Unique presynaptic alpha 2-receptor selectivity and specificity of the antihypertensive agent moxonidine.
The characteristics of the alpha-receptor activating property of the new antihypertensive agent moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methyl-2-methyl-5-pyrimidinamine, BDF 5895) was studied using peripheral vasculature and brain membranes of various animals. Moxonidine exerted a full agonist effect in elevating diastolic blood pressure in the pithed rat. Activation of postsynaptic alpha 1- and alpha 2-receptors contribute to the vasoconstrictory effect in rats. In the vasculature of the rabbit, moxonidine was a full agonist at presynaptic alpha 2-receptors in inhibiting transmitter release induced by electrical stimulation of pulmonary artery strips. At postsynaptic sites, exogenously applied moxonidine was a full agonist at alpha 1-receptors in the isolated aorta, pulmonary artery and vena cava of the rabbit. Selectivity for alpha 2-receptors in the pulmonary artery was 106-fold. In rat brain membranes, moxonidine showed 288-fold greater selectivity for alpha 2-receptors, when the displacement of [3H]-rauwolscine was compared with the displacement of [3H]-prazosin. On the whole, clonidine exhibited greater potency than moxonidine on both alpha-receptor subtypes, but moxonidine consistently showed greater alpha 2-receptor selectivity than clonidine. In the guinea pig myocardium, moxonidine caused neither bradycardia nor tachycardia in the isolated right atrium and produced a negligible positive inotropic effect at 100 mumol/l in the isolated papillary muscle.
Armah
B I
BI
Department of Pharmacology, BDF Research Laboratories, Hamburg, Fed. Rep. of Germany.
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003000:Clonidine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D014684:Venae Cavae / Q000187:drug effects; D015016:Yohimbine / Q000378:metabolism
D000959:Antihypertensive Agents; D007093:Imidazoles; D008024:Ligands; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D015016:Yohimbine; C043482:moxonidine; D003000:Clonidine; D009638:Norepinephrine; D011224:Prazosin