: 1. Centrally acting imidazoline antihypertensive agents clonidine and moxonidine also act peripherally to contract blood vessels. While these agents act at both I(1)-imidazoline and alpha 2 adrenergic receptors centrally, the receptor types by which they mediate contraction require further definition. We therefore characterized the receptor subtype by which these agents mediate contraction of proximal rat-tail artery. 2. Dose-response curves were determined for phenylephrine and for several imidazoline ligands, using endothelium denuded, isolated ring segments, of tail arteries from adult male Sprague-Dawley rats. Ring segments were mounted on a force transducer with platinum wires and immersed in a tissue bath containing Krebs solution, to which drugs could be added. Signals were digitized and recorded by a computer. 3. Tail artery contractions expressed as a percent of contraction to 106 mM potassium were phenylephrine (96%), moxonidine (88%), clonidine (52%), and UK14304 (30%). Neither rilmenidine nor harmane caused contraction. Contraction of tail artery to moxonidine or clonidine could be blocked by alpha 1 antagonist urapidil or prazosin, and also by alpha 1A subtype selective antagonist WB4101. Schild plots were generated and a calculated pA2 value of 9.2 for prazosin in the presence of clonidine confirms clonidine as an agonist at alpha 1A receptors in proximal segments of rat-tail artery. 4. Our work suggests that clonidine and moxonidine are promiscuous compounds at micromolar concentrations and that harmane and rilmenidine are more selective compounds for in vivo imidazoline research.
Metabolic Syndrome X, characterized by insulin resistance, dyslipidemia, obesity, and hypertension, affects over 70 million Americans. Imidazoline drugs, such as moxonidine, are emerging therapeutic agents for conditions associated with Syndrome X. Studies from our laboratory showed a reduction in blood pressure when moxonidine was injected into the rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHR). Moxonidine also activated the insulin signaling cascade and increased glucose uptake in HEK 293T cells. Recently, we obtained a novel imidazoline compound, S43126. Interestingly, like moxonidine, S43126 reduced blood pressure in SHR rat model, whose effect was offset by I1‐imidazoline antagonist, efaroxan. However, S43126 showed no activity at the adrenoreceptors in rat tail artery. Immunoblotting analyses also showed that S43126 activated components of the insulin signaling pathway, such as protein kinase B (PKB/Akt) and insulin receptor substrates (IRS1/2), which were abolished by efaroxan. Furthermore, treatment of cells overexpressing cloned I1‐imidazoline receptor (IRAS) or siRNA‐silenced IRAS confirmed that the I1‐imidazoline receptor contributed to moxonidine and S43126 stimulation of the insulin signaling cascade. These results implicate S43126 and moxonidine as centrally acting antihypertensive agents that may regulate the insulin receptor signaling. This work is supported by NIH RO3DK067945‐01.
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