Co-treatment with clonidine and a GRK2 inhibitor prevented rebound hypertension and endothelial dysfunction after withdrawal in diabetes


Hypertension and diabetes are associated with a risk of cardiovascular disease. Clonidine is currently used as a fourth-line drug therapy for hypertension because of its rebound hypertensive effect and short half-life. The purpose of this study was to investigate the combined effect of an antihypertensive drug (clonidine) and a G-protein-coupled receptor kinase 2 (GRK2) inhibitor on rebound hypertension and endothelial dysfunction. The clonidine and/or GRK2 inhibitor were administered by continuous infusion for 14 days by using an osmotic pump that was implanted subcutaneously. To test the effects of GRK2 inhibitotr, we measured blood pressure by using a tail-cuff system in diabetic mice in which rebound hypertension was induced by withdrawal after clonidine treatment and measured vascular responses in isolated aortas from these mice. The mice were then euthanized 7 days later. We observed that, in diabetes mellitus (DM) mice, blood pressure began to decline after 3 days of clonidine or clonidine + GRK2-inhibitor infusion. However, 15 days after initiation of treatment, the blood pressure of the clonidine only-treated DM mice began to increase and resulted in a high final blood pressure. At 21 days, clonidine withdrawal triggered rebound hypertension together with impaired endothelium-dependent relaxation, increased GRK2 activity, and reduced Akt/endothelial NO synthase (eNOS)/NO production in aortas. Conversely, withdrawal of the combination clonidine/GRK2-inhibitor treatment did not cause rebound hypertension, and normal induction of endothelium-dependent relaxation, decreased GRK2 activity, and increased Akt/eNOS were observed in aortas from DM mice. These results suggest that suppression of GRK2 activity affects rebound hypertension-associated vascular endothelial dysfunction by targeting the Akt/eNOS signaling pathway.

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The present work was supported, in part, by JSPS KAKENHI (Grant Numbers JP15K07975 and JP17K08318). We thank Mari Hida for technical support. We also thank Enago for the English language review.

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Correspondence to Tsuneo Kobayashi.

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