Involvement of imidazoline-preferring receptors in regulation of sympathetic tone

Abstract We examined the contribution of imidazoline-preferring receptors (IPR) and α 2 -adrenoceptors at different levels of the central nervous system in the antihypertensive and sympathoinhibitory actions of rilmenidine in 2 conscious animal models, the spontaneously hypertensive rat (SHR) and the normotensive rabbit. In conscious SHRs, we compared the potency of rilmenidine and clonidine administered intravenously into the lateral cerebral ventricle, the cisterna magna, and into the subarachnoidal space of the thoracolumbar spinal cord. In SHRs, we found that rilmenidine was more potent and more effective by the intrathecal than the intracisternal route. By contrast, clonidine was most effective after administration into the cisterna magna. Intravenous administration of rilmenidine or clonidine induced dose-dependent and prolonged decreases in blood pressure and heart rate. Neither rilmenidine nor clonidine altered mean arterial pressure or heart rate when given into the lateral cerebral ventricle. These data suggest that in SHRs the spinal cord may be an important site for the antihypertensive action of rilmenidine. We therefore characterized the receptor type involved. We observed in conscious SHRs that intrathecal post-treatment with idazoxan, a mixed α 2 -adrenoceptor and IPR antagonist, abolished the antihypertensive effect of rilmenidine, whereas 2-methoxyidazoxan, a selective α 2 -adrenoceptor antagonist, caused only a partial reversal of the blood pressure effects of rilmenidine. These results suggest that rilmenidine acts mainly through IPR rather than α 2 -adrenoceptors in the spinal cord. In view of these findings, we compared the hypotensive actions of rilmenidine and clonidine, administered into the lateral cerebral ventricle, the cisterna magna, and the subarachnoid space of the thoracolumbar spinal cord in conscious normotensive rabbits. Both drugs were less potent and effective when administered intrathecally than intracisternally. These experiments suggest that the hypotensive action of rilmenidine and clonidine in the rabbit is mediated through receptors mainly located in the brainstem. Further, we found that idazoxan reversed the hypotensive action of rilmenidine more readily than 2-methoxyidazoxan. Surprisingly, both idazoxan and 2-methoxyidazoxan completely reversed the depressor effects of clonidine. Therefore, in the rabbit, rilmenidine acts through IPR located in the brainstem and clonidine acts predominantly through α 2 -adrenoceptors. In conclusion, our studies demonstrate that IPR are involved in the vasodepressor action of rilmenidine in both conscious SHRs and rabbits. However, although the main site of action of rilmenidine in SHRs may be located in the thoracolumbar spinal cord, in the rabbit it appears to be in the brainstem. The IPR selectivity for rilmenidine and the limited locations of this novel receptor may account for its good acceptability as a second-generation centrally acting antihypertensive agent.