Influence of the adrenal gland on the pressor effect and antagonistic potency of angiotensin II analogs.

In ganglion blocked vagotomized rats, several 1,8-substituted angiotensin II analogs (250 ng/kg/min, i.v.) antagonized the pressor effect of angiotensin II. Dose ratios measured at the ED20 levels were: [Sar1,Ile8]-28; [Gac1,Ile8]- 19;[MeAla1,Ile8i1- 16;[MeIle1,Ile8]- 10;[sar1,Ala8]- 9;[me2Gly1,Ile8]- 4. Elimination of aspajtic acid in position 1 of [Ile8]-angiotensin II significantly reduced the antagonistic potency of the analog. No antagonistic effect was observed with [Phe4,Ile8] and [Ala4,Ile8]-angiotensin II even when infused at 6 mug/kg/min. During infusion, a partial rise in blood pressure was observed with all the above 1,8-substituted angiotensin II analogs. Phentolamine (100 mug/rat) injected 30 min after the start of the analog infusion reduced and sometimes abolished the pressor effect. However, phenoxybenzamine )Pbz, 2 mg/kg) injected 30 min prior to the analog infusion diminished but did not completely abolish the initial pressor effect. In adrenalectomized rats, the pressor effect was reduced by approximately 50 percent and disappeared completely 15-30 min after start of the infusion. Under these conditions, dose ratios of [Sar1,Ile8]-,[MeAla1,Ile8]- and [Gac1,Ile8]-angiotensin II were significantly reduced. Noradrenaline, 83 ng/kg/min. increased the ED20 value of angiotensin II(ratio 1.79) in normal rats but did not do so in adrenalectomized rats. In these rats no regular correlation was found between the angiotensin II ED20 values and initial blood pressure. These data indicate that under the present experimental conditions, the low pressor effect observed with these angiotensin II antagonists appears to be due to both adrenal catecholamine release and a direct vasoconstrictor effect. Variations in antagonistic activity of angiotensin II analogs, apart from changes introduced in the molecule, may be the manifestation of a complex interaction between angiotensin II, its antagonists, and the sympathoadrenal system.