Evidence for Synergy Between 2-Adrenergic and Nonadrenergic Mechanisms in Central Blood Pressure Regulation

Background—Both 2-adrenergic and non– 2-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). Methods and Results—LNP 509, which appeared in this study to be devoid of 2A-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46 4% and 16 2%, respectively. In D79N mice, which lack functional 2A-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17 2%. The hypotension induced by LNP 509 (100 g/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I1-imidazoline binding sites (I1BS). A synergy between LNP 509 and the 2-adrenergic agonist -methylnoradrenaline ( -MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ventricle injection) but not, as expected, in D79N mice. Similar to LNP 509 alone, rilmenidine (fourth ventricle injection), which binds both to 2-adrenergic receptors and to I1BS, decreased BP in D79N mice. In WT animals, rilmenidine had a significantly greater effect. Microinjections performed in rabbits showed that the synergism occurred at least in part in the nucleus reticularis lateralis of the brain stem. Conclusions—These results demonstrate that a central imidazoline-sensitive, but non– 2-adrenergic, mechanism can modify BP by itself. This mechanism, which may involve I1BS, interacts synergistically with an 2-adrenergic mechanism to decrease BP. (Circulation. 2002;105:1116-1121.)