(Stroke. 1997;28:1264-1271.)
© 1997 American Heart Association, Inc.
Articles |
Role of Potassium Channels in Relaxations of Canine Middle Cerebral Arteries Induced by Nitric Oxide Donors
From the Departments of Anesthesiology and Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minn.
Correspondence to Zvonimir S. Katusic, MD, PhD, Departments of Anesthesiology and Pharmacology, Mayo Clinic, Rochester, MN 55905.
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Abstract |
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Background and Purpose The mechanisms underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide (NO) and cyclic GMP (cGMP) are still not completely understood. The present study was designed to determine the role of potassium channels in the relaxations to NO donors 3-morpholinosydnonimine (SIN-1) and sodium nitroprusside (SNP), as well as 8-bromo-3',5'-cGMP (a synthetic analogue of cGMP) and zaprinast (a selective cGMP phosphodiesterase inhibitor).
Methods Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of cGMP were measured by radioimmunoassay. Relaxations to NO donors 8-bromo-cGMP and zaprinast were studied in the presence and in the absence of K+ channel blockers charybdotoxin (large-conductance Ca2+-activated K+ channels), glyburide (ATP-sensitive K+ channels), 4-aminopyridine (delayed rectifier K+ channels), and BaCl2 (multiple types of K+ channels).
Results Concentration-dependent relaxations caused by NO donors (SIN-1 and SNP) were significantly reduced in arteries treated with BaCl2 (3x10-4 mol/L) or charybdotoxin (3x10-8 mol/L). Relaxations to 8-bromo-cGMP were not affected by the same concentrations of BaCl2 and charybdotoxin; however, they were reduced by higher concentrations of BaCl2 (3x10-3 mol/L) and charybdotoxin (10-7 mol/L). Zaprinast-induced relaxations were significantly reduced by BaCl2 (3x10-4 mol/L) or charybdotoxin (3x10-8 mol/L). Glyburide (10-5 mol/L) and 4-aminopyridine (10-3 mol/L) did not alter the relaxations to SIN-1 or SNP. The production of cGMP stimulated by SIN-1 in the vascular smooth muscle was not affected by BaCl2 (3x10-3 mol/L) or charybdotoxin (10-7 mol/L).
Conclusions These results indicate that in canine middle cerebral arteries, a significant portion of relaxations to NO liberated from nitrovasodilators is mediated by large-conductance Ca2+-activated K+ channels. Other K+ channels, sensitive to BaCl2, may also be involved in the mechanism of relaxations induced by NO.
Key Words: cerebral arteries • cyclic GMP • nitric oxide • vasodilation • dogs
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nitric oxide is a major mediator of endothelium-dependent relaxations in various vascular beds.1 2 It is generally accepted that NO and exogenous nitrovasodilators relax smooth muscle cells by activation of the soluble form of guanylate cyclase and subsequent production of cGMP.3 However, the precise mechanisms underlying vascular smooth muscle relaxations via NO and cGMP still remain to be defined. In recent years, electrophysiological and pharmacological studies demonstrated an important role of K+ channels in the hyperpolarization and relaxations of smooth muscle cells.4 5 6 Several studies have suggested that native endothelium-derived relaxing factor/NO and NO liberated from nitrovasodilators can activate K+ channels in blood vessels. Although NO reportedly activates large-conductance KCa through cGMP-dependent protein kinase,7 8 9 it has been also demonstrated that NO itself can directly (independently of cGMP) activate KCa in rabbit aortic smooth muscle cells.10
NO plays an essential role in regulation of the cerebral circulation,11 12 and impaired NO-mediated relaxations appear to be involved in the pathogenesis of cerebral vasospasm associated with subarachnoid hemorrhage.13 14 15 Recent evidence suggests that several types of K+ channels, including KCa, KATP, KIR, and KDR, are functional in cerebral blood vessels.16 17 18 19 20 The role of K+ channels in mediation of vasodilation to NO has not been studied in large cerebral arteries. Therefore, the present study was designed to determine whether activation of K+ channels may play a role in NO-induced relaxations of isolated canine middle cerebral arteries.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The experiments were performed on rings (4 mm long) of middle cerebral arteries taken from dogs (15 to 20 kg) anesthetized with 30 mg/kg IV pentobarbital sodium. All procedures were conducted in accordance with institutional guidelines. The arterial rings were placed in modified Krebs-Ringer bicarbonate solution (control solution) of the following millimolar composition: NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.0, calcium EDTA 0.026, and glucose 11.1. In all rings, the endothelium was removed mechanically by gentle rubbing of the intimal surface with a stainless-steel wire (31-gauge diameter).21 Each ring was connected to an isometric force-displacement transducer (Grass FT03, Grass Instrument Co) and suspended in an organ chamber filled with 25 mL control solution (37°C, pH 7.4) aerated with 94% O2-6% CO2. Isometric tension was recorded continuously. The rings were allowed to stabilize at a resting tension of 0.2 to 0.4 g for 1 hour. Each ring was then gradually stretched to the optimal point of its length-tension curve (approximately 3.0 g) as determined by the contraction to 10-5 mol/L UTP.22 The successful removal of endothelium was verified by the absence of relaxation induced by 10-6 mol/L bradykinin.23
Radioimmunoassay of cGMP
A radioimmunoassay technique was used to determine the levels of
cGMP. Rings without endothelium were initially
incubated in control solution bubbled with a 94% O2-6%
CO2 gas mixture and maintained at 37°C. After 1 hour, the
rings were incubated for an additional 30 minutes in a solution
containing 10-3 mol/L IBMX to inhibit the
degradation of cGMP by phosphodiesterases. During the last 10 minutes
of the incubation period, some arteries were treated with SIN-1
(10-6 mol/L). To determine the effect of
K+ channel blockers on production of cGMP,
BaCl2 (3x10-3 mol/L) or
charybdotoxin (10-7 mol/L) was added to the
solution 10 minutes before the addition of SIN-1. To determine the
effect of zaprinast on cGMP levels, control rings were not treated with
IBMX, whereas treated rings were incubated in a solution containing
10-3 mol/L zaprinast for 30 minutes. After the
incubation, the rings were immediately removed from the solution and
frozen in liquid nitrogen. cGMP radioimmunoassay kits (Amersham) were
used to perform the measurements. Protein assay was performed by DC
Protein Assay Kit (Bio-Rad).
Drugs
The following pharmacological agents were used: UTP (Sigma
Chemical Co), bradykinin (Sigma), SIN-1 (Molecular Probes), SNP
(Sigma), 8-bromo-cGMP (Sigma), zaprinast (BIOMOL Research
Laboratories, Inc), diltiazem hydrochloride (Sigma), BaCl2
(Sigma), charybdotoxin (Sigma), glyburide (BIOMOL),
4-aminopyridine (Research Biochemicals International),
and papaverine hydrochloride (Sigma). Drugs were dissolved in distilled
water; volumes of <0.15 mL were added to the organ chambers. Stock
solutions of zaprinast and glyburide were prepared in DMSO (Sigma).
Concentrations of all drugs are expressed as final molar (moles per
liter) concentration in the control solution. The rings were contracted
with 10-5 mol/L UTP 10 minutes before the
addition of vasodilator agents. Concentration-response curves were
obtained in a cumulative fashion. Several rings prepared from the same
artery were studied in parallel, and a concentration-response curve was
established by each preparation. The relaxations were expressed as a
percentage of maximal relaxations induced by
3x10-4 mol/L papaverine. The drugs used as
K+ channel blockers were added 20 minutes before obtaining
the concentration-response curve for each vasodilator agent.
K+ channel blockers (except glyburide) caused contractions
of quiescent middle cerebral arteries (Table 1
).
However, because UTP produced only small contractions in the rings
already contracted by K+ channel blockers, absolute values
of tension did not differ significantly between the control arteries
and arteries treated with K+ channel blockers (see figure
and table legends). In certain experiments, the EC50 was
calculated for each ring by linear interpolation between the two
concentrations evoking responses just above and below 50% of the
maximal response.
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Statistical Analysis
The results are expressed as mean±SEM; n refers to the number
of animals studied. Statistical evaluation of the data was performed by
ANOVA, followed by Fisher's test. Statistical significance was
accepted at the level of P<.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects of K+ Channel Blockers on Relaxations to NO Donors SIN-1 and SNP
BaCl2 (3x10-5 to 3x10-3 mol/L) caused concentration-dependent reduction of relaxations to SIN-1 (Fig 1
). The effect
was significant in the presence of 3x10-4 and
3x10-3 mol/L BaCl2; these
concentrations of BaCl2 also significantly reduced maximal
relaxations to SIN-1. In the presence of increasing concentrations of
charybdotoxin (10-8 to
10-7 mol/L), relaxations to SIN-1 were also
significantly reduced (Fig 2). Small but significant
reduction of maximal relaxations to SIN-1 was detected in the presence
of the highest concentration (10-7 mol/L) of
charybdotoxin. The inhibitory effect of
3x10-3 mol/L BaCl2 on relaxations
to SIN-1 was significantly greater than that of
10-7 mol/L charybdotoxin (Fig 3A); however, the effect of
3x10-4 mol/L BaCl2 was identical
to inhibition observed in the presence of 10-7
mol/L charybdotoxin (Fig 3A). Further significant reduction of
relaxations to SIN-1 was obtained in arteries treated with
charybdotoxin (10-7 mol/L) plus
BaCl2 (3x10-4 mol/L) compared
with arteries treated with charybdotoxin alone (Fig 3B).
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The relaxations to SNP were also inhibited by BaCl2 and
charybdotoxin in the same manner as those to SIN-1 (Figs 4 and 5).
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Glyburide (10-5 mol/L) and
4-aminopyridine (10-3 mol/L)
did not alter values of EC50 and maximal relaxations
induced by SIN-1 or SNP (Tables 2 and 3).
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Effects of K+ Channel Blockers on Relaxations to
8-Bromo-cGMP
In contrast to NO donors, the relaxations to 8-bromo-cGMP were not
affected by 3x10-4 mol/L BaCl2
and 3x10-8 mol/L charybdotoxin (Fig 6A and 6B). However, BaCl2
(3x10-3 mol/L) and charybdotoxin
(10-7 mol/L) significantly suppressed the
responses to 8-bromo-cGMP.
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Effects of K+ Channel Blockers on Relaxations to
Zaprinast
The relaxations induced by zaprinast
(10-7 to 10-4 mol/L)
were significantly reduced by BaCl2
(3x10-4 mol/L) or charybdotoxin
(3x10-8 mol/L; Fig 7).
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Effects of K+ Channel Blockers on Relaxations to
Diltiazem
Diltiazem-induced relaxations were not affected by
BaCl2 and charybdotoxin even in the presence of the highest
concentrations of 3x10-3 and
10-7 mol/L, respectively. EC50
(-log mol/L) and maximal relaxations to diltiazem detected in the
absence or presence of BaCl2
(3x10-3 mol/L) were 6.30±0.08 and
87.8±2.0% (n=10) and 6.32±0.09 and 95.3±1.3% (n=5), respectively.
Those in the presence of charybdotoxin (10-7
mol/L) were 6.45±0.08 and 91.1±2.2% (n=5).
Effects of K+ Channel Blockers on Production
of cGMP
In canine middle cerebral arteries without
endothelium, SIN-1 (10-6
mol/L) produced approximately a 10-fold increase in levels of cGMP. The
increase in cGMP levels was not affected by the highest concentrations
of BaCl2 (3x10-3 mol/L) and
charybdotoxin (10-7 mol/L; Fig 8).
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Effects of Zaprinast on cGMP Levels
In canine middle cerebral arteries without
endothelium, zaprinast (10-3
mol/L) caused a significant increase in cGMP levels (Fig 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of the present study demonstrate that KCa play an important role in mediation of cerebral arterial relaxations to NO. This conclusion is based on the experiments demonstrating that a selective large-conductance KCa inhibitor, charybdotoxin,5 24 25 26 reduced the relaxations induced by two chemically different NO donors, SIN-1 and SNP.3 Selectivity of charybdotoxin was confirmed by the fact that relaxations to a calcium channel antagonist, diltiazem, were not affected in the presence of the highest concentration of charybdotoxin (10-7 mol/L). Furthermore, charybdotoxin did not affect production of cGMP stimulated by SIN-1, ruling out the possibility that the inhibitory effect of charybdotoxin is due to nonselective inactivation of guanylate cyclase. Our findings are in agreement with conclusions of the previous in vivo study performed in rat cerebral arterioles.27 However, we extended previous observations to demonstrate that KCa mediate a significant portion of relaxations to NO in large canine cerebral arteries.
BaCl2 also strongly reduced the relaxations to NO donors without having any effect on relaxations to diltiazem or production of cGMP. These results further supported the proposition that K+ channels play an important role in cerebral arterial relaxations to NO. However, previous studies demonstrated that even at the very high concentration of 10-2 mol/L, BaCl2 has little effect on KCa.5 28 The highest concentration of BaCl2 used in our study was 3x10-3 mol/L, suggesting that the effect of BaCl2 is possibly mediated via K+ channels other than KCa. This conclusion is also supported by the fact that the inhibitory effect of BaCl2 on relaxations to NO donors was significantly larger than the inhibitory effect of charybdotoxin. Furthermore, in arteries treated with a high concentration of charybdotoxin (10-7 mol/L), a lower concentration of BaCl2 (3x10-4 mol/L) exerted an additional inhibitory effect on relaxations to SIN-1, suggesting that charybdotoxin and BaCl2 may affect different populations of K+ channels. KIR are most sensitive to extracellular barium ions and should be blocked by micromolar concentrations of BaCl25 29 30 31 32 ; however, the relaxations to SIN-1 and SNP were not reduced in the presence of 3x10-5 mol/L BaCl2. These observations minimize the possibility that KIR activation is involved in the relaxant actions of nitrovasodilators. In addition, our results demonstrated that glyburide (10-5 mol/L), a selective KATP inhibitor,5 17 33 34 and 4-aminopyridine (10-3 mol/L), the most reliable KDR inhibitor,5 18 35 36 did not affect the relaxations to SIN-1 or SNP, ruling out a contribution of these K+ channels to NO-induced relaxations. The results of our study do not allow any conclusion regarding the type of K+ channels responsible for a BaCl2-sensitive component of relaxations to nitrovasodilators. Interestingly, in canine colonic smooth muscle cells, NO activates K+ channels that are resistant to known specific K+ channel blockers.37 This finding is in agreement with our results, and it is very likely that in canine middle cerebral artery, NO may activate a population of K+ channels that cannot be characterized by the available pharmacological tools used in the present study.
In contrast to NO donors, the relaxations to a cGMP analogue, 8-bromo-cGMP, were not affected by 3x10-4 mol/L BaCl2 and 3x10-8 mol/L charybdotoxin. Such selective inhibition of relaxations to NO donors by K+ channel blockers suggests that NO may directly (independently of cGMP) activate K+ channels. Although previous studies using patch-clamp techniques have documented that NO activates large-conductance KCa through cGMP-dependent protein kinase in calf thoracic aorta,7 rabbit basilar artery,8 and rat pulmonary artery,9 it has also been reported that NO itself can directly activate KCa in rabbit aortic smooth muscle cells.10 Therefore, it is possible that a similar direct effect of NO is involved in the mechanisms of relaxation in canine cerebral arteries. Another possibility is that SIN-1 and SNP may generate peroxynitrite and cyanide, respectively,38 39 and that these products may activate K+ channels independently of cGMP production. However, we obtained identical results with two different NO donors, suggesting that our findings are best explained by formation of NO rather than peroxynitrite or cyanide. More importantly, the relaxations to zaprinast, which selectively inhibits cGMP phosphodiesterase and thereby increases endogenous cGMP levels,40 41 42 were strongly reduced by 3x10-4 mol/L BaCl2 or 3x10-8 mol/L charybdotoxin. Furthermore, the relaxations to 8-bromo-cGMP were reduced by higher concentrations of BaCl2 (3x10-3 mol/L) or charybdotoxin (10-7 mol/L), suggesting that the relaxations caused by exogenous cGMP are also mediated partly by the activation of K+ channels. An exact reason for the lower sensitivity of 8-bromo-cGMP–induced relaxations to K+ channel blockers is not clear. One possible explanation is that exogenous cGMP may not have access to the same molecular targets as endogenous cGMP generated after guanylate cyclase activation or phosphodiesterase inhibition. Thus, our results suggest that the activation of K+ channels by NO donors is most likely mediated by increased production of cGMP. It remains to be determined whether cGMP-independent interaction between NO and K+ channels is an important mechanism of relaxations in cerebral arteries.
The results of the present study suggest that in canine cerebral arteries, large-conductance KCa on the smooth muscle play a role in mediation of relaxations to NO. The activation of KCa appears to be dependent on cGMP production. Other K+ channels, sensitive to BaCl2, may also be involved in the mechanism of relaxations induced by NO. These findings provide a basis for further analysis of the physiological and pathological significance of NO in the regulation of the cerebral circulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Heart, Lung, and Blood Institute grant HL-53524 and by the Mayo Foundation. Dr Onoue was supported by a scholarship from Uehara Memorial Foundation (Tokyo, Japan).
Received November 21, 1996; revision received March 5, 1997; accepted March 28, 1997.
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 P. E. Kudlacek, J. L. Pluznick, R. Ma, B. Padanilam, and S. C. Sansom Role of h{beta}1 in activation of human mesangial BK channels by cGMP kinase Am J Physiol Renal Physiol, August 1, 2003; 285(2): F289 - F294. [Abstract] [Full Text] [PDF]
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 V. Gerzanich, F. Zhang, G. A. West, and J. M. Simard Chronic Nicotine Alters NO Signaling of Ca2+ Channels in Cerebral Arterioles Circ. Res., February 16, 2001; 88(3): 359 - 365. [Abstract] [Full Text] [PDF]
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C.-W. Sun, J. R. Falck, H. Okamoto, D. R. Harder, and R. J. Roman Role of cGMP versus 20-HETE in the vasodilator response to nitric oxide in rat cerebral arteries Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H339 - H350. [Abstract] [Full Text] [PDF]
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 J. H. Jaggar, V. A. Porter, W. J. Lederer, and M. T. Nelson Calcium sparks in smooth muscle Am J Physiol Cell Physiol, February 1, 2000; 278(2): C235 - C256. [Abstract] [Full Text] [PDF]
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N. C. Adragna, R. E. White, S. N. Orlov, and P. K. Lauf K-Cl cotransport in vascular smooth muscle and erythrocytes: possible implication in vasodilation Am J Physiol Cell Physiol, February 1, 2000; 278(2): C381 - C390. [Abstract] [Full Text] [PDF]
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 M. Alonso-Galicia, A. G. Hudetz, H. Shen, D. R. Harder, R. J. Roman, and H. A. Kontos Contribution of 20-HETE to Vasodilator Actions of Nitric Oxide in the Cerebral Microcirculation • Editorial Comment Stroke, December 1, 1999; 30(12): 2727 - 2734. [Abstract] [Full Text] [PDF]
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C. G. Sobey and L. Quan Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1718 - H1724. [Abstract] [Full Text] [PDF]
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V. A. Porter, A. D. Bonev, H. J. Knot, T. J. Heppner, A. S. Stevenson, T. Kleppisch, W. J. Lederer, and M. T. Nelson Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides Am J Physiol Cell Physiol, May 1, 1998; 274(5): C1346 - C1355. [Abstract] [Full Text] [PDF]
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M. Yu, C.-W. Sun, K. G. Maier, D. R. Harder, and R. J. Roman Mechanism of cGMP contribution to the vasodilator response to NO in rat middle cerebral arteries Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1724 - H1731. [Abstract] [Full Text] [PDF]
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