alpha-2-Adrenergic activation of proopiomelanocortin-containing neurons in the arcuate nucleus causes opioid-mediated hypotension and bradycardia.
Treatment of rats for 4 days with alpha-methyldopa, 200 mg/kg/day i.p., increases steady state levels of proopiomelanocortin (POMC) mRNA in the mediobasal hypothalamus, as measured by DNA excess solution hybridization. The increase is prevented by parallel treatment with yohimbine, 2 mg/kg/day i.p., but not by naltrexone, 2 mg/kg/day i.p. Treatment with the peripheral vasodilator hydralazine, 2 mg/kg/day, does not affect POMC mRNA levels. In situ hybridization histochemistry with a cRNA probe for POMC indicates that POMC-containing cells are located within the confines of the arcuate nucleus both in control and in alpha-methyldopa-treated rats, and confirms the increase in POMC mRNA in the latter. Microinjection of 2 micrograms of alpha-methylnorepinephrine unilaterally into the arcuate nucleus of urethane-anesthetized rats causes hypotension and bradycardia, which can be inhibited by 200 ng of yohimbine microinjected into the same site, or by 100 ng l-naloxone microinjected into the ipsilateral nucleus tractus solitarii, but not into the arcuate nucleus. These findings are interpreted to indicate that activation of alpha 2-adrenergic receptors located on POMC-containing neurons in the arcuate nucleus causes beta-endorphin release and stimulation of opiate receptors in the NTS, which results in hypotension and bradycardia, and that this mechanism contributes to the hypotensive action of alpha-methyldopa.
Li
S J
SJ
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
Scanlon
M N
MN
Járai
Z
Z
Varga
K
K
Gantenberg
N S
NS
Lazar-Wesley
E
E
Kunos
G
G
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000503:physiopathology*; D001919:Bradycardia / Q000139:chemically induced* / Q000503:physiopathology; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D017403:In Situ Hybridization; D008297:Male; D008750:Methyldopa / Q000494:pharmacology; D008845:Microinjections; D009474:Neurons / Q000502:physiology*; D008771:Nordefrin / Q000008:administration & dosage / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology; D001615:beta-Endorphin / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D008750:Methyldopa; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D008771:Nordefrin