Effect of pretreatment with the selective β1-adrenoceptor antagonist bisoprolol on the subsequent cardiovascular actions and β-adrenoceptor subtype specific occupancy of celiprolol in healthy man

Abstract

The cardiovascular effects at rest and during exercise and beta 1- and beta 2-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p.o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p.o., using a placebo-controlled, 2-way cross-over design. The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median beta 1-RRA and beta 2-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to beta 1-adrenoceptors, moderately to beta 2-adrenoceptors, acts as beta 1-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect beta 1-adrenergic agonism, but which might reflect beta 2-adrenergic agonism.

Method specificity of the auscultatory estimates of the inodilatory reduction of diastolic blood pressure based on Korotkoff IV and V criteria.

“…increases in systolic forward pump performance associated with systemic peripheral vasodilatation. The overall inodilatory profile of eating [13], isoprenaline [19,20], PDE-III inhibition [21,22] and high doses of celiprolol [23] observed here, confirms previous findings with similar methods in similar populations. In the presence of such inodilatory changes, DBPkv and DBPkIv estimates were found to disagree substantially, the former estimating far larger DBP reductions and less efficient BP-homeostasis (on the basis of MBP) than the latter.…”

Do saw palmetto extracts block human?1-adrenoceptor subtypes in vivo?

“…The primary indicator of in vivo a 1 -adrenoceptor antagonism in our study was a recently developed radioreceptor assay which uses cloned human a 1A -, a 1B -, and a 1D -adrenoceptors as the receptor source [12]. Radioreceptor assays have primarily been developed for studies of b-adrenoceptor antagonists [16,17,19,20], but have also been adapted to studies of muscarinic acetylcholine receptors [18], angiotensin II receptors (21) and a 1 -adrenoceptors [12,23]. These assays have several advantages relative to classical pharmacokinetic techniques such as HPLC.…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…This approach even allows for the construction of Schild plots, which otherwise can only be done for in vitro assays, to determine drug affinity in vivo. Moreover, such radioreceptor assays can be seen as a more relevant way to study pharmacokinetics, and this has been validated against classic pharmacokinetic measurements not only for ARBs (Malerczyk et al, 1998) but also for antagonists at other types of receptors such as adrenoceptors (Wellstein et al, 1988;de Mey et al, 1993;Taguchi et al, 1998).…”