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Cocaine does not inhibit inwardly rectifying K+ channel dilatation in rat basilar artery in situ
International Journal of Cardiology 214 (2016) 134–135
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Cocaine does not inhibit inwardly rectifying K+ channel dilatation in rat basilar artery in situ SeongHun Yoon a,1, Mario Zuccarello b,2, Robert M. Rapoport c,⁎,1 a b c
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, NJ 17103, United States Department of Neurosurgery, Neuroscience Institute, University of Cincinnati College of Medicine, PO Box 670515, Cincinnati, OH 45267-0515, United States Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, PO Box 670575, Cincinnati, OH 45267-0575, United States
a r t i c l e
i n f o
Article history: Received 25 March 2016 Accepted 26 March 2016 Available online 29 March 2016
Keywords: Cocaine Cerebral Vascular Dilatation Constriction In situ Extracellular K+ Rat Basilar artery KIR channels
Although cocaine constriction of the cerebral vasculature is thought to contribute to the associated cerebral ischemia, the mechanisms responsible for the constriction remain unclear [1]. Indeed, it appears that multiple mechanisms are involved as reflected by the location and type of vessel, i.e., large and resistance-type vessels, including vessels in the neurovascular unit [1]. One possible mechanism of cocaine constriction thus far not investigated is inhibition of inwardly rectifier potassium (KIR) channels. KIR channel activation, which causes dilatation, represents a fundamental mechanism for the regulation of cerebral vascular resistance and, thus, cerebral blood flow [2]. This regulatory mechanism has been identified in large and resistance-type vessels, including microvasculature,
⁎ Corresponding author. E-mail address: [email protected] (R.M. Rapoport). 1 Affiliations during study performance: Research Service, Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, United States and Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, PO Box 670575, Cincinnati, OH 45267-0575, United States. 2 Affiliations during study performance: Surgical Service, Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, United States and Department of Neurosurgery, Neuroscience Institute, University of Cincinnati College of Medicine, PO Box 670515, Cincinnati, OH 45267-0515, United States.
http://dx.doi.org/10.1016/j.ijcard.2016.03.190 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
neurons, and astrocytes in the neurovascular unit [2,3]. Thus, disruption of this dilator function results in relative vasoconstriction [2,3]. To investigate whether cocaine inhibited functional KIR activation an in situ preparation of the rat basilar artery [4] was challenged with elevated K+ (KCl), an endogenous KIR channel activator [2,3]. This vessel and, furthermore, this preparation were previously demonstrated to dilate in response to elevated KCl [3]. In terms of the KIR channel isoform present in the rat basilar artery, KIR2.1 mRNA was detected in this vessel [3]. Furthermore, Ba2+ (BaCl2; 30–100 μM) at least partially inhibited the KCl dilation, consistent with the presence of this isoform [2,3]. Cumulative addition of 5 mM, 10 mM, and 20 mM KCl resulted in 25.8 ± 7.1, 49.1 ± 9.5, and 57.2 ± 9.5% dilatation (n = 10), respectively (Fig. 1). In the presence of 30 μM BaCl2, dilatations to 5 mM and 20 mM KCl were significantly reduced to 0 and 17.9 ± 1.6%, respectively, and dilatation to 10 mM KCl tended to be reduced (10.1 ± 1.3%; n = 3 in each case; Fig. 1). Although it was suggested that a component of the KCl dilatation of basilar artery from male rats was mediated by muscarinic type 2 receptors [5], 1 μM methoctramine did not reverse the KCl dilatation that remained in the presence of BaCl2 (not shown). BaCl2 (30 μM) did not alter basal tone (n = 3; Fig. 1). Cocaine (100 μM) elicited 11.2 ± 0.9% (n = 3) constriction (Fig. 1). Dilatations to 5 mM, 10 mM, and 20 mM KCl in the presence of cocaine were 16.4 ± 2.9, 32.8 ± 2.3, and 46.8 ± 8.3% (n = 3), respectively, which were not significantly different than corresponding dilatations in the absence of cocaine (Fig. 1). These findings suggest that cocaine constriction does not involve inhibition of at least KIR2.1 channels. By extension, KIR2.1 channels present in astrocytes and neurons, cells which make up the neurovascular unit, and also parenchymal arterioles [2], are not involved in cocaine constriction. These conclusions are consistent with the inability of cocaine to inhibit KIR2.1 channels expressed in Xenopus oocytes [6]. However, whether cocaine inhibits other KIR channel isoforms located on the smooth muscle and on cell types which make up the neurovascular unit [2], remains for further investigation. In this regard, KIR3 channels are present in neurons and astrocytes within the neurovascular unit [2] and cocaine inhibits these channels expressed in Xenopus oocytes [6].
Disclosure statement The authors report no relationship that could be construed as a conflict of interest.
Correspondence
135
Acknowledgements This work was supported by grants from the Office of Research and Development, Medical Research Service, U.S. Department of Veterans Affairs and the Department of Neurosurgery, College of Medicine, University of Cincinnati, and the Mayfield Educational Research Fund (MERF). References
Fig. 1. Effects of cocaine on KCl-induced dilatation in rat basilar artery in situ. Rat basilar artery was pretreated with 100 μM cocaine, Ba2+ or remained unexposed (“Basal”). Shown are means ± SE. “n” In parentheses represents the number of rats. Constriction was calculated as a percent basal diameter. Dilatation was calculated as percent decrease from basal or cocaine constriction. Statistical difference was determined by the Kruskal– Wallis test followed by Dunn's multiple comparison test with significance accepted at p ≤ 0.05. *Significantly less dilatation as compared to the corresponding KCl concentration under “Basal” condition.
[1] R.M. Rapoport, S. Yoon, M. Zuccarello, Cocaine constrictor mechanisms of the cerebral vasculature, J Cardiovasc Pharmacol (2016) in press. [2] T.A. Longden, M.T. Nelson, Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow, Microcirculation 22 (2015) 183–196. [3] S. Chrissobolis, J. Ziogas, Y. Chu, F.M. Faraci, C.G. Sobey, Role of inwardly rectifying K(+) channels in K(+)-induced cerebral vasodilatation in vivo, Am J Phys 279 (2000) H2704–H2712. [4] S. Yoon, M. Zuccarello, R.M. Rapoport, EndothelinA–endothelinB receptor cross-talk in rat basilar artery in situ, Naunyn Schmiedebergs Arch Pharmacol 385 (2012) 437–441. [5] S. Chrissobolis, C.G. Sobey, Influence of gender on K+-induced cerebral vasodilatation, Stroke 35 (2004) 747–752. [6] T. Kobayashi, D. Nishizawa, T. Iwamura, K. Ikeda, Inhibition by cocaine of G proteinactivated inwardly rectifying K+ channels expressed in Xenopus oocytes, Toxicol In Vitro 21 (2007) 656–664.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Cocaine does not inhibit inwardly rectifying K+ channel dilatation in rat basilar artery in situ SeongHun Yoon a,1, Mario Zuccarello b,2, Robert M. Rapoport c,⁎,1 a b c
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, NJ 17103, United States Department of Neurosurgery, Neuroscience Institute, University of Cincinnati College of Medicine, PO Box 670515, Cincinnati, OH 45267-0515, United States Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, PO Box 670575, Cincinnati, OH 45267-0575, United States
a r t i c l e
i n f o
Article history: Received 25 March 2016 Accepted 26 March 2016 Available online 29 March 2016
Keywords: Cocaine Cerebral Vascular Dilatation Constriction In situ Extracellular K+ Rat Basilar artery KIR channels
Although cocaine constriction of the cerebral vasculature is thought to contribute to the associated cerebral ischemia, the mechanisms responsible for the constriction remain unclear [1]. Indeed, it appears that multiple mechanisms are involved as reflected by the location and type of vessel, i.e., large and resistance-type vessels, including vessels in the neurovascular unit [1]. One possible mechanism of cocaine constriction thus far not investigated is inhibition of inwardly rectifier potassium (KIR) channels. KIR channel activation, which causes dilatation, represents a fundamental mechanism for the regulation of cerebral vascular resistance and, thus, cerebral blood flow [2]. This regulatory mechanism has been identified in large and resistance-type vessels, including microvasculature,
⁎ Corresponding author. E-mail address: [email protected] (R.M. Rapoport). 1 Affiliations during study performance: Research Service, Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, United States and Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, PO Box 670575, Cincinnati, OH 45267-0575, United States. 2 Affiliations during study performance: Surgical Service, Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, United States and Department of Neurosurgery, Neuroscience Institute, University of Cincinnati College of Medicine, PO Box 670515, Cincinnati, OH 45267-0515, United States.
http://dx.doi.org/10.1016/j.ijcard.2016.03.190 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
neurons, and astrocytes in the neurovascular unit [2,3]. Thus, disruption of this dilator function results in relative vasoconstriction [2,3]. To investigate whether cocaine inhibited functional KIR activation an in situ preparation of the rat basilar artery [4] was challenged with elevated K+ (KCl), an endogenous KIR channel activator [2,3]. This vessel and, furthermore, this preparation were previously demonstrated to dilate in response to elevated KCl [3]. In terms of the KIR channel isoform present in the rat basilar artery, KIR2.1 mRNA was detected in this vessel [3]. Furthermore, Ba2+ (BaCl2; 30–100 μM) at least partially inhibited the KCl dilation, consistent with the presence of this isoform [2,3]. Cumulative addition of 5 mM, 10 mM, and 20 mM KCl resulted in 25.8 ± 7.1, 49.1 ± 9.5, and 57.2 ± 9.5% dilatation (n = 10), respectively (Fig. 1). In the presence of 30 μM BaCl2, dilatations to 5 mM and 20 mM KCl were significantly reduced to 0 and 17.9 ± 1.6%, respectively, and dilatation to 10 mM KCl tended to be reduced (10.1 ± 1.3%; n = 3 in each case; Fig. 1). Although it was suggested that a component of the KCl dilatation of basilar artery from male rats was mediated by muscarinic type 2 receptors [5], 1 μM methoctramine did not reverse the KCl dilatation that remained in the presence of BaCl2 (not shown). BaCl2 (30 μM) did not alter basal tone (n = 3; Fig. 1). Cocaine (100 μM) elicited 11.2 ± 0.9% (n = 3) constriction (Fig. 1). Dilatations to 5 mM, 10 mM, and 20 mM KCl in the presence of cocaine were 16.4 ± 2.9, 32.8 ± 2.3, and 46.8 ± 8.3% (n = 3), respectively, which were not significantly different than corresponding dilatations in the absence of cocaine (Fig. 1). These findings suggest that cocaine constriction does not involve inhibition of at least KIR2.1 channels. By extension, KIR2.1 channels present in astrocytes and neurons, cells which make up the neurovascular unit, and also parenchymal arterioles [2], are not involved in cocaine constriction. These conclusions are consistent with the inability of cocaine to inhibit KIR2.1 channels expressed in Xenopus oocytes [6]. However, whether cocaine inhibits other KIR channel isoforms located on the smooth muscle and on cell types which make up the neurovascular unit [2], remains for further investigation. In this regard, KIR3 channels are present in neurons and astrocytes within the neurovascular unit [2] and cocaine inhibits these channels expressed in Xenopus oocytes [6].
Disclosure statement The authors report no relationship that could be construed as a conflict of interest.
Correspondence
135
Acknowledgements This work was supported by grants from the Office of Research and Development, Medical Research Service, U.S. Department of Veterans Affairs and the Department of Neurosurgery, College of Medicine, University of Cincinnati, and the Mayfield Educational Research Fund (MERF). References
Fig. 1. Effects of cocaine on KCl-induced dilatation in rat basilar artery in situ. Rat basilar artery was pretreated with 100 μM cocaine, Ba2+ or remained unexposed (“Basal”). Shown are means ± SE. “n” In parentheses represents the number of rats. Constriction was calculated as a percent basal diameter. Dilatation was calculated as percent decrease from basal or cocaine constriction. Statistical difference was determined by the Kruskal– Wallis test followed by Dunn's multiple comparison test with significance accepted at p ≤ 0.05. *Significantly less dilatation as compared to the corresponding KCl concentration under “Basal” condition.
[1] R.M. Rapoport, S. Yoon, M. Zuccarello, Cocaine constrictor mechanisms of the cerebral vasculature, J Cardiovasc Pharmacol (2016) in press. [2] T.A. Longden, M.T. Nelson, Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow, Microcirculation 22 (2015) 183–196. [3] S. Chrissobolis, J. Ziogas, Y. Chu, F.M. Faraci, C.G. Sobey, Role of inwardly rectifying K(+) channels in K(+)-induced cerebral vasodilatation in vivo, Am J Phys 279 (2000) H2704–H2712. [4] S. Yoon, M. Zuccarello, R.M. Rapoport, EndothelinA–endothelinB receptor cross-talk in rat basilar artery in situ, Naunyn Schmiedebergs Arch Pharmacol 385 (2012) 437–441. [5] S. Chrissobolis, C.G. Sobey, Influence of gender on K+-induced cerebral vasodilatation, Stroke 35 (2004) 747–752. [6] T. Kobayashi, D. Nishizawa, T. Iwamura, K. Ikeda, Inhibition by cocaine of G proteinactivated inwardly rectifying K+ channels expressed in Xenopus oocytes, Toxicol In Vitro 21 (2007) 656–664.