Objective: To evaluate the pharmacodynarnic properties of carvedilol across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol. Methodr: Twelve healthy male subjects were investigated on six separate occasions at least 1 week apart when they received either a single peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carvedilol, or placebo. The subjects were extensively profiled at supine rest, and they underwent supine bicycle ergometry before and at 2,4, 6,9, 12, and 22 hours after dosing. At these time points blood was drawn for the high performance liquid chromatographic determination of the enantiomers of carvedilol and for the radioreceptor assay determination of a,-and P,-adrenergic receptor binding and related concentrations. Results: Carvedilol was confirmed to bind to P,-adrenergic receptors and (albeit to a lesser extent) to a,-adrenergic receptors. Carvedilol furthermore attenuated the ergometric increase in heart rate in a closely dose-related fashion, which exemplified its P,-adrenergic receptor blocking effects. However, the basal efferent adrenergic drive might have been too low to show consistent a,-blocking properties. The radioreceptor and enantiomer kinetics were proportional with dose. There was no indication that the overall kinetic behavior of contributing active metabolites would differ from that of the S(-)-enantiomer. On average, there was a smooth linear relationship between the ergometric treatment responses and log-transformed dose, log-transformed concentrations of the S( -)-enantiomer, and the radioreceptor assay derived P,-adrenergic receptor occupancies. Conclztsion: The relative complexity of the kinetics of carvedilol (enantiospecific kinetics and dynamics, protein binding, and involvement of active metabolites) does not preclude relatively simple and straightforward dose-effect and kinetic-dynamic relationships.

This study compared cardiac stroke volumes using four noninvasive techniques in healthy volunteers: dual-beam Doppler echoaortography, electrical impedance cardiography, mechanosphygmography and M mode echocardiography of the left ventricle. Variations in stroke volume were induced by intravenous atropine in increasing doses and venous tourniquets in the absence and presence of propranolol. Biometrical analysis used correlations and principal components in order to find the common reality, reflected by the four techniques. Three of the four techniques showed good correlations between themselves as well as to the principal component. The correlation closest to the principal component was the electrical impedance cardiography (0.89) followed by the Doppler method (0.87) and the mechanosphygmography (0.84); the results from left ventricular echocardiography (0.66) were poorest. These results can be interpreted in the sense that the first three techniques are of good validity in the noninvasive assessment of stroke volume in man, and the selection of one of these techniques for use in a clinical study should depend on the study’s design and scope.

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