Our findings suggest that augmentation index may be a useful marker of cardiovascular risk. Further studies are required to investigate the relationship between age and augmentation index in subjects with atherosclerotic disease.

Pulse wave velocity (PWV) and augmentation index are widely used measures of arterial stiffness. The purpose of this study was to evaluate the role of blood pressure as a determinant of both indices independent of potentially confounding factors including gender, age and cardiovascular disorders. A total of 77 young, healthy subjects were investigated under resting conditions. Augmentation index was derived by pulse wave analysis using carotid applanation tonometry. PWV was determined from pressure tracing over the carotid and femoral artery. The relations between stiffness markers and haemodynamic parameters were analysed by simple (r) and multiple (b) regression analysis. Using simple regression analysis, augmentation index was correlated to age (r ¼ 0.292, P ¼ 0.0105), diastolic blood pressure (DBP, r ¼ 0.483, Po0.0001), mean arterial blood pressure (MAP, r ¼ 0.381, P ¼ 0.0007), pulse pressure (r ¼ À0.414, P ¼ 0.0002) and total peripheral resistance (r ¼ 0.266, P ¼ 0.0204). After multiple regression analysis, augmentation index remained significantly correlated only to DBP (b ¼ 0.347, P ¼ 0.0051). Using simple regression analysis, PWV was correlated to age (r ¼ 0.304, P ¼ 0.0067), systolic blood pressure (r ¼ 0.280, P ¼ 0.0129). DBP (r ¼ 0.455, Po0.0001), MAP (r ¼ 0.446, Po0.0001) and heart rate (r ¼ 0.348, P ¼ 0.0018). After multiple regression analysis, PWV remained correlated only to age (b ¼ 0.218, P ¼ 0.0422) and DBP (b ¼ 0.4105, P ¼ 0.0316). In summary, DBP is an important determinant of augmentation index and PWV in young, healthy males. Further studies are needed to characterize the impact of blood pressure on arterial stiffness in other populations including females and older subjects.

This study aimed firstly to compare the in vivo cardiovascular effects of exogenously administered and of endogenously released noradrenaline; secondly to characterize the adrenoceptors mediating these responses; thirdly to assess the influence of parasympathetic tone on the cardiovascular effects of noradrenaline. In two randomised placebo-controlled studies, healthy, young, male volunteers received intravenous (i.v.) infusions of noradrenaline at six incremental doses of 10-160 ng/kg/min and-in order to release endogenous noradrenaline-tyramine at four incremental doses of 5-20 micrograms/kg/min. Noradrenaline and tyramine were administered in the absence and presence of alpha 1-adrenoceptor blockade with doxazosin (2 mg p.o.), alpha 2-adrenoceptor blockade with yohimbine (15 mg p.o.), selective beta 1-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (1.5 micrograms/kg i.v. loading dose followed by 0.15 microgram/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (Pdiast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS2c). I.v. noradrenaline increased Pdiast (delta max 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS2c (delta max -22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by biosprolol. I.v. tyramine reduced Pdiast (delta max -7 mmHg), which was not affected by alpha 1-adrenoceptor blockade, and profoundly shortened QS2c (delta max -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (Psyst) (delta max 57 mmHg). The shortening of QS2c and the rise in Psyst were not influenced by alpha-adrenoceptor blockade but were antagonized by bisoprolol. Atropine potentiated the blood pressure rise and the shortening of QS2c induced by i.v. noradrenaline and converted the fall in Pdiast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by alpha 1-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by beta 1-adrenoceptor-mediated positive inotropic effects. The rise in Psyst with i.v. tyramine most likely reflects positive inotropism and not a vascular "pressor' response.

No abstract

Aims Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear. Methods We studied the effects of the ET A -selective antagonist BQ-123 and the ET Bselective antagonist BQ-788 (both 10 induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler¯owmetry and double injection technique.Results BQ-123 caused a dose-dependent vasodilatation (maximum effect:+949t84 AUC-PU, P<0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: x388t96 AUC-PU, P<0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10AUC-PU vs ET alone, P<0.001), followed by noradrenaline (maximim effect at 10 x16 M:+580t107 AUC-PU vs NA alone, P<0.01) and angiotensin II (maximim effect at 10 x14 M:+493t111 AUC-PU vs AT alone, P<0.001). Conclusions ET A -selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This bene®cial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.

Aims A radioreceptor assay has been developed for a 1 -adrenoceptor subtypes and applied to a pharmacokinetic analysis of tamsulosin and terazosin. Methods Young, male, healthy volunteers received 0.4 mg tamsulosin (as OmnicA modified release capsules) or 5 mg terazosin (as FlotrinA tablets) in a randomized, cross-over design. Before and after 1, 3, 5, 7, 10 and 23.5 h plasma was analyzed by radioreceptor assay using cloned human a 1A -, a 1B -and a 1D -adrenoceptors and specific h.p.l.c. analysis. Results Following ingestion of tamsulosin median peak plasma levels of 16 ng ml −1 were reached after 5 h and declined to 2 ng ml −1 at 23.5 h. The time course in the radioreceptor assay was similar, and at most time points binding to a 1A -adrenoceptors was significantly greater than to a 1B -and a 1D -adrenoceptors. Following ingestion of terazosin median peak plasma levels of 91 ng ml −1 were reached after 1 h and declined to 11 ng ml −1 at 23.5 h. In the radioreceptor assay binding also peaked at 1 h and declined thereafter, but even after 23.5 h considerable binding activity remained detectable at all three subtypes. At most time points binding to the a 1A -and a 1D -adrenoceptor was significantly greater than to the a 1B -adrenoceptor.Conclusions We conclude that a 1 -adrenoceptor antagonist pharmacokinetics can be monitored by radioreceptor assays in a subtype-selective manner. Tamsulosin and terazosin exhibit subtype selective receptor binding ex vivo. The discordance between terazosin blood levels as determined by h.p.l.c. and radioreceptor assay at late time points indicates the possible involvement of metabolites in in vivo terazosin effects.

The safety and efficacy of telmisartan found in controlled studies is maintained in a large postmarketing population that included sizeable patient subgroups potentially at higher risk for adverse events.

A C825T polymorphism was recently identified in the gene for the G-protein beta3 subunit, the T-allele being associated with hypertension. To better understand the underlying pathophysiological mechanisms, we compared the haemodynamics of young healthy males with and without the T-allele. In three studies, subjects were investigated with regard to cardiac and vascular function at rest and following intravenous administration of the beta-adrenoceptor antagonist, propranolol, and the alpha2-adrenoceptor agonist, alpha-methylnoradrenaline, and with regard to local venous vasoconstriction in the dorsal hand vein in situ following infusion of the alpha2-adrenoceptor agonist, azepexol. alpha2-Adrenoceptor agonists were chosen as vasoconstrictor drugs since alpha2-adrenoceptors couple to pertussis toxin (PTX)-sensitive G-proteins and since in-vitro studies have demonstrated enhanced signal transduction of PTX-dependent pathways in the presence of the T-allele. Total peripheral resistance was determined as a parameter of vasoconstrictor tone and heart rate, stroke volume and systolic time intervals for cardiac function. T-allele carriers had a significantly elevated stroke volume and lower total peripheral resistance at baseline. After propranolol, their fall in stroke volume was significantly greater. During alpha-methylnoradrenaline infusion, elevation of total peripheral resistance was not increased relative to controls. Similarly, the constriction response of the dorsal hand vein to azepexol was not different. Our study does not support the idea of increased vasoconstrictor tone in T-allele carriers either at rest or during stimulation of alpha2-adrenoceptors. However, this allele may be associated with elevated cardiac stroke volume.