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Rho-kinase and the nitric oxide pathway modulate basilar arterial reactivity to acetylcholine and angiotensin II in streptozotocin-induced diabetic mice

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Abstract

Diabetes mellitus comprises a heterogeneous group of metabolic disorders with underlying hyperglycemia and secondary cardiovascular complications. Growing evidence suggests that vascular dysfunction is among the most important causes of diabetic cardiovascular disease. Therefore, we determined whether streptozotocin (STZ)-induced diabetes in mice affects blood pressure and cerebral arterial responsiveness to angiotensin (Ang) II and acetylcholine (ACh), which are important modulators of cerebrovascular autoregulation. Diabetes was induced using a single intraperitoneal injection of STZ (50 mg/kg). Blood pressure was measured in conscious mice using the indirect tail-cuff method. Functional studies of the isolated arteries’ response to vasoactive substances were performed using a micro-organ-bath system at 60 days after STZ injection. Systolic, diastolic, and mean blood pressures significantly increased at days 45 and 60 in the STZ-induced diabetic mice. In the isolated basilar arteries, ACh-induced relaxation, which is dependent on nitric oxide (NO) production from endothelial cells, decreased. In contrast, Ang II-induced contraction, mediated via rho-kinase activation in the smooth muscle, increased in the diabetic mice. There was significantly greater relaxation in the precontracted isolated basilar arteries of diabetic mice that had been treated with Y27632, a rho-kinase inhibitor, than in the control mice arteries. Pretreatment with Nω-nitro-l-arginine (L-NAME), an NO synthase inhibitor, significantly enhanced Ang II-induced contraction and Y27632-induced relaxation in the control basilar arteries but not in the STZ-induced diabetic mice arteries. These results suggest that decreased NO bioavailability and enhanced rho-kinase activity in basilar arteries contribute to altered reactivity to ACh and Ang II, respectively, in STZ-induced diabetic mice.

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research (C) (no. 26450407) from the Japan Society for the Promotion of Sciences (JSPS).

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  1. Department of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-0065, Japan

    Md. Zahorul Islam, Cuong Van Dao, Atsushi Miyamoto & Mitsuya Shiraishi

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  1. Md. Zahorul Islam
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  2. Cuong Van Dao
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  3. Atsushi Miyamoto
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Correspondence to Mitsuya Shiraishi.

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ESM 1

Effect of streptozotocin (STZ) treatment on blood pressure and heart rate. Systolic [a], diastolic [b], and mean [c] blood pressure, and heart rate [d] were measured every 15 days in conscious mice using the indirect tail-cuff method at 30 days after injection of STZ or vehicle. Results are expressed as the mean ± SEM (n = 11/group). (TIFF 1180 kb)

ESM 2

Effect of streptozotocin (STZ) treatment on blood glucose levels (a), and on basilar arterial responsiveness to acetylcholine (ACh) (b), angiotensin (Ang) II (c), and Y27632 (d) in mice. Mice received a single intraperitoneal injection of STZ (50 mg/kg) or vehicle (0.1 M citrate buffer solution) after an overnight fast. Blood glucose levels and basilar artery response to ACh, Ang II, and Y27632 were measured 30 days after the injection. Results are expressed as the mean ± SEM (n = 5-8/group). (TIFF 1181 kb)

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Islam, M.Z., Van Dao, C., Miyamoto, A. et al. Rho-kinase and the nitric oxide pathway modulate basilar arterial reactivity to acetylcholine and angiotensin II in streptozotocin-induced diabetic mice. Naunyn-Schmiedeberg's Arch Pharmacol 390, 929–938 (2017). https://doi.org/10.1007/s00210-017-1396-x

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