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(Circulation. 2002;105:1116.)
© 2002 American Heart Association, Inc.

Basic Science Reports

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

Véronique Bruban, PhD^*; Vanessa Estato, PhD^*; Stephan Schann, PhD; Jean-Daniel Ehrhardt, PhD; Laurent Monassier, MD, PhD; Pierre Renard, PhD; Elizabeth Scalbert, PhD; Josiane Feldman, PhD; Pascal Bousquet, MD, PhD

From the Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (V.B., S.S., J.-D.E., L.M., J.F., P.B.), Faculté de Médecine, Université Louis Pasteur, Strasbourg, France; the Departamento de Fisiologia e Farmacodinâmica (V.E.,), Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; and Institut de Recherches Internationales Servier (P.R., E.S.), Courbevoie, France.

Correspondence to Pascal Bousquet, MD, PhD, Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, 11 rue Humann, 67000 Strasbourg, France. E-mail Pascal.Bousquet{at}medecine.u-strasbg.fr

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 µg/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.

Key Words: nervous system, sympathetic • hypertension • pharmacology • receptors, adrenergic, alpha

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