Aims We attempted to explore the possible differential involvement of badrenoceptor subtypes in the dilator response of the human dorsal hand vein to isoprenaline by examining the ability of bisoprolol, a selective b 1 -adrenoceptor antagonist, and nadolol, a nonselective b 1 /b 2 -adrenoceptor antagonist, to antagonize the response. Methods Twelve healthy male volunteers participated in four weekly sessions. In the preliminary session a dose-response curve to the vasoconstrictor effect of phenylephrine was constructed and the dose producing 50±75% maximal response was determined for each individual. In each of the remaining three (treatment) sessions, nadolol (40 mg), bisoprolol (5 mg) or placebo was ingested, and isoprenaline hydrochloride (3.33±1000 ng min x1 ) was infused locally into the dorsal hand vein along with a constant dose of phenylephrine hydrochloride (to preconstrict the vein) 2 h after the ingestion of the drugs. Changes in vein diameter were monitored with the dorsal hand vein compliance technique. Subjects were allocated to treatment session according to a double-blind balanced cross-over design. Systolic and diastolic blood pressure, and heart rate were also measured. Results Isoprenaline produced dose-dependent venodilatation which was antagonized by nadolol but remained unaffected by bisoprolol (ANOVA with repeated measures: P<0.025; Dunnett's test: placebo vs nadolol, P<0.01; placebo vs bisoprolol, P=NS). Mean log ED 50 (ng min x1 ) was signi®cantly increased in the presence of nadolol and remained unchanged in the presence of bisoprolol (ANOVA, P<0.025; Dunnett's test: placebo vs nadolol, P<0.005; placebo vs bisoprolol, P=NS; differences between mean log ED 50 [95% CI]: placebo vs bisoprolol x0.11 [-0.38, 0.16

We have measured the diameter of the human dorsal hand vein (DHV) in situ and compared the venoconstrictor dose-response curves to locally infused noradrenaline at different venous congestion pressures using the DHV compliance technique. Congestion pressure was defined as the inflation pressure of a sphygmomanometer cuff on the ipsilateral upper arm. Male healthy volunteers (20-45 years) participated in two experimental sessions. In Session I, DHV diameter was measured at congestion pressures of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 mmHg. In Session II, venoconstrictor dose-response curves to six doses (0.1-33.33 ng min-1) of (-)noradrenaline acid tartrate were established at congestion pressures 30 and 45 mmHg. DHV diameter increased as a function of congestion pressure. The rate of increase in DHV diameter (mm/5 mmHg) declined at higher values of congestion pressure (e.g. 0.14 mm/5 mmHg between 20 and 45 mmHg, and 0.04 mm/5 mmHg between 45 and 70 mmHg). Noradrenaline was less potent at 45 mmHg than at 30 mmHg. Mean log ED50 was significantly greater at 45 mmHg than at 30 mmHg congestion pressure, while mean E(max) did not differ at the two congestion pressures. The geometric mean ED50 was approximately 195% greater at 45 mmHg than at 30 mmHg. These results show that DHV diameter is positively related to congestion pressure, and that as the congestion pressure increases, the apparent sensitivity of the vein to the venoconstrictor effect of noradrenaline decreases. This latter finding is consistent with the physiological antagonism between congestion-induced venodilatation and noradrenaline-evoked venoconstriction. It is recommended that a standard congestion pressure is used in order to facilitate the comparison of results obtained in different laboratories.

Aims The aim of this study was to examine the effects of bisoprolol (BIS), a selective b 1 -adrenoceptor antagonist without partial agonistic activity, on noradrenaline-and phenylephrine-evoked venoconstriction in man using the dorsal hand vein compliance technique. Methods Twelve healthy male volunteers participated in three weekly experimental sessions. Subjects were allocated to treatments and sessions on a double-blind basis. In each session either BIS 5 mg (BIS5), or BIS 10 mg (BIS10), or placebo was administered orally, and noradrenaline acid tartrate (0.1-33.33 ng min −1 ) followed by phenylephrine hydrochloride (0.033-10 mg min −1 ) was infused into the dorsal hand vein. Systolic and diastolic blood pressure and heart rate were also measured. Results Both noradrenaline and phenylephrine produced dose-dependent venoconstriction: the geometric mean ED 50 for noradrenaline was 3.21 ng min −1 and for phenylephrine 135.04 ng min −1; the potency ratio (noradrenaline/phenylephrine) was 42. Both BIS5 and BIS10 significantly decreased the venoconstriction to noradrenaline (ANOVA; P<0.005), and to phenylephrine (ANOVA; P<0.001).The antagonism of the venoconstrictor responses was also reflected in a significant increase in logED 50 values for both noradrenaline (ANOVA; P<0.005), and phenylephrine (ANOVA; P<0.0025) in the presence of both doses of BIS. Both doses of BIS significantly decreased heart rate (ANOVA; P<0.0001), and systolic blood pressure (ANOVA; P<0.0025). Conclusions Bisoprolol can antagonize a 1 -adrenoceptor mediated venoconstriction in the human dorsal hand vein in vivo through a mechanism which remains to be elucidated.

AimsIn an attempt to explore the possible involvement of venodilator b-adrenoceptors in the constrictor response of the human dorsal hand vein to noradrenaline, we examined the ability of nadolol, a non-selective b 1 /b 2 -adrenoceptor antagonist, and bisoprolol a selective b 1 -adrenoceptor antagonist, to potentiate the response. Methods Twelve healthy male volunteers participated in three weekly sessions. In each session nadolol (40 mg), bisoprolol (5 mg ) or placebo was ingested, and (-) noradrenaline acid tartrate (0.33-33.33 ng min −1 ) was infused locally into the dorsal hand vein 2 h after the ingestion of the drugs. Changes in vein diameter were monitored with the dorsal hand vein compliance technique. Subjects were allocated to treatments and sessions according to a double-blind balanced cross-over design. Systolic and diastolic blood pressure, and heart rate were also measured. Results Noradrenaline produced dose-dependent venoconstriction which was antagonized by bisoprolol but remained unaffected by nadolol (ANOVA with repeated measures: F (2, In the present study we compared the effects of is generally acknowledged that venodilator b-adrenoceptors are of the b 2 subtype, the possible involvement of b 1 -pharmacodynamically active small single oral doses [18] of the non-selective b 1 /b 2 -adrenoceptor antagonist, nadolol adrenoceptors has not been excluded [9][10][11][12].The physiological sympathomimetic amine noradrenaline and the selective b 1 -adrenoceptor antagonist, bisoprolol on noradrenaline-evoked venoconstriction in man, using the has affinity for both a-and b-adrenoceptors [9]. Although noradrenaline is a powerful constrictor of the human dorsal dorsal hand vein compliance technique. Our prediction was that if the venoconstrictor response to noradrenaline is hand vein [13][14], it is possible that the constrictor response is attenuated by the activation of masked venodilator attenuated by masked b 2 -adrenoceptors, but not by b 1 -adrenoceptors, nadolol would potentiate the response but b-adrenoceptors. The possible involvement of these masked receptors could be revealed by the use of b-adrenoceptor bisoprolol would be without any effect. On the other hand, if both b 2 -and b 1 -adrenoceptors are involved both antagonists would cause potentiation of the response.

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