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Department of Nutrition, School of Medicine, University of Tokushima, Tokushima City, 770-8503 Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Measurements of isometric tensions of rat aortic rings revealed
the fact that when aortic rings with intact endothelium were precontracted (preconditioned) for 20 min by the
1-adrenergic agonist phenylephrine (10 µM), the tonic
level of subsequent contraction by the same agonist was depressed
and/or declined regardless of the presence or absence of endothelium
during the second contraction. The removal of endothelium before
preconditioning showed no such phenomenon. With the use of specific
blockers, involvements of adenosine or of ATP-sensitive K+
(KATP) channels during preconditioning or second
contraction, respectively, were evaluated. Actions of nitric oxide
synthase, cyclooxygenase, P2 ATP purinoceptors, or
KATP channels during preconditioning appear not to be
involved. Exogenous adenosine (up to 100 µM) without endothelium
could mimic the preconditioning; however, contractile preconditioning
by phenylephrine, mechanical stretching, or activation of protein
kinase C needed to be done. The release of adenosine and adenine
nucleotides from aortic rings was augmented by phenylephrine or by
mechanical stretching of the rings with intact endothelium. Our results
suggest that during vasocontraction, endothelium-derived adenosine
acquires an ability to protect vascular tone against subsequent
repeated contractions by mediating a delayed, possibly indirect,
opening of KATP channels.
endothelium; smooth muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WELL KNOWN
THAT -adrenergic receptor agonists induce a contractile
response in blood vessels. The subsequent contraction by the same
agonist is depressed considerably in the presence of intact endothelium
(14, 17, 27). Experiments (13, 25) involving
the use of arteries from pheochromocytoma or involving epinephrine
infusion also show a similar phenomenon. Although these decreased
vascular contractile responses have been regarded as
"desensitization" of the blood vessels to certain contractile stimuli, the decrease is mainly due to increased inhibitory effects by
endothelium rather than to the desensitized responses of the smooth
muscle cells themselves (14). Consequently, to reflect such roles of endothelium in the attenuation of contractile responses after preconditioned contraction, we have used the term "contractile preconditioning" in the present study.
The vascular endothelium releases a variety of vasoactive substances, including endothelium-derived relaxing factors (EDRF), endothelium-derived hyperpolarizing factors (EDHF), and contracting factors, prostaglandins, and adenosine (7, 11, 33). In this regard, Kaneko and Sunano (17) found that the contractile depression of the blood vessels induced by repeated exposure to noradrenaline was mainly attributable to an increase in the release of endothelium-derived nitric oxide (NO). Thus many studies have focused on NO-dependent mechanisms involved in the depression of blood vessel contraction. However, no reports have appeared on NO-independent mechanisms.
Removal of endothelium after contractile preconditioning is able to
restore maximal blood vessel contractility (14). However, the tonic contractile levels of such preconditioned blood vessels are
not known. With the use of an 1-adrenergic agonist,
phenylephrine, the data presented here show that the
endothelium-dependent, NO-independent component also participates in
the vascular contractile preconditioning, which causes a decline in the
tonic phase of contraction, independent of the existence of endothelium
during a second challenge to the vasoconstrictor. We also examined
whether adenosine, a factor known for its involvement in
ischemic preconditioning (23), has a key role in
this type of contractile preconditioning.
Ischemic preconditioning of the heart constitutes an adaptive phenomenon for the myocardium, in which a brief period of conditioning ischemia protects the myocardium against subsequent lethal ischemia (23). Adenosine, which is released from myocardium and coronary arteries during hypoxia (1, 5), enhances ischemic preconditioning and coronary vasodilation but attenuates myocardial contractility (9, 23, 31). Recently, Gysembergh et al. (12) reported that myocardial stretch also preconditions the heart through an adenosine-related pathway. A similar mechanism might be involved in vascular smooth muscle action, and the results of our studies suggest that adenosine is involved in the contractile type of preconditioning, analogous to the mechanism of ischemic preconditioning. Thus adenosine is a common factor between ischemic and contractile preconditioning, and this may indicate that adenosine plays a significant protective role in cardiovascular systems by mediating a delayed inhibitory response to repeated interventions, in addition to its acute responses.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation of aortic rings. Male Wistar rats (350 g) were anesthetized and euthanized by decapitation. The thoracic aortas were dissected free of connective tissue and cut into 2- to 3-mm-long ring segments. Each ring was placed in a 5-ml organ bath (Micro Easy Magnus, Kishimoto Medical; Kyoto, Japan) and mounted on two stainless steel wires, one of which was fastened to the baths and the other connected to a force transducer so that isometric tension could be measured. The bath was filled with Krebs-Ringer bicarbonate (KRB) buffer solution at 36°C and bubbled with a mixture of 95% O2-5% CO2. The KRB contained (in mmol/l) 118 NaCl, 4.6 KCl, 2.5 CaCl2, 24.8 NaHCO3, 1.2 MgSO4, 1.2 KH2PO4, and 5.6 glucose. The rings were equilibrated for 40 min under a resting tension of 1 g, and solution was changed at 20-min intervals.
Contractile preconditioning. In some experiments, the aortic endothelium was removed at the beginning of the experiment by inserting a cotton thread into the lumen, followed by gentle rubbing. In other experiments, the endothelium was removed after preconditioning. The presence or absence of endothelium was confirmed by addition of acetylcholine (1 µM), an endothelium-dependent vasodilator, after a contraction had been induced by phenylephrine (1 µM).
After a 40-min equilibration period, the rings were incubated with or without (controls) 10 µM phenylephrine for 20 min (contractile preconditioning). In some experiments, the rings with or without endothelium were subjected to mechanical stretch alone (without phenylephrine) during preconditioning. The magnitude of the stretch was adjusted to an extent similar to that achieved by 10 µM phenylephrine (1.2-1.4 g). This duration of preconditioning was sufficient to depress the subsequent contractile response in the aortic ring with intact endothelium. After the 20-min incubation period, the rings were washed three times. Each ring was allowed to equilibrate at a resting tension of 1 g for 40 min (KRB was changed every 20 min). After the rings were equilibrated, aortic rings were contracted by a high-K+ solution (50 mM KCl within the bath solution). Contractile responses in the preconditioned or nonpreconditioned rings were then studied by an application of phenylephrine (1 µM). After phenylephrine was applied, the contractile tensions were continued for 20-30 min to maintain a steady level. The contractile response was expressed relative to that of a 50 mM KCl-induced contraction.Studies on the role of endothelium. In some experiments, to examine which specific substance from the endothelium contributed to the preconditioning of the tonic phase, NG-nitro-L-arginine (L-NNA; 30 µM), an inhibitor of NO synthesis, indomethacin (10 µM), an inhibitor of prostaglandin synthesis, suramin (100 µM), an antagonist of P2 (ATP) purinoceptors, or 8-sulfophenytheophylline (8-SPT) (100 µM), an antagonist of P1 (adenosine) purinoceptors, was incubated during preconditioning.
Studies on the roles of adenosine, ATP-sensitive K+ channels, and protein kinase C. To examine the contribution of adenosine to the preconditioning of the tonic phase, adenosine was incubated at three different concentrations (1, 10, and 100 µM) in the rings without endothelium during preconditioning.
In some experiments, the involvement of ATP-sensitive K+ (KATP) channels in the preconditioning of the tonic phase was studied by using glibenclamide (3 µM), a KATP channel inhibitor, which was incubated during preconditioning or the second contraction with phenylephrine. The effect of pinacidil (1 µM), a KATP channel opener, was also tested in some ring preparations. To test an involvement of protein kinase C (PKC) in the preconditioning of the tonic phase, phorbol 12-myristate 13-acetate (PMA; 1 µM), an activator of PKC, was used to contract the ring preparations.Measurement of adenosine and adenine nucleotides. Adenosine and adenine nucleotides released from the aortic preparations were measured by high-performance liquid chromatography (HPLC) plus fluorescence detection as described by Ishii et al. (15) with some modifications. The aortic rings were mounted in the organ baths containing KRB and equilibrated for 40 min at a resting tension of 1 g as described above. After the confirmation of the presence or absence of the endothelium using acetylcholine, the aortas were stimulated with phenylephrine or subjected to mechanical stretch for the indicated times, while others were incubated without stimulation and served as controls reflecting the basal condition. Subsequently, 2 ml of bathing solution was collected, acidified to pH 4.0 with 0.4 ml of citrate-phosphate buffer solution (30% of 0.1 M citric acid and 59.4% of 1 M Na2HPO4), and placed on ice. Chloroacetaldehyde (100 µl of a 1 mol/l solution) was added to each acidified sample solution and the samples were then incubated in a dry bath at 80°C for 40 min. We terminated the reaction by placing the samples on ice. The resulting ethenoadenosine and ethenonucleotides were separated by HPLC (Capcell Pak C18 column, Shiseido; Tokyo, Japan), and fractions of the drained sample solutions were collected at appropriate retention times. Mobile phase A, which contained 100 mM of phosphate buffer, was adjusted to pH 4.5, whereas mobile phase B, which contained 100 mM of phosphate buffer with 5% acetonitrile, was adjusted to pH 4.0. HPLC was conducted under conditions where mobile phase A was pumped at a flow rate of 1.0 ml/min at 30°C for 22 min, followed by a step gradient to 100% mobile phase B, which was run for an additional 43 min at the same rate and temperature. Before the next sample was injected, the column was allowed to reequilibrate for 15 min with a flow of mobile phase A. Representative retention times, as determined by the absorbance of solutions at 260 nm with the use of a spectrophotometer, for etheno-ATP, -ADP, -AMP, and -adenosine were 14.60, 16.46, 32.44, and 38.11 min, respectively. Each drained fraction was collected for 2 min after a time lag of 20 s.
Fluorescence detection of the ethenoadenosine and ethenonucleotides in the collected fractions was subsequently performed with the use of a fluorescence spectrophotometer (F-3010, Hitachi; Tokyo, Japan) at an excitation wavelength of 305 nm and an emission wavelength of 420 nm and by using standard curves with known concentrations of each ethenoadenosine and ethenonucleotide. The release of adenosine and adenine nucleotides was normalized by microgram quantities of aorta protein (1 mg wet weight of rat aorta corresponded to 29.1 ± 1.1 µg of protein). Measurement of the protein concentration was conducted with the use of a bicinchoninic acid protein assay kit (Pierce; Rockford, IL). Without fluorescence detection, the detection threshold for this HPLC system was 10 pmol for both adenosine and nucleotide, whereas with the fluorescence method used here, the limit was improved to ~0.5 pmol for each ethenopurine derivative.Chemicals. Phenylephrine, adenosine, and 40% chloroacetaldehyde solution, three of the chemical used in the present study, were purchased from Wako Chemical (Tokyo, Japan). Acetylcholine, L-NNA, indomethacin, suramin, 8-SPT, glibenclamide, PMA, and pinacidil were purchased from Sigma (St. Louis, MO).
Statistical analysis. Data are expressed as means ± SE. In all of the experiments, n refers to the number of animals used. Data were analyzed by analysis of variance and by Bonferroni multiple comparison tests. Student's t-test for paired or unpaired data was used when appropriate. A level of P < 0.05 was accepted as statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Contractile responses of aortic rings preconditioned by
phenylephrine.
Figure 1 shows the effect of contractile
preconditioning by phenylephrine (10 µM) on subsequent contractile
responses by the same agonist in rings with intact endothelium. In the
presence of intact endothelium, phenylephrine-induced contraction
reached an initial contractile level followed by gradual relaxation,
which led to a second plateau level (Fig. 1A). Contractile
preconditioning, as the result of a 20-min exposure to phenylephrine,
significantly depressed subsequent contraction both at the first and
second levels (Fig. 1B). Figure 1C summarizes
tensions of the first and second contractile levels in rings with or
without preconditioning. Both the first and second levels were
significantly decreased, whereas the percent relaxation from the first
level was greater in the preconditioned rings than in the untreated
rings (Fig. 1C).
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Role of adenosine in preconditioning.
Treatment of endothelium-intact rings for 20 min with inhibitors or
antagonists of endothelium-derived substances at basal condition,
followed by the washing out of those treatment factors, did not change
the phenylephrine contraction (data not shown). Incubations with
L-NNA, indomethacin, and suramin during preconditioning in
the presence of endothelium also did not change the preconditioning of
the tonic phase (Fig. 3A). On
the other hand, 8-SPT significantly, but not completely, inhibited the
phenomenon (Fig. 3A).
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KATP channels in preconditioning. Elevation of K+ concentration (50 mM) in the bath solution induced smooth muscle contractions, but these contractions were not affected by the preconditioning (0.853 ± 0.082 vs. 0.864 ± 0.052 g in rings with or without preconditioning, respectively; not significant, Fig. 2). The absence of a decline in contraction suggests an involvement of potassium conductance in the preconditioning of the tonic phase.
To test an involvement of KATP channels, glibenclamide was used to block the channels. In preliminary studies, we determined that a 1 µM dose of pinacidil, a KATP channel opener, directly, and largely, depressed the phenylephrine-induced contraction of endothelium-denuded aortic rings (58.3 ± 4.0% depression of the tonic phase) and that the contraction was almost completely restored (91.3 ± 16.6%) by an application of glibenclamide (3 µM). Glibenclamide by itself did not affect phenylephrine contraction or basal tension in endothelium-denuded rings (phenylephrine contraction: 1.462 ± 0.050, basal tension: 0.010 ± 0.014, not significant vs. rings without glibenclamide). In the preconditioned rings, application of glibenclamide during the tonic phase relaxation significantly restored contraction (P < 0.05, Fig. 4A), but the drug did not affect basal tension (0.001 ± 0.010, not significant vs. nonpreconditioned rings).
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Interaction between adenosine and contractile signals during
preconditioning.
Application of adenosine without phenylephrine could not cause the
preconditioning of the tonic phase (Fig.
5A). On the other hand,
adenosine applied to mechanically stretched rings elicited the
contractile preconditioning (Fig. 5A).
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Involvement of PKC.
We also tested an involvement of PKC in the contractile preconditioning
(Fig. 6). Phenylephrine-induced
contraction in endothelium-denuded rings precontracted by PMA (1 µM)
was weak and consisted of a first contractile level, followed by a
gradual contraction which reached a second contractile level, which is
a different contractile curve compared with that of contraction after
preconditioning by phenylephrine (Fig. 6B).
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Production of adenosine and adenine nucleotides during contraction.
In the aortic rings with intact endothelium, phenylephrine released
adenine compounds (ATP, ADP, AMP, and adenosine), which reached peak
levels 5 min after stimulation, whereas no increase was observed in
rings without stimulation (Fig. 7,
top). Figure 7, bottom, shows the release of
adenosine and adenine nucleotides from rings with or without
endothelium. In rings with intact endothelium, mechanical stretching
increased the release of adenosine and adenine nucleotides, like
phenylephrine-induced contraction had done. None of these means of
stimulation was able to increase the release of adenosine and adenine
nucleotides from rings without endothelium.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our findings show that the contractile preconditioning of the aorta by phenylephrine caused a depression and/or decline of the subsequent tonic contraction, regardless of the presence or absence of aortic endothelium during the second contraction. No change in contraction was observed in rings in which the endothelium had been denuded before preconditioning. Contractile preconditioning of the tonic phase was also observed when the aorta with intact endothelium was preconditioned by a mechanical stretch in the absence of phenylephrine. Applications of 8-SPT, an antagonist of the adenosine receptor, or of glibenclamide, a blocker of KATP channels, during preconditioning or the second contraction, respectively, could inhibit preconditioning of the tonic phase. These results suggest that an adenosine-induced KATP channel opening contributes to the contractile type of preconditioning.
Vascular endothelium plays an important role in the maintenance of vascular tone via the production of a variety of vasorelaxant factors, such as NO, prostaglandins, EDHF, and adenine nucleotides or adenosine (7, 11, 33). In the present study, incubations with L-NNA, indomethacin, and suramin during preconditioning in the presence of endothelium failed to inhibit the preconditioning of the tonic phase. On the other hand, 8-SPT inhibited the decline in the second contraction, suggesting that endothelium-derived adenosine during preconditioning might be related to this phenomenon. This hypothesis was supported by the fact that incubation with adenosine during preconditioning in the endothelium-denuded rings could mimic the contractile preconditioning of the tonic phase. These results also suggest that during preconditioning, the endothelium may alter the subsequent contractile ability of the smooth muscle cells and that the preconditioning of smooth muscle cells by phenylephrine does not cause the downregulation of the receptors (21, 37) or the desensitization in the contractile signals (24) in the cells.
Adenosine is produced by a variety of cells, including cardiomyocytes
(1), endothelial cells (33), and smooth
muscle cells (2, 29) via the degradation of adenine
nucleotides, i.e., ATP, ADP, or AMP (5, 29). The
production of the adenine compounds is stimulated by hypoxia,
ischemia, and 1-adrenoceptor stimulation
(5, 33). In the present study, phenylephrine augmented the
release of adenosine and adenine nucleotides from aortic rings with
intact endothelium, whereas no increase was observed in rings without
endothelium, suggesting that the vascular endothelium is a major source
of adenine compounds released by 1-adrenergic
stimulation. On the other hand, a mechanical stretch without
phenylephrine mimicked the effect of phenylephrine in releasing the
compounds. Mechanical stress has been reported (3) to
increase the release of ATP from vascular endothelium. The fact that
suramin, a P2 ATP purinoceptor antagonist, did not affect preconditioning of the tonic phase suggests the possibility that endothelium-derived adenine nucleotides released extracellularly were
sequentially degraded to adenosine and the resulting increase in
adenosine caused the preconditioning by stimulating P1
(adenosine) purinoceptors on smooth muscle cells. Rapid breakdown of
extracellular adenine nucleotides to adenosine by vascular smooth
muscle cells has been previously demonstrated in cultured cells
(29).
In the present study, incubation of endothelium-intact rings with 8-SPT did not completely prevent the preconditioning of the tonic phase, whereas this antagonist almost completely prevented the effect of exogenous adenosine on rings preconditioned in the absence of endothelium, suggesting that another factor from endothelium, together with adenosine, might be involved in the preconditioning effect of endothelium. This may also explain the observation that physiological concentrations of adenosine (1-10 µM) alone could not cause as much relaxation as the preconditioning in the presence of endothelium. According to the report of Von Borstel et al. (36), the plasma adenosine level in the rat is 1-4 µM and a plasma concentration of 5-6 µM could decrease blood pressure. In the vascular tissues, however, the local concentrations of each adenine compound derived from the endothelium may be much higher than the concentration in the incubation baths, although the measured concentrations of adenosine and total adenine compounds in the incubation baths after 5 min of phenylephrine stimulation were low (7-8 and 30-32 nM, respectively) in this study. It is pertinent to point out that Burnstock (6) has shown that endothelium-derived adenine compounds can act locally on the neighboring smooth muscle cells.
Adenosine is a potent vasodilator and reduces intracellular Ca2+ by preventing the entry of extracellular Ca2+ (38). Activation of the KATP channels by adenosine also causes vasodilation (4, 18, 31). The gradual relaxation in the preconditioned rings was not observed when the rings were contracted by high levels of K+ solution, suggesting an involvement of potassium currents in the preconditioning of the tonic phase. Various types of K+ channels exist in smooth muscle cells, including voltage-dependent K+ channels, Ca2+-activated K+ channels, KATP channels, and inward rectifier K+ channels (28). These K+ currents hyperpolarize the smooth muscle cell membrane and prevent the entry of Ca2+ by closing the voltage-dependent Ca2+ channels, thus leading to vasorelaxation (28). Studies involving the use of a specific blocker showed that the KATP channels contributed to the preconditioning-induced contractile decline in the second contraction.
It has been suggested that KATP channels do not participate in the regulation of vascular tone under resting conditions (10, 16). Consistent with these conclusions, the present study showed that glibenclamide had no effect on the resting tone in aortic rings either with or without preconditioning. However, glibenclamide restored contraction in the preconditioned rings. Although glibenclamide applied after preconditioning inhibited the preconditioning of the tonic phase, the same drug applied during preconditioning could not. Furthermore, pinacidil, a KATP channel opener, did not cause the preconditioning effect. That is, opening of KATP channels during preconditioning appears not to be responsible for the opening of KATP channels during the second contraction.
We demonstrated here that the contractile preconditioning of the tonic phase needs two key factors during preconditioning, namely, adenosine and contractile signals in the smooth muscle cells, especially those leading to activation of PKC. PKC activation is necessary to regulate the force of both phenylephrine- and mechanical stretch-induced contraction in vascular smooth muscle cells (20, 26). Adenosine inhibits PKC-mediated vasocontraction (8, 32), which is consistent with results in this study, whereas vasoconstrictors, such as phenylephrine and angiotensin II, suppress vascular KATP channels through activation of PKC (4, 19). On the other hand, Bonev and Nelson (4) proposed that KATP channel activity in arterial smooth muscle cells are balanced by the opposing effects of activation (stimulated by adenosine) and inhibition (mediated by PKC). In the present study, phenylephrine-induced contraction of aortic rings that had been PMA precontracted was depressed by pretreatment with adenosine, and glibenclamide restored contractility. Thus we hypothesize that the most likely mechanism underlying the preconditioning of the tonic phase is that the conditions with activated PKC are inhibited in the presence of endothelium-derived or exogenous adenosine (during preconditioning), and the balance regulating KATP channel activities in the smooth muscle cells might be altered, i.e., blockade of KATP channels is partly attenuated, so that it indirectly helps KATP channel opening at subsequent contraction. There is a supporting report (34) for this hypothesis in that a blockade of the AT1 receptor caused an opening of KATP channels in the coronary vascular beds, and the inhibition of PKC, which is one of the main components of angiotensin II actions, might mediate channel opening (19, 34).
The precise mechanisms by which the second contraction caused KATP channel opening under the conditions that PKC was preinhibited could not be determined in the present study. However, phenylephrine-induced mechanical stretching of smooth muscle cells itself might be a key component related to the channel opening. Direct activation of KATP channels by mechanical stretching was demonstrated in isolated atrial myocytes (35), although the intermediate mechanisms remain unclear. On the other hand, a recent study (12) has also shown that myocardial stretch preconditions the heart to protect it from ischemic injury through pathways involving links between adenosine receptors, PKC, and KATP channels. Such complex interactions could be involved in the mechanisms of preconditioning presented in this study, but possibly in a different fashion, because PKC effects on the KATP channels seem to have opposite actions in the heart, in which PKC activates KATP channels (22), and the blood vessels, in which PKC inhibits the channels (4, 19). As a deeper understanding of the mechanisms of delayed responses, like preconditioning, helps us to create direct and early treatments for the various pathophysiological conditions, further studies are needed to clarify these details.
Adenosine, which is derived from endothelium, controls local vascular tone in autocrine and paracrine fashions by acting on smooth muscle cells directly to produce a long-lasting component of vasorelaxation in addition to its endothelium-dependent effects (6, 30, 38). Given these facts, our results indicate an integral role of endothelium-derived adenosine in the protection of vascular tone by mediating delayed, as well as acute, responses to the contractile strains to which blood vessels are constantly subjected.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. Nakaya, Dept. of Nutrition, School of Medicine, Tokushima Univ. 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan (E-mail: nakaya{at}nutr.med.tokushima-u.ac.jp).
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. Section 1734 solely to indicate this fact.
Received 17 October 2000; accepted in final form 19 February 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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P < 0.05 vs. control rings.
P < 0.05 vs. rings preconditioned by PE with ADO
100 µM (B, c).
, Time course of percent relaxation from the F
level in the PC rings (n = 12). Glibenclamide restored
contraction (
; n = 7). B:
effect of glibenclamide on the exogenous ADO-induced preconditioning of
the tonic phase. Glibenclamide was incubated after (b;
n = 5) or during (c; n = 5)
preconditioning. In some rings, 1 µM pinacidil (d;
n = 5) was incubated alone during preconditioning. Data
are means ± SE. *P < 0.05 vs. rings without
glibenclamide. 
