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The a1- and a2-adrenoreceptor types are defined in terms of the selective binding of radioligands and their displacement from membrane preparations by a range of agonists and antagonists. Their distribution is described in brain, kidney, heart, and peripheral blood vessels. A group of centrally acting clonidine-like drugs are classified in terms of their selectivity for the a2-adrenoreceptors, and it is suggested that differences between a-adrenoreceptors in various tissues may allow development of highly selective a2-adrenoreceptor agonists for specific tissue sites such as the juxtaglomerular cells and brainstem nuclei controlling blood pressure. It is further suggested that the aim of treatment with such compounds is to modulate adrenergic activity while retaining normal homeostatic mechanisms. For this purpose, competitive agonists and antagonists are preferable to compounds which bind irreversibly to the receptor.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in < 2 h after dosing with an elimination t1/2 of 1–2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5–8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked ∼0.5 h later than perindopril, with an elimination t1/2 of ∼2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2–8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in pre-dose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5–7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.

The centrally acting α-adrenoceptor agonists clonidine, lofexidine, and S3341 vary in their selectivity for the α2-adrenoceptor subtype (S3341 > clonidine > lofexidine). The aim of this study was to examine the frequency and duration of rapid eye movement (REM) sleep episodes, and the cardiovascular changes associated with these episodes, during and after the continuous (10-day) infusion of saline (0.9 wt/vol), clonidine (10 μg/kg/h), lofexidine (10 μg/kg/h), or S3341 (50 or 100 μg/kg/h) in unrestrained, chronically instrumented rats. During a typical 24-h period, the saline infusion animals (n = 4) had 46 ± 3 REM sleep episodes of 2.4 ± 0.1 min duration. The majority of these episodes were associated with relatively minor phasic and tonic changes in arterial blood pressure and heart rate. During infusion, the three drugs markedly reduced the cardiovascular and behavioural signs of REM sleep. On cessation of the clonidine and lofexidine infusions, rebound increases (i.e., to values greater than controls) in the frequency and duration of REM sleep episodes were observed. These episodes were associated with markedly exaggerated fluctuations in arterial blood pressure and heart rate. The REM sleep rebound and associated cardiovascular responses were greater during the post-lofexidine infusion phase. A relatively minor rebound increase in total REM sleep time was observed after cessation of the 100-μg/kg/h, but not the 50-μg/kg/h, infusion rate of S3341. The cardiovascular responses during the REM sleep episodes were mildly exaggerated after cessation of the higher infusion rate of S3341. These results indicate that the magnitude of the REM sleep rebound (lofexidine > clonidine > S3341) may be inversely related to α2-adrenoceptor selectivity. As such, the α1-adrenoceptor activities of the clonidine and lofexidine infusions may underlie the subsequent rebound phenomenon.