Investigations into the Mechanism of the Antihypertensive Effect of SGB-1534, a Novel α1-Adrenoceptor Antagonist, in Rats

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.