title: Investigations into the mechanism of the antihypertensive effect of SGB-1534, a novel alpha 1-adrenoceptor antagonist, in rats.
abstract: Experiments in vitro and in vivo were undertaken to examine possible involvement of a central effect in the hypotensive mechanism of SGB-1534. SGB-1534 selectively antagonized the contraction of isolated rat aortae to phenylephrine with a pA2 value of 10.57, 3.9 times higher than prazosin, and markedly displaced the alpha 1-adrenoceptor ligand 3H-prazosin (pKi: 8.81) in rat brain. In anesthetized spontaneously hypertensive rats (SHRs), SGB-1534 (0.3-3 micrograms/kg) and prazosin (3-30 micrograms/kg) given intravenously (i.v.) and intracerebroventricularly (i.c.v.) produced a dose-dependent and long-lasting depressor response associated with no change in heart rate (HR). The two drugs (i.c.v.), however, significantly attenuated the pressor response to i.v. noradrenaline. Single i.v. injections of SGB-1534, prazosin and yohimbine dose-dependently inhibited the St 587 (a highly specific and centrally acting alpha 1-adrenoceptor agonist) enhanced flexor reflex and the pressor response to i.v. phenylephrine in pithed rats. However, the activities of SGB-1534 and prazosin in inhibiting the St 587-enhanced flexor reflex were 16,000 and 660 times, respectively, less than those in attenuating the pressor response to i.v. phenylephrine. It seems that the hypotensive action of SGB-1534 is due to the peripheral alpha 1-adrenoceptor antagonistic mechanism rather than the central one.
authors.affiliation: Department of Pharmacology, Fujigotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Aono
authors.forename: K
authors.initials: K
authors.lastname: Sakai
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D011799:Quinazolines; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D015016:Yohimbine; C042712:SGB 1534; D003000:Clonidine; D011224:Prazosin