Noninvasive estimates of the inodilatory effects of isoprenaline and their inhibition by transdermally delivered mepindolol in healthy men

Abstract

We analyzed the reproducibility and sensitivity of noninvasive estimates of cardiovascular performance (impedance cardiography and systolic time intervals) to detect and describe the inodilatory responses to isoprenaline (ISO) and their attenuation by transdermally applied mepindolol. The responses to 5-min intravenous (i.v.) infusions of 1 microgram/min ISO in 9 young male healthy volunteers were evaluated repeatedly before and at the end of chronic treatments with daily applied TSD skin patches for transdermal drug delivery with either mepindolol or placebo (double-blind randomized cross-over design). ISO caused a clear increase in mean heart rate (HR), systolic blood pressure (SBP), maximum velocity of impedance changes, estimated stroke volume (SV), and the Heather index, and a reduction in diastolic BP (DBP), estimated systemic vascular resistance (SVR), and a shortening of all systolic time intervals (STIs). These responses were effectively blunted at the end of 1-week treatment with mepindolol TSD patches. Despite overall good agreement of the mean baseline data (under placebo), their within-subject reproducibility nevertheless was too weak to guarantee adequate power to detect small changes under active treatment. Reproducibility of the ISO responses was quite poor, although in a method-independent way. The methods used allowed us to describe the cardiac and vascular components of the ISO responses with adequate detail. Transdermally delivered mepindolol was shown to block ISO responses effectively, but the overall variability of the responses was too large to detect slight changes in them, although the methods in themselves did not appear to be the main cause of this lack of sensitivity.