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Am J Physiol Regul Integr Comp Physiol 285: R149-R154, 2003; doi:10.1152/ajpregu.00003.2003
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LOCAL CONTROL OF CIRCULATION

Differential role of PTK and ERK MAPK in superoxide impairment of KATP and KCa channel cerebrovasodilation

John Ross and William M. Armstead

Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104

Submitted 6 January 2003 ; accepted in final form 24 March 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previously, superoxide (O2 -) has been observed to impair pial artery dilation (PAD) to activators of the ATP-sensitive (KATP) and calcium-sensitive (KCa) K+ channels. This study tested the hypothesis that activation of protein tyrosine kinase (PTK) and the ERK isoform of MAPK by O2 - contribute to impairment of KATP and KCa channel PAD. Exposure of the cerebral cortex to a xanthine oxidase O2 --generating system (OX) blunted PAD to cromakalim, a KATP agonist, but preadministration of genistein, a PTK antagonist, or U-0126, an ERK MAPK inhibitor, almost completely prevented such impairment (11 ± 1 and 22 ± 1 vs. 3 ± 1 and 7 ± 1 vs. 10 ± 1 and 16 ± 2% for cromakalim with 10-8 and 10-6 M PAD during control, OX, and OX + genistein conditions). In contrast, neither genistein nor U-0126 robustly protected PAD to NS-1619, a KCa agonist, after OX exposure (11 ± 1 and 18 ± 2 vs. 1 ± 1 and 2 ± 1 vs. 4 ± 1 and 6 ± 1% for 10-8 and 10-6 M NS-1619 during control, OX, and OX + genistein conditions). These data show that PTK and ERK MAPK activation contribute to O2 --induced KATP and KCa channel PAD impairment and suggest a differential greater role for PTK and ERK MAPK in KATP vs. KCa channel PAD impairment.

oxygen free radicals; K+ channels; signal transduction

RELAXATION OF BLOOD VESSELS can be mediated by several mechanisms, including cGMP, cAMP, and K+ channels (21). Membrane potential of vascular muscle is a major determinant of vascular tone, and activity of K+ channels is a major regulator of membrane potential (27). Activation or opening of these channels increases K+ efflux, thereby producing hyperpolarization of vascular muscle. Membrane hyperpolarization closes voltage-dependent calcium channels and thereby causes relaxation of vascular muscle (26, 27). Direct measurements of membrane potential and K+ current in vitro indicate that several different types of K+ channels are present in cerebral blood vessels. In addition, a number of pharmacological studies using activators and inhibitors have provided functional evidence that K+ channels, especially ATP-sensitive (KATP) and calcium-sensitive (KCa) K+ channels, regulate tone of cerebral blood vessels in vitro and in vivo (21). Although several recent studies have characterized the role of K+ channels in cerebrovascular control under physiological conditions, less is known concerning their contributions under pathological conditions. Of note, in that regard, is the observation that KATP and KCa channel function is impaired after fluid percussion brain injury (FPI) and that altered dilation to some stimuli after insult could relate to such impairment (4–11, 19).

Activation of PKC is thought to contribute to the cerebral vasospasm associated with pathological conditions such as subarachnoid hemorrhage (22). Activation of PKC, in turn, promotes interaction with other, more distal signaling pathways, such as protein tyrosine kinase (PTK) and its substrate, MAPK, also thought to contribute to cerebral vasospasm (22). MAPK is actually a family of kinases, including the p38, JNK, and ERK isoforms. Previous studies in the piglet have observed a role for superoxide (O2-) generated via PKC activation in the impairment of pial artery dilation to activators of the KATP but not the KCa channel after FPI (6, 10). More recent studies have noted the contribution of PTK activation to KATP channel pial artery dilator impairment following FPI in the rat, although a role in KCa channel impairment was less clear (16). In the piglet, however, PTK and ERK MAPK activation appear to contribute to both KATP and KCa channel dilator impairment after FPI (11). The mechanism that might link PTK, ERK MAPK, and O2- to impaired KATP and KCa channel vasodilator impairment, however, is uncertain. Curiously, it has been observed that O2- generation by subarachnoid hemorrhage was inhibited by a PTK antagonist (16). Therefore, this study tested the hypothesis that activation of PTK and ERK MAPK by O2- produces impairment of KATP and KCa channel-mediated vasodilation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Newborn (1–5 days old, 1.3–2.1 kg) pigs of either sex were used in these experiments. All protocols were approved by the Institutional Animal Care and Use Committee. Animals were sedated with isoflurane (1–2 minimum alveolar concentration). Anesthesia was maintained with {alpha}-chloralose (30–50 mg/kg, supplemented with 5 mg · kg-1 · h-1 iv). The trachea was cannulated, and the animals were mechanically ventilated with room air. A heating pad was used to maintain the animals at 37–39°C.

A cranial window was placed 0.5 cm from bregma and the midsagittal line in the parietal skull of these anesthetized animals. This window consisted of three parts: a stainless steel ring, a circular glass coverslip, and three ports consisting of 17-gauge hypodermic needles attached to three precut holes in the stainless steel ring. For placement, the dura was cut and retracted over the cut bone edge. The cranial window was placed in the opening and cemented in place with dental acrylic. The volume under the window was filled with a solution, similar to cerebrospinal fluid (CSF), of the following composition (in mM): 3.0 KCl, 1.5 MgCl2, 1.5 CaCl2, 132 NaCl, 6.6 urea, 3.7 dextrose, and 24.6 NaHCO3. This artificial CSF was warmed to 37°C and had the following chemistry: pH 7.33, Pco2 46 mmHg, and Po2 43 mmHg, similar to that of endogenous CSF. Pial arterial vessels were observed with a dissecting microscope, a television camera mounted on the microscope, and a video output screen. Vascular diameter was measured with a video microscaler.

Protocol. Two types of pial arterial vessels, small arteries (resting diameter 120–160 µm) and arterioles (resting diameter 50–70 µm), were examined to determine whether segmental differences in the effects of O2 - generation on KATP and KCa channel agonist pial dilation could be identified. The O2 - generation system (OX) consisted of 0.2 U/ml of xanthine oxidase, 0.6 mM hypoxanthine, and 0.02 mM FeCl3 administered repeatedly at 5-min intervals over a 20-min period. The FeCl3 was used to convert the O2- generated to the ·OH, because this species may contribute to O2 - pathology (33).

Ten major types of experiments were performed (all n = 6): 1) sham control, 2) generation of O2 -, 3) generation of O2 the PTK inhibitor genistein, 4) generation of O2 - with the PTK inhibitor tyrphostin A23, 5) generation of O2 - with the ERK MAPK inhibitor U-0126, 6) generation of O2 - with the ERK MAPK inhibitor PD-98059, 7) determination of the amount of O2- present under sham control conditions, 8) determination of the amount of O2 - generated by OX, 9) determination of the amount of O2 - generated by OX in genistein-pretreated animals, and 10) determination of the amount of O2 animals. - with - generated by OX in U-0126-pretreated animals.

In the sham control experiments, the responses of arterial vessels to the synthetic KATP channel agonist (-) cromakalim (10-8 and 10-6 M; SmithKline Beecham), the endogenous KATP channel activator calcitonin gene-related peptide (CGRP; 10-8 and 10-6 M; Sigma), and the synthetic KCa channel activator NS-1619 (10-8 and 10-6 M; Sigma) were obtained initially and then 60 min later. Agonist order administration was randomized, and 20-min rest periods were used between dose-response curves. A maximum of three agonists and one antagonist were administered in each animal.

In the O2 - generation experiments, responses of arterial vessels to cromakalim, CGRP, and NS-1619 were obtained before and 60 min after O2 - generation in the absence and presence of pretreatment 30 min before exposure to an activated oxygen-generating system with genistein (10-6 M), tyrphostin A23 (10-5 M), U-0126 (10-6 M), or PD-98059 (10-5 M). The agonists were applied in an ascending-concentration manner. There was a period of 20 min after the highest concentration of one agonist was washed off before a different agonist was infused. The percent change in artery diameter values were calculated on the basis of the diameter measured in the control period for each drug before O2- generation for (control) values, whereas the diameter present in the control period before the drug administration after O2 - generation was used for post-OX values.

O2 - analysis. Superoxide dismutase (SOD)-inhibitable nitro blue tetrazolium (NBT) reduction was determined as an index of O2 - generation. Such reduction was determined by placing NBT (2.4 mmol/l; Sigma) dissolved in artificial CSF under one cranial window and NBT (2.4 mmol/l) and SOD (60 U/ml; Sigma) in artificial CSF under a second window. Because such solutions remained on the surface for 20 min, data are quantified as picomoles of NBT reduced for 20 min.

NBT is water soluble and forms a yellow solution that is converted to nitro blue formazan, an insoluble purple precipitate, in the presence of reducing agents, e.g., O2 -. The SOD-inhibitable NBT reduction was determined by the difference in the quantities of nitro blue formazan precipitated on the brain surface under the two windows. Although NBT can be reduced by a variety of agents, SOD provides specificity for the assay. Slices of the brain surface 1 mm thick under each cranial window were obtained. The slices were minced and homogenized in 1 N NaOH and 0.1% SDS solution. The supernatant was discarded, and the pellet was resuspended in 3 ml pyridine. The formazan was dissolved in the pyridine during heating at 80°C for 1 h. Particulate matter was removed by a second centrifugation at 10,000 g for 10 min. The concentration of nitro blue formazan in the supernatant was then determined spectrophotometrically at 515 nm. The nitro blue formazan on the side with NBT alone was analyzed against the background of the SOD-treated side. Freshly prepared calibration solutions were used with each set of samples and treated identically to the samples.

Statistical analysis. Systemic arterial pressure and NBT reduction values were analyzed by using ANOVA for repeated measures. If the value was significant, the data were then analyzed by Fisher's protected least significant difference test. Nonparametric analysis was used for pial artery diameter data and was expressed as percentage change from baseline. An {alpha} level of P < 0.05 was considered significant in all statistical tests. Values are represented as means ± SE of the absolute values or percent changes from control values. The n values reflect data for one experiment in each animal.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Role of PTK activation in O2 --induced impairment of KATP and KCa channel agonist-induced pial artery dilation. Cromakalim, CGRP, and NS-1619 induced reproducible pial small artery (120–160 µm) and arteriole (50–70 µm) vasodilation (data not shown). Cromakalim-, CGRP-, and NS-1619-induced pial artery dilation was blunted after OX administration (Figs. 1, 2, 3, 4). On a percentage basis, these values reflect 65 ± 7, 66 ± 3, 69 ± 9, and 68 ± 6% inhibition by OX for responses to cromakalim (10-8 and 10-6 M) in pial small arteries and arterioles, respectively. Similar percentage inhibition was observed for CGRP. The inhibition for NS-1619 on a percentage basis was 92 ± 3, 91 ± 2, 89 ± 2, and 88 ± 7% for responses to NS-1619 (10-8 and 10-6 M) in pial small arteries and arterioles, respectively.



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  		Fig. 1. Influence of cromakalim and calcitonin gene-related peptide (CGRP; 10-8 and 10-6 M) on pial small artery diameter before (control) and after exposure to an activated oxygen-generating system (OX), after OX in tyrphostin A23 (10-5 M) -pretreated animals, and after OX in genistein (10-6 M) -pretreated animals (all n = 6). *P < 0.05 vs. control; +P < 0.05 vs. corresponding OX nonpretreated value.

 


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  		Fig. 2. Influence of NS-1619 (10-8 and 10-6 M) on pial small artery diameter before (control) and after exposure to OX, after OX in tyrphostin A23 (10-5 M) -pretreated animals, and after OX in genistein (10-6 M) -pretreated animals (all n = 6). *P < 0.05 vs. control; +P < 0.05 vs. corresponding OX nonpretreated value.

 


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  		Fig. 3. Influence of cromakalim and CGRP (10-8 and 10-6 M) on pial small artery diameter before (control) and after exposure to OX, after OX in U-0126 (10-6 M) -pretreated animals, and after OX in PD-98059 (10-5 M) -pretreated animals (all n = 6). *P < 0.05 vs. control; +P < 0.05 vs. corresponding OX nonpretreated value.

 


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  		Fig. 4. Influence of NS-1619 (10-8 and 10-6 M) on pial small artery diameter before (control) and after exposure to OX, after OX in U-0126 (10-6 M) -pretreated animals, and after OX in PD-98059 (10-5 M) -pretreated animals (all n = 6). *P < 0.05 vs. control; +P < 0.05 vs. corresponding OX nonpretreated value.

 

In animals pretreated with the PTK inhibitors genistein (10-6 M) or tyrphostin A23 (10-5 M), responses to cromakalim and CGRP were robustly, if not fully, restored after OX (Figs. 1 and 2). On a percentage basis, these results reflect 23 ± 6, 24 ± 7, 37 ± 5, and 26 ± 6% inhibition by OX for responses to cromakalim (10-8 and 10-6 M) in pial small arteries and arterioles, respectively, in genistein-pretreated animals. Such values were significantly different from those obtained in the absence of genistein. Similar results were obtained for tyrphostin A23.

In contrast, responses to NS-1619 after OX were only modestly protected by genistein or tyrphostin A23 pretreatment (Figs. 1 and 2). On a percentage basis, these results reflect 62 ± 6, 59 ± 3, 68 ± 6, and 59 ± 7% inhibition for responses to NS-1619 (10-8 and 10-6 M) in pial small arteries and arterioles, respectively, for genistein pretreatment. Such values were significantly different from those after OX in nonpretreated animals but were also significantly different from those obtained in response to cromakalim or CGRP in genistein-pretreated animals. Similar results were obtained for tyrphostin A23.

Role of ERK MAPK activation in O2 --induced impairment of KATP and KCa channel agonist-induced pial artery dilation. Pretreatment with either U-0126 (10-6 M) or PD-98059 (10-5 M), both ERK MAPK inhibitors, produced robust protection of responses to cromakalim and CGRP after OX (Figs. 3 and 4). On a percentage basis, these results reflect 34 ± 3, 33 ± 3, 29 ± 7, and 34 ± 6% inhibition for cromakalim (10-8 and 10-6 M) in pial small arteries and arterioles after OX in U-0126-pretreated animals, respectively. Similar values were observed for PD-98059 pretreatment, and both were significantly different from OX nonpretreated values.

In contrast, responses to NS-1619 after OX were only modestly protected by U-0126 or PD-98059 pretreatment (Figs. 3 and 4). On a percentage basis, these results reflect 56 ± 6, 64 ± 3, 65 ± 7, and 72 ± 4% inhibition for responses to NS-1619 (10-8 and 10-6 M) in pial small arteries and arterioles, respectively, for U-0126 pretreatment. Such values were significantly different from those after OX in nonpretreated animals but were also significantly different from those obtained in response to cromakalim or CGRP in U-0126-pretreated animals. Similar results were obtained for PD-98059.

Influence of PTK and ERK MAPK inhibitors on pial artery diameter and O2 -. Neither PTK inhibitors genistein and tyrphostin A23 nor the ERK MAPK inhibitors U-0126 and PD-98059 had any significant effect on pial artery diameter (123 ± 6 vs. 125 ± 7 µm before and after genistein). Using NBT reduction as an index of O2- generation, it was observed that NBT reduction was elevated compared with sham controls in an equivalent manner in untreated, genistein-pretreated, and U-0126-pretreated animals (1 ± 1 vs. 18 ± 3 vs. 17 ± 3 vs. 18 ± 4 pmol NBT for control, OX, OX + genistein, and OX + U-0126, respectively).

Blood chemistry. Blood chemistry values were obtained at the beginning and the end of all experiments. These values were 7.50 ± 0.04, 34 ± 2, and 98 ± 9 vs. 7.49 ± 0.04, 35 ± 3, and 89 ± 8 mmHg for pH, Pco2, and Po2, respectively. There were no group or treatment differences.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Results of the present study show that generation of oxygen free radicals through an activated oxygen-generating system results in blunted pial artery dilation to the synthetic and endogenous KATP channel agonists cromakalim and CGRP, respectively, and the synthetic KCa agonist NS-1619, consistent with previous observations. In animals pretreated with either the PTK inhibitors genistein and tyrphostin A23 or the ERK MAPK inhibitors U-0126 and PD-98059, responses to the KATP agonists cromakalim and CGRP were robustly, if not fully in some cases, restored after OX administration. However, vasodilator impairment to the KCa channel agonist NS-1619 was only modestly prevented by pretreatment with the same PTK and ERK MAPK inhibitors. Such impairment of NS-1619-induced vasodilation by OX, however, was significantly less in the presence of PTK or ERK MAPK inhibitors than in their absence. These data indicate that PTK and ERK MAPK activation contribute to O2--induced KATP and KCa channel pial artery dilator impairment. These data suggest a greater role for PTK or ERK MAPK activation in KATP vs. KCa channel-induced pial artery dilator impairment. Data from the present study strengthen conclusions for the role of PTK and ERK MAPK activation in such OX-induced KATP and KCa dilator impairment in that several structurally unrelated inhibitors of these pathways yielded similar results. Using NBT reduction as an index of O2- generation, it was also observed that the amount of O2- generation was equivalent in untreated and PTK/MAPK-pretreated animals. These data suggest that the PTK and MAPK inhibitors used in this study do not scavenge free radicals or inhibit their production by xanthine oxidase. However, K+ channels may be present in both vascular and nonvascular cells. The closed cranial window technique, however, does not allow the distinction of the contribution of mechanisms that may differ based on cellular type. In fact, pial artery dilation in this preparation is only used as an indirect index of K+ channel activity. Thus it may be an oversimplification to draw conclusions regarding the relative importance of signed transduction mechanisms for K+ channel subtypes using this technique.

The cerebrovascular consequences of free radical production are not fully understood. It has been suggested that O2- could be involved in irreversible vascular damage, delayed hypoperfusion, and edema produced by cerebral ischemia-reperfusion (30). The topical application of a xanthine/xanthine oxidase-activated oxygen-generating system, severe hypertension, topical application of arachidonic acid, and fluid percussion brain injury cause morphological, functional, and biochemical cerebral artery abnormalities, which include reduced responsiveness to vasoconstrictor and vasodilator stimuli (19, 23, 31–33). O2- and species derived from it, such as H2O2 and ·OH, appear to mediate these abnormalities (19, 33). Intracellular generation of O2- or other species could alter structure and/or production of nucleotides, second messengers, receptors, and membranes, and the movement of O2- out of the cell through anion channels could result in high concentrations of activated oxygen species at cell surfaces, including the endothelium. More importantly, current concepts point toward the significant contribution to damage by the reaction of O2- with nitric oxide to form the highly reactive prooxidant peroxynitrite (12, 24). The latter species and not O2- is currently thought to be the more direct mediator of damage.

The mechanism whereby O2- might contribute to K+ channel function impairment has been considered previously. Initial studies observed that PKC activation contributed to O2- generation and impaired dilation to KATP channel agonists after FPI (6). Subsequently, other studies obtained data indicating that endothelin and vasopressin released into CSF following FPI (2, 7, 18) can activate PKC (6, 10) to impair KATP channel-mediated pial artery dilation (10, 18) via sequential activation of PTK and ERK MAPK. Interestingly, the PTK inhibitor genistein has recently been observed to inhibit O2- production resulting from exposure of cerebral vessels to whole blood (29). In that study, impaired autoregulatory pial artery vasodilation to hypotension after subarachnoid hemorrhage in the rat was also fully recovered by genistein administration (29). Since pial dilation to hypotension is dependent on KATP and KCa channel function (7, 16), these data suggest that PTK activation results in O2- generation to impair K+ channel agonist-mediated pial artery dilation. Curiously, however, a role for PKC activation in O2- generation in this rat subarachnoid hemorrhage model was not observed (29). Furthermore, the role of MAPK activation in O2- generation was not considered.

The present study was designed to investigate the above topic from an alternative standpoint. Results of this study are the first to note the ability of O2- to activate PTK and ERK MAPK and thereby contribute to OX-induced impairment of KATP and KCa channel agonist-mediated pial artery vasodilation. Although the converse situation of PTK and ERK MAPK activation resulting in O2- generation cannot be eliminated, such a possibility is limited by the robust protection of KATP channel agonist dilation by PTK and ERK MAPK inhibitors after OX administration. Interestingly, such protection was much less pronounced for KCa channel agonist dilation after OX, suggesting that, although PTK and ERK MAPK activation may be involved, such involvement is significantly less for the interaction with this K+ channel. In the case of PTK, these data are consistent with the idea that PKC activates PTK (6) but concomitantly has little role in KCa channel agonist-induced dilator impairment by OX (10).

A caveat of the pharmacological approach utilized in the present study relates to efficacy and specificity of the antagonists for PTK and MAPK. Since a higher concentration for genistein or U-0126 (e.g., 10-5 M) than that used in the present study did not have any further protective effect in another cerebral injury model (hypoxia/ischemia) (17), these data suggest that the lower concentration (10-6 M) used in this study was near maximally efficacious in the inhibition of PTK and ERK MAPK, respectively. Regarding selectivity, other studies point toward the concentration used in the present study for genistein and U-0126 as being quite selective for PTK and ERK MAPK, respectively (20, 25). However, because direct correlation between O2- generation and MAPK phosphorylation (activation) cannot be made, caution is urged regarding conclusions drawn from the above pharmacological approach.

Previous studies have investigated the selectivity of the agents used as probes for KATP and KCa channel activation-induced pial artery dilation. Cromakalim-induced pial artery dilation has been observed to be blocked by glibenclamide and unchanged by iberiotoxin, KATP, and KCa channel antagonists, respectively (1). Conversely, NS-1619-induced pial artery dilation was blocked by iberiotoxin and unchanged by glibenclamide (1, 3, 4). These data suggest that cromakalim and NS-1619 are selective KATP and KCa channel agonists in the piglet cerebral circulation. Pial arteries have been shown to be innervated by CGRP-containing nerve fibers (13). CGRP produces hyperpolarization of cerebral vascular muscle in vitro (28), and cross-selectivity experiments have similarly been performed supportive of its selectivity for the KATP channel in the piglet (1). Inclusion of data for CGRP in the present study, therefore, lends a physiological functional perspective to results indicative of O2-'s modulatory role in KATP channel vascular function. However, it has also been observed that NS-1619 may additionally possess calcium channel antagonistic activity and, therefore, may not be useful as a probe for KCa channel activation (15). In contrast, recent observations in the piglet show that vasoconstrictor responses to the calcium channel agonist Bay K8644 were unchanged in the presence of NS-1619 (3). These results suggest that NS-1619 has no calcium channel-blocking activity and, therefore, may be considered to be selective for activation of KCa channels in the newborn pig.

In conclusion, results of the present study show that PTK and ERK MAPK activation contribute to O2--induced KATP and KCa channel pial artery dilator impairment. These data suggest a differential greater role for PTK and ERK MAPK in KATP vs. KCa channel pial artery dilator impairment.


   ACKNOWLEDGMENTS
 
This research was supported by grants from the National Institutes of Health, the Pennsylvania and Delaware Affiliate of the American Heart Association, and the University of Pennsylvania.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. M. Armstead, Dept. of Anesthesia, Univ. of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104 (E-mail: armsteaw{at}uphs.upenn.edu).

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.


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 RESULTS
 DISCUSSION
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