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Beta-adrenergic receptor responsiveness to isoprenaline in humans: concentration-effect, as compared with dose-effect evaluation and influence of autonomic reflexes.

1. Different techniques of assessing beta-adrenoceptor sensitivity in vivo, by use of i.v. infusions or bolus injections of isoprenaline (ISO), were compared in healthy volunteers. The importance of autonomic reflexes for responses to ISO was evaluated by studying the influence of 'autonomic blockade' by atropine and clonidine, which antagonize muscarinic effects and reduce sympathetic activity, respectively. Estimates of in vivo responsiveness to ISO were compared with parameters reflecting beta 2-adrenoceptor function in vitro in lymphocytes. 2. Heart rate responses to infused ISO were not significantly altered by 'autonomic blockade' when evaluated from concentration-effect curves. When related to the infused dose of ISO, however, sensitivity was artefactually increased (P less than 0.05), as the plasma concentrations of ISO were 40% higher after atropine and clonidine. Heart rate responses to bolus injections of ISO were attenuated (P less than 0.05) by 'autonomic blockade', suggesting that facilitatory reflexes contribute to these non-steady state responses. Intersubject variations in heart rate responsiveness to ISO were greater than the intrasubject variability caused by counterregulatory reflexes. 3. 'Autonomic blockade' lowered venous plasma noradrenaline at rest. The noradrenaline response to ISO infusion was attenuated and the diastolic blood pressure response enhanced, indicating that a counterregulatory vasoconstrictor reflex normally is activated by ISO-induced vasodilatation. The plasma cyclic AMP response to ISO, on the other hand, was unaffected by atropine and clonidine and reflects beta 2-adrenoceptor responsiveness in vivo. 4. In vitro data for beta-adrenoceptor binding sites (Bmax;[125I]-IHYP binding) and cyclic AMP responses to ISO in lymphocytes correlated with DBP and noradrenaline responses to infused ISO. No correlations were found between in vitro data and heart rate, plasma cyclic AMP or plasma glycerol responses to infused ISO in vivo. 5. During prolonged ISO infusions (in six other healthy subjects) physiological responses reached greater than 90% of their steady state level after 8 min, but no definite steady state level could be defined for the plasma concentration of ISO during 40 min of infusion. 6. The ISO infusion test showed a good reproducibility, especially when repeated on the same day. Evaluation of plasma concentration-effect relationships increase the precision of the ISO infusion test as confounding inter- and intra-individual variations in ISO concentrations (as caused by e.g. autonomic blockade) will be taken into account.(ABSTRACT TRUNCATED AT 400 WORDS)