Quantitative assessment of the central versus peripheral effect of intravenous clonidine using baroreflex equilibrium diagrams

Toru Kawada,Keita Saku,Tadayoshi Miyamoto,Yohsuke Hayama,Takuya Nishikawa,Masaru Sugimachi,Can Zheng,Kazunori Uemura,Meihua Li

doi:10.1186/s12576-021-00824-y

Abstract

Clonidine is a first-generation central antihypertensive that reduces sympathetic nerve activity (SNA). Although clonidine also exerts peripheral vasoconstriction, the extent to which this vasoconstriction offsets the centrally mediated arterial pressure (AP)-lowering effect remains unknown. In anesthetized rats (n = 8), we examined SNA and AP responses to stepwise changes in carotid sinus pressure under control conditions and after intravenous low-dose (2 μg/kg) and high-dose clonidine (5 μg/kg). In the baroreflex equilibrium diagram analysis, the operating-point AP under the control condition was 115.2 (108.5–127.7) mmHg [median (25th–75th percentile range)]. While the operating-point AP after low-dose clonidine was not significantly different with or without the peripheral effect, the operating-point AP after high-dose clonidine was higher with the peripheral effect than without [81.3 (76.2–98.2) mmHg vs. 70.7 (57.7–96.9), P < 0.05]. The vasoconstrictive effect of clonidine partly offset the centrally mediated AP-lowering effect after high-dose administration.

Highlights

Clonidine is a first-generation antihypertensive agent that suppresses sympathetic outflow from the central nervous system by acting on α2-adrenergic and I1-imidazoline receptors [1,2,3]
The maximum arterial pressure (AP) was lower in S4 than in S2, the minimum AP was higher in S4 than in S2
The sympathetic nerve activity (SNA) was nearly silenced after high-dose clonidine

Summary

Introduction

Clonidine is a first-generation antihypertensive agent that suppresses sympathetic outflow from the central nervous system by acting on α2-adrenergic and I1-imidazoline receptors [1,2,3]. Rilmenidine and moxonidine preferentially act on I1-imidazoline receptors [1,2,3,4], thereby reducing side effects associated with central α2-adrenergic stimulation, such as dry mouth and sedation. Intravenously administered moxonidine increased AP at any given sympathetic nerve activity (SNA), suggesting that a peripheral effect of moxonidine significantly offset the centrally mediated AP-lowering effect [6]. Administered guanfacine exhibited a peripheral effect that nearly canceled the reduction of AP at the operating point of the arterial baroreflex [7]. Intravenously administered rilmenidine showed a weak vasoconstrictive effect that was unmasked by opening the baroreflex negative feedback loop [8]

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Discussion

Conclusion