doi: 10.1161/01.STR.0000021720.54018.22
(Stroke. 2002;33:1742.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Re: Role of Endothelial Nitric Oxide and Smooth Muscle Potassium Channels in Cerebral Arteriolar Dilation in Response to Acidosis
Department of Pathology and Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia
To the Editor:
The article by Horiuchi et al1 in the March issue of Stroke contains potentially important data implicating both nitric oxide (NO) and the KATP ion channel in the dilation of rat cerebral parenchymal arterioles produced by acidosis. The authors employ 2 different inhibitors of NO synthase (NOSI) and demonstrate partial impairment of the response. To demonstrate a role for KATP channels, they demonstrate impairment by glibenclamide, a selective inhibitor of the channel. Unfortunately, the authors fail to cite articles by Kontos and Wei,2,3 which demonstrated that hypercapnic acidosis of rat (same species) pial arterioles was mediated by KATP. Like Horiuchi et al, Kontos and Wei also showed that NOSI inhibited the response to acidosis. However, Kontos and Wei also found that the same NOSI had a second, previously unreported action: under their experimental conditions these NOSI also prevented opening of KATP. Unless Horiuchi et al have tested the NOSI against an opener of KATP channels (eg, against pinacidil), we cannot say whether NO was really involved in the dilation of the parenchymal arterioles. The authors showed that glibenclamide plus NOSI produced significantly greater inhibition than NOSI alone. This was further evidence for a role of KATP channels. However, we are not told whether a maximally effective dose of NOSI was used. If it was, then it was warranted to conclude that 2 different mechanisms of impairment were superimposed. But if a maximally effective dose of NOSI was not used, then the possibility exists that both the NOSI and the glibenclamide were acting on KATP, as shown by Kontos and Wei.
Horiuchi et al demonstrated that endothelial injury impairs the response to acidosis. This implied that some endothelium-derived substance, such as NO, was involved. However, such substances might also affect the resting potential of the vascular smooth muscle, and the function of K channels is known to be highly dependent on resting potential. Thus the effect of endothelial injury in this study does not necessarily mean that NO or any other endothelium-derived material acted as a true mediator of the dilation produced by acidosis.
Until these issues are resolved, it may be that the data of Horiuchi et al, as presented in their article, simply supports a role for KATP as shown by Kontos and Wei.
References
1. Horiuchi T, Dietrich HH, Hongo K, Goto T, Dacey RG Jr. Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation In response to acidosis. Stroke. 2002; 33: 844–849.
2. Kontos HA, Wei EP. Arginine analogues inhibit responses mediated by ATP-sensitive K+ channels. Am J Physiol. 1996; 271: H1498–H1506.[Medline] [Order article via Infotrieve]
3. Kontos HA, Wei EP. Cerebral arteriolar dilations by KATP channel activator need L-lysine of L-arginine. Am J Physiol. 1998; 274: H974–H981.[Medline] [Order article via Infotrieve]
Response
Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri
We agree with Dr Rosenblum’s assertion that, if a maximally effective concentration of NOS inhibitor was used, we have to conclude that 2 mechanisms must be involved in the acidosis-induced vessel dilation: (1) a nitric oxide–dependent component and (2) a KATP-dependent component independent of a possible effect of the NOS inhibitor on KATP.
We have shown that a number of NOS inhibitors significantly constrict isolated, cannulated, and pressurized rat cerebral penetrating arterioles.1,2 We also demonstrated that an increase of the NOS inhibitor concentration above 100 µmol/L causes vessel dilation and as such a pharmacological effect of the drug.2 The NOS inhibitor–induced constriction is reversed by L-arginine, while the D-arginine as well as D-NAME had no effect.1 This conclusively demonstrates that the NOS inhibitors and concentrations chosen have a significant physiological effect and specificity that are related to the conversion of L-arginine and production of NO by NOS without causing pharmacological side effects.
In the present letter to the editor, the work of Kontos and Wei is cited.3,4 Of the 2 articles, only one4 presents data obtained in the rat model while the majority of results in both articles were obtained in the cat model. However, when studying the results presented, 20 µmol/L LNNA causes either no constriction (control diameter of 48 µm versus 48 µm after L-NNA) or a small dilation (average 2 µm after L-NNA) in rat pial arterioles.4 We find that 10 µmol/L L-NNA significantly constricts our vessel preparation by 24% (23% with 10 µmol/L L-NMMA),5 demonstrating the efficacy and potency of NOS inhibition in our experiments.
KATP inhibition significantly reduced acidosis-induced dilation both after initial NOS inhibition (18%) as well as after KATP inhibition alone (23%).5 We reanalyzed the 2 data sets and did not find them to be different (t test). Thus, we can only conclude that in our preparation, NOS inhibition did not directly affect KATP.
Dr Rosenblum indicates that after air embolism, the loss of endothelium-derived factors such as NO or others may cause smooth muscle depolarization with subsequent potassium channel inactivation. We cannot exclude that air embolus–induced endothelial damage causes smooth muscle depolarization. However, our data already exclude the participation of endothelial factors such as prostaglandins (inhibitable by indomethacin) or EDHF (inhibitable by MS-PPOH) in both resting and acidotic conditions.5 Air embolism caused a modest but significant vasoconstriction (6%) in our study.5 Previously, we reported that smooth muscle cells in our preparation have on average a resting membrane potential of -37.5 mV6 and that a constriction of 6% results in a depolarization of 2.5 mV,6 raising the membrane potential to -35 mV. Thus, it is not likely that air embolus–induced membrane depolarization inactivated any potential sensitive potassium channels, but it is likely that an endothelial factor, notably NO, is involved.
We thank Dr Rosenblum for his interest in our article and allowing us to clarify and substantiate our conclusions drawn.5
References
1. Kimura M, Dietrich HH, Dacey RG Jr. Nitric oxide regulates cerebral arteriolar tone in rats. Stroke. 1994; 25: 2227–2234.[Abstract]
2. Kajita Y, Takayasu M, Mori Y, Dietrich HH, Dacey RG Jr. Role of nitric oxide in autoregulatory response in rat intracerebral arterioles. Neurosurgery. 1998; 42: 834–842.[Medline] [Order article via Infotrieve]
3. Kontos HA, Wei EP. Cerebral arteriolar dilations by KATP channel activators need L-lysine or L-arginine. Am J Physiol Heart Circ Physiol. 1998; 274: H974–H981.
4. Kontos HA, Wei EP. Arginine analogues inhibit responses mediated by ATP-sensitive K+ channels. Am J Physiol Heart Circ Physiol. 1996; 271: H1498–H1506.
5. Horiuchi T, Dietrich HH, Hongo K, Goto T, Dacey RG Jr. Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation in response to acidosis. Stroke. 2002; 33: 844–849.
6. Dietrich HH, Dacey RG Jr. Effects of extravascular acidification and extravascular alkalinization on constriction and depolarization in rat cerebral arterioles in vitro. J Neurosurg. 1994; 81: 437–442.[Medline] [Order article via Infotrieve]
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