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Involvement of Gi protein–dependent BKCa channel activation in β2-adrenoceptor-mediated dilation of retinal arterioles in rats

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Abstract

Circulating catecholamines contribute to the regulation of retinal vascular tone. Our previous studies have demonstrated that the activation of large-conductance Ca2+-activated K+ (BKCa) channels is involved in the β2-adrenoceptor-mediated dilation of retinal arterioles in rats. The present study aimed to examine the role of Gi protein in the β2-adrenoceptor-mediated activation of BKCa channels in the retinal arterioles. Images of in vivo rat ocular fundi were captured, and the diameters of retinal arterioles were measured. Systemic blood pressure and heart rate were recorded continuously. Intravenous infusion of formoterol (0.01–0.3 μg/kg/min), a β2-adrenoceptor agonist, increased the diameter of retinal arterioles but decreased mean arterial pressure in a dose-dependent manner. Intravitreal injection of iberiotoxin (20 pmol/eye), an inhibitor of BKCa channels, significantly attenuated the formoterol-induced dilation of retinal arterioles. Similar results were obtained when salbutamol (0.03–3 μg/kg/min), another β2-adrenoceptor agonist, was used instead of formoterol. However, iberiotoxin had no significant effect on retinal vasodilator responses to intravenous infusion of denopamine (1–30 μg/kg/min; a β1-adrenoceptor agonist), CL316243 (0.3–10 μg/kg/min; a β3-adrenoceptor agonist), prostaglandin I2 (0.03–10 μg/kg/min; a prostanoid IP receptor agonist), and forskolin (1–10 μg/kg/min; an adenylyl cyclase activator). Intravitreal injection of pertussis toxin (66 ng/eye; a Gi protein inhibitor) significantly attenuated the dilation of retinal arterioles induced by formoterol but not by denopamine and CL316243. In the presence of pertussis toxin, iberiotoxin had no inhibitory effect on formoterol-induced dilation of retinal arterioles. These results suggest that stimulation of β2-adrenoceptors dilates retinal arterioles through pertussis toxin–sensitive Gi protein–dependent activation of BKCa channels in rats in vivo.

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Funding

This study was supported by Kitasato University Research Grant for Young Researchers (AM), and by Grants-in-Aid for Scientific Research (Grant Numbers: 24790261, 15K08242 and 18K06704 AM) from the Ministry of Education, Culture, Sports, Science.

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Author notes

  1. Asami Mori & Kenji Sakamoto

    Present address: Laboratory of Medical Pharmacology, Department of Clinical & Pharmaceutical Sciences, Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

Authors and Affiliations

  1. Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Asami Mori, Ayumi Taniai, Mami Hasegawa, Kenji Sakamoto & Tsutomu Nakahara

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  1. Asami Mori
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  2. Ayumi Taniai
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  3. Mami Hasegawa
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  4. Kenji Sakamoto
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  5. Tsutomu Nakahara
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Contributions

AM and TN conceived and designed research. AM, AT, and MH conducted experiments. AM and KS analyzed data. AM and TN wrote the manuscript. All authors read and approved the manuscript. All data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Tsutomu Nakahara.

Ethics declarations

This study was approved by the Institutional Animal Care and Use Committee for Kitasato University (approval number: 17–18). The use of animals in this study was in accordance with institutional guidelines and in compliance with the Association for Research in Vision and Ophthalmology Statement.

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The authors declare that they have no conflict of interest.

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Mori, A., Taniai, A., Hasegawa, M. et al. Involvement of Gi protein–dependent BKCa channel activation in β2-adrenoceptor-mediated dilation of retinal arterioles in rats. Naunyn-Schmiedeberg's Arch Pharmacol 393, 2043–2052 (2020). https://doi.org/10.1007/s00210-020-01895-1

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  • DOI: https://doi.org/10.1007/s00210-020-01895-1

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