Evidence for synergy between alpha(2)-adrenergic and nonadrenergic mechanisms in central blood pressure regulation.
BACKGROUND
Both alpha(2)-adrenergic and non--alpha(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).


RESULTS
LNP 509, which appeared in this study to be devoid of alpha(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 alpha(2A)-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17 +/- 2%. The hypotension induced by LNP 509 (100 microg/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I(1)-imidazoline binding sites (I(1)BS). A synergy between LNP 509 and the alpha(2)-adrenergic agonist alpha-methylnoradrenaline (alpha-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 alpha(2)-adrenergic receptors and to I(1)BS, 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--alpha(2)-adrenergic, mechanism can modify BP by itself. This mechanism, which may involve I(1)BS, interacts synergistically with an alpha(2)-adrenergic mechanism to decrease BP.
Bruban
Véronique
V
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
Estato
Vanessa
V
Schann
Stephan
S
Ehrhardt
Jean-Daniel
JD
Monassier
Laurent
L
Renard
Pierre
P
Scalbert
Elizabeth
E
Feldman
Josiane
J
Bousquet
Pascal
P
D000322:Adrenergic Agonists / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology; D004357:Drug Synergism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D008771:Nordefrin / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D011941:Receptors, Adrenergic / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000077769:Rilmenidine; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
C431512:2-(2-fluoro-5-methylphenyl)-4,5-dihydro-1H-imidazole; D000322:Adrenergic Agonists; D000316:Adrenergic alpha-Agonists; D000959:Antihypertensive Agents; D003521:Cyclopropanes; D007093:Imidazoles; C427228:LNP 509; D010080:Oxazoles; D011758:Pyrroles; D011941:Receptors, Adrenergic; D018341:Receptors, Adrenergic, alpha-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000077769:Rilmenidine; D008771:Nordefrin