beta 1-Blockade of nebivolol 5 mg is larger after repeated dosing than after a single oral intake. After once daily repeated dosing nebivolol 5 mg and atenolol 25 mg are equipotent in beta 1-antagonism. No difference in beta 1-selectivity is observed between the two drugs. Nebivolol has no additional alpha 1-blocking property, which may at least in part explain its vasodilating effect.

Aims To investigate the peripheral vascular effects and pharmacokinetics of dihydroergotamine (DHE) 0.5 mg after a single subcutaneous administration in humans. Methods A double-blind, placebo-controlled cross-over study was performed in 10 healthy male subjects. A wash-out period of 2 weeks separated the two study periods. During each period, just before and at regular intervals after drug administration, vascular measurements were performed and venous blood samples were drawn. Vessel wall properties were assessed at the brachial artery, by ultrasound and applanation tonometry. Blood pressure and heart rate were recorded with an oscillometric device. Forearm blood¯ow was measured with venous occlusion plethysmography. For all parameter-time curves the area under the curve (AUC) was calculated. Differences in AUC after placebo and DHE (DAUC) were analysed and the time-course of the difference assessed. DHE pharmacokinetics were analysed according to a two-compartment open model with an absorption phase. Results AUC for blood pressure, heart rate and forearm vascular resistance did not change after DHE. Brachial artery diameter and compliance decreased (P<0.01); DAUC (95% con®dence interval) equalled x8.81 mm h (x12.97/x4.65) and x0.98 mm 2 kPa x1 h (x1.61/x0.34), respectively. Diameter decreased (P<0.05) from 1 until 24 h after DHE (peak decrease 9.7% at 10 h); compliance from 2 until 32 h (24.8% at 2 h). Time to reach maximum plasma concentration of DHE averaged 0.33t0.08 h (ts.e.mean); terminal half-life was 5.63t1.15 h. Conclusions DHE decreased diameter and compliance of the brachial artery whereas forearm vascular resistance remained unchanged. Thus, DHE acts on conduit arteries without affecting resistance arteries. Furthermore, a discrepancy was demonstrated between the plasma concentrations of DHE which rapidly reach peak levels and quickly decline, and its long lasting vasoconstrictor activity.

Selective 5-HT1B/1D-receptor agonists induce vasoconstriction and decrease compliance of conduit arteries. These effects are more pronounced at muscular (temporal, brachial) compared with elastic (carotid) arteries. Resistance is only increased at the temporal artery vascular bed, suggesting cranioselectivity for resistance vessels. Endothelial function is not differently affected by any of the triptans tested.

AimsTo assess the reproducibility of the forearm blood flow (FBF) response to intra-arterial infusion of calcitonin-gene related peptide (CGRP), measured by venous occlusion plethysmography. In addition, to compare different ways of expressing the F BF response and perform sample size calculations. MethodsOn two separate visits, CGRP (10 ng min -1 dl -1 forearm) was infused for 45 min into the brachial artery of six healthy subjects. Reproducibility was assessed by calculating mean difference, repeatability coefficient, within-subject coefficient of variation (WCV) and intraclass correlation coefficient. ResultsCGRP increased FBF from 2.8 ± 0.4 and 3.2 ± 0.7 (at baseline) to 15.4 ± 1.4 and 15.2 ± 1.5 ml min -1 dl -1 forearm (at 45 min) on visits 1 and 2, respectively ( P < 0.0001 for both visits). Mean difference in FBF at 45 min between both visits was 0.3 ml min -1 dl -1 forearm (repeatability coefficient: 4.1 ml min -1 dl -1 forearm). This FBF response appeared to be more reproducible when expressed as absolute FBF in the infused arm (WCV 11%) compared with absolute FBF-ratio between both arms (WCV 37%), percentage change from baseline in FBF in the infused arm (WCV 29%) and percentage change from baseline in FBF-ratio (WCV 40%). When expressed as absolute FBF, a sample size of five (95% confidence interval: 2-12) subjects gives 90% power at a type I error probability of 0.05 to detect a 25% shift in FBF response. ConclusionsIntra-arterial infusion of CGRP results in a forearm vasodilator response which is reproducible between days. This response is most reproducible when expressed as absolute FBF. The presented methodology provides a suitable pharmacodynamic model to assess the in vivo activity of CGRP-receptor antagonists in a small number of subjects.