The central hypotensive effect induced by alpha 2-adrenergic receptor stimulation is dependent on endothelial nitric oxide synthase.
OBJECTIVE
The aim of the present study was to determine whether the central antihypertensive effect of drugs that act via central alpha 2-adrenergic receptors is mediated by the nitric oxide-ergic system.


METHODS
The hypotensive effects of dexmedetomidine, a 'pure' alpha2-adrenergic agonist, were compared in endothelial nitric oxide synthase knockout and wild-type control mice.


RESULTS
When injected intravenously (5 mug/kg) in wild-type mice, dexmedetomidine elicited a depressor response (60 +/- 4 to 34 +/- 1 mmHg, P < 0.05), but had no hypotensive effect in endothelial nitric oxide synthase (eNOS) knockout mice (84 +/- 7 to 84 +/- 7 mmHg, P > 0.05). In the presence of N-omega-nitro-L-arginine, a nonselective nitric oxide synthase (NOS) blocker that does not cross the blood-brain barrier, the hypotensive effect of dexmedetomidine was not abolished (Delta MAP = 21 +/- 2 mmHg vs. Delta MAP = 26 +/- 3 mmHg, P > 0.05).


CONCLUSIONS
It is concluded that the central cardiovascular effects of alpha 2-adrenergic agonists, such as dexmedetomidine, require an intact expression of eNOS within the brain. This study raises the interesting question of whether central eNOS itself might be considered as a target for new cardiovascular drugs regardless of any activation of alpha 2-adrenergic receptors.
Feldman
Josiane
J
Laboratory of Neurobiology and Cardiovascular Pharmacology, INSERM U715, Faculty of Medicine, Louis Pasteur University, Strasbourg, France.
Fellmann
Lyne
L
Bousquet
Pascal
P
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000502:physiology*; D020927:Dexmedetomidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse