experiments (18), whereas the glibenclamide effect was shown in cats (15) and rabbits (6). Interestingly, NO synthase inhibition blunted hypercapnic vasodilation in a variety of species (10, 15). We have recently shown that hypercapnic vasodilation is also NO dependent in humans using the same methods as in the present study (22). On the basis of our results we cannot rule out a possible interaction between the L-arginine-NO system and KATP channels as postulated from cat experiments (15), but the formation of endothelial NO seems to represent the predominant mediator of hypercapnic vasodilation in humans in vivo rather than effects of KATP channels.
In conclusion, we have demonstrated a strong vasodilatory response to hypercapnia in cerebral and ocular vessels. However, these potent effects were not influenced by systemic doses of glibenclamide, indicating minor contribution of vascular KATP channels on hypercapnic vasodilation in healthy humans in vivo.
Perspectives
The mechanism of hypercapnic vasodilation in the particularly sensitive cerebral and ocular vasculature is not directly comparable with animal physiology, and several species differences exist. It appears that the main regulator of the acute vasodilatory response to hypercapnia is the L-arginine-NO system, probably interacting with other mediators, but the contribution of KATP channels is small, at least in the physiological range of oxygen tension and pH changes.| |
ACKNOWLEDGEMENTS |
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We thank Susan Entlicher, RN, for excellent technical support.
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FOOTNOTES |
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The study was supported by the Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: L. Schmetterer, Dept. of Clinical Pharmacology, Währinger Gürtel 18-20, A-1090 Vienna, Austria (E-mail: leopold.schmetterer{at}univie.ac.at).
Received 26 April 1999; accepted in final form 27 December 1999.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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) or insulin (
) on fundus pulsation
amplitude (FPA) and mean flow velocity (MFV) in the middle cerebral
artery (MCA) and MFV in the ophthalmic artery (OA). Drug effects on
baseline measurements and during inhalation of 5% CO2-95%
air are shown; data are presented as means ± SE (n = 10).
Breathing periods are symbolized by shaded columns. * Significant
differences vs. preinhalation measurements (P < 0.05, paired
t-test).
) or nicorandil alone (