The role of serotonin-1A receptor activation and alpha-1 adrenoceptor blockade in the hypotensive effect of 5-methyl-urapidil.
Our study had three purposes: 1) to determine whether 5-methyl-urapidil, topically applied to the ventrolateral medulla, produces hypotension by activating serotonin-1A (5-HT1A) receptors, 2) to determine whether 5-methyl-urapidil given i.v. produces hypotension in part by activating 5-HT1A receptors in the ventrolateral medulla, and 3) to determine the specific site within the ventrolateral medulla where 5-methyl-urapidil elicits a hypotensive response. In terms of the first purpose, 5-methyl-urapidil applied bilaterally to the intermediate area of the ventral surface of the medulla (1.2 micrograms/side) of chloralose-anesthetized cats produced a decrease in mean arterial pressure of -39 +/- 4 mm Hg (N = 8). Prior blockade of 5-HT1A receptors at this site with bilateral application of spiperone (30 micrograms/side) prevented the hypotensive effect of 5-methyl-urapidil (mean blood pressure now increased by 5 +/- 4 mm Hg). Pretreatment with the alpha-1 adrenoceptor antagonist, prazosin, did not prevent the hypotensive effect of 5-methyl-urapidil. In terms of the second purpose, spiperone applied bilaterally to the ventral surface of the medulla counteracted a significant portion of the hypotensive effect of 5-methyl-urapidil given by the i.v. route. The dose of 5-methyl-urapidil given intravenously was below the dose that produces alpha-1 adrenoceptor blockade. In terms of the third purpose, microinjection of 5-methyl-urapidil into central nervous system sites associated with the intermediate area was found to have its greatest hypotensive effect at the subretrofacial nucleus. Mean arterial pressure decreased by 74 +/- 14 mm Hg (N = 3) after bilateral microinjection of 25 ng of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Mandal
A K
AK
Department of Pharmacology, Georgetown University School of Medicine, Washington, D.C.
Kellar
K J
KJ
Gillis
R A
RA
D000287:Administration, Topical; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced*; D007275:Injections, Intravenous; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects; D008845:Microinjections; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D013134:Spiperone / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011985:Receptors, Serotonin; C057446:5-methylurapidil; D013134:Spiperone