13–15 The nonadrenergic component of the central hypotension induced by imidazoline-like drugs was afterward attributed to their ability to act at specific binding sites, insensitive to catecholamines, called imidazoline binding sites (IBS) and located in the NRL/RVLM region. This assumption was based on structure-activity relationship studies and on antagonism experiments. 5,11,12 Nevertheless, several groups have reported that a nonadrenergic mechanism also contributes to their hypotensive action. As a matter of fact, a large body of experimental data indicates that these drugs also activate α 2AARs to reduce BP. The mechanism of the central antihypertensive effects of imidazoline-related compounds appears more complex. This catecholamine is the active metabolite of α-methyldopa, and it reduces blood pressure (BP) in inhibiting the vasomotor tone by activating α 2ARs in the NTS. One unique mechanism of action explains the central hypotensive effect of the α 2-adrenergic agonist, α-methylnoradrenaline (α-MNA). 9 Experiments performed in D79N and α 2A-knockout mice have confirmed that α 2A is the α 2AR subtype that mediates the central effects of α 2AR agonists, including their hypotensive action. 8 Thus, D79N mice constitute functional α 2A-knockout animals. The mutation of Asp79 to Asn uncouples the α 2AAR from its transduction pathways in vivo. For example, D79N mice have a point mutation of the α 2aAR gene. 7 Gene-targeted mice have been engineered for each α 2AR subtype to determine the functional relevance of subtype diversity. 5 α 2ARs have been classified into 3 subtypes: α 2AAR, α 2BAR, and α 2CAR. 4 Thus, α 2AR agonists administered centrally cause hypotension. 2,3 They are known to mediate many effects, such as sedation, anesthetic-sparing response, analgesia, and sympathoinhibition. Α 2-Adrenergic receptors (α 2ARs) are distributed throughout the CNS, including the NTS and the NRL/RVLM. The nucleus tractus solitarii (NTS) and the nucleus reticularis lateralis of the rostral ventrolateral medulla (NRL/RVLM) are 2 nuclei that are highly involved in this control. The central nervous system (CNS) plays a key role in the regulation of cardiovascular function. This mechanism, which may involve I 1BS, interacts synergistically with an α 2-adrenergic mechanism to decrease BP. Microinjections performed in rabbits showed that the synergism occurred at least in part in the nucleus reticularis lateralis of the brain stem.Ĭonclusions- These results demonstrate that a central imidazoline-sensitive, but non–α 2-adrenergic, mechanism can modify BP by itself. In WT animals, rilmenidine had a significantly greater effect. Similar to LNP 509 alone, rilmenidine (fourth ventricle injection), which binds both to α 2-adrenergic receptors and to I 1BS, decreased BP in D79N mice. A synergy between LNP 509 and the α 2-adrenergic agonist α-methylnoradrenaline (α-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ventricle injection) but not, as expected, in D79N mice.

The hypotension induced by LNP 509 (100 μg/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I 1-imidazoline binding sites (I 1BS). In D79N mice, which lack functional α 2A-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17☒%.

Mean arterial pressure decreased by a maximum of 46±4% and 16☒%, respectively. Methods and Results- LNP 509, which appeared in this study to be devoid of α 2A-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). Customer Service and Ordering Informationīackground- Both α 2-adrenergic and non–α 2-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs.

Stroke: Vascular and Interventional Neurology.

Journal of the American Heart Association (JAHA).

Circ: Cardiovascular Quality & Outcomes.

Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).

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