1. Studies were performed to evaluate whether chronic prazosin treatment alters the alpha 2-adrenoceptor function for orthostatic control of arterial blood pressure in conscious spontaneously hypertensive rats (SHR). 2. Conscious SHR (male 300-350 g) were subjected to 90 degrees head-up tilts for 60 s following acute administration of prazosin (0.1 mg kg-1 i.p.) or rauwolscine (3 mg kg-1 i.v.). Orthostatic hypotension was determined by the average decrease (%) in mean arterial pressure (MAP femoral) over the 60-s tilt period. The basal MAP of conscious SHR was reduced to a similar extent by prazosin (-23%(-)-26% MAP) and rauwolscine (-16%(-)-33% MAP). However, the head-up tilt induced orthostatic hypotension in the SHR treated with prazosin (-16% MAP, n = 6), but not in the SHR treated with rauwolscine (less than +2% MAP, n = 6). 3. Conscious SHR were treated for 4 days with prazosin at 2 mg kg-1 day-1 i.p. for chronic alpha 1-adrenoceptor blockade. MAP in conscious SHR after chronic prazosin treatment was 14% lower than in the untreated SHR (n = 8). Head-up tilts in these rats did not produce orthostatic hypotension when performed either prior to or after acute dosing of prazosin (0.1 mg kg-1 i.p.). Conversely, administration of rauwolscine (3 mg kg-1 i.v.) in chronic prazosin treated SHR decreased the basal MAP by 12-31% (n = 4), and subsequent tilts induced further drops of MAP by 19-23% in these rats. 4. The pressor responses and bradycardia to the alpha 1-agonist cirazoline (0.6 and 2 micrograms kg-1 i.v.), the alpha 2-agonist Abbott-53693 (1 and 3 micrograms kg-1 i.v.), and noradrenaline (0.1 and 1.0 micrograms kg-1 i.v.) were determined in conscious SHR with and without chronic prazosin pretreatment. Both the pressor and bradycardia effects of cirazoline were abolished in chronic prazosin treated SHR (n = 4) as compared to the untreated SHR (n = 4). On the other hand, the pressor effects of Abbott-53693 were similar in both groups of SHR, but the accompanying bradycardia was greater in SHR with chronic prazosin treatment than without such treatment. Furthermore, the bradycardia that accompanied the noradrenaline-induced pressor effect in SHR was similar with and without chronic prazosin treatment despite a 47-71% reduction of the pressor effect in chronic alpha 1-receptor blocked SHR.(ABSTRACT TRUNCATED AT 400 WORDS)

Abbott-81988 (A-81988) was selected from a series of related compounds as a highly potent and selective antagonist of angiotensin receptors. In the rabbit aorta, A-81988 exhibited a pA2 of 10.12 (+/- 0.08) vs. angiotensin-II, for type 1 receptors (AT1), and the antagonism appeared competitive. These results agreed with radioligand assays in which A-81988 inhibited the binding of [125I]-Sar1-Ile8-Angiotensin-II to rat liver membranes with a pKI of 9.12 (+/- 0.63). A-81988 was selective for AT1 receptors based on its lack of activity at other sites, such as aortic alpha 1 receptors. Moreover, A-81988 lacked affinity for AT2 receptors of bovine cerebellar membranes or for alpha or beta adrenergic receptors in binding assays. A-81988 lowered blood pressure significantly in vivo in renal artery-ligated rats at doses of 0.3 mg/kg administered either i.v. or p.o. The compound was rapidly and almost completely absorbed from the duodenum of anesthetized rats and demonstrated very low first-pass metabolism in the rat liver. These properties of selectivity toward and potency for antagonizing AT1 receptors, activity in lowering blood pressure in experimental animals, and favorable pharmacokinetic properties indicate that A-81988 should be a useful antihypertensive agent in man.