in atherosclerosis [7, 22C25]

in atherosclerosis [7, 22C25]. For a given vasoconstriction, a 10-fold higher dose of noradrenaline and angiotensin II was needed compared with ET. 814 93 AUC-PU ET only, < 0.001), followed by noradrenaline (maximim effect at 10?16 m: + 580 107 AUC-PU NA alone, < 0.01) and angiotensin II (maximim effect at 10?14 m: + 493 111 AUC-PU AT alone, < 0.001). Conclusions ETA-selective antagonism inhibits vasoconstriction to AT and NA in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic providers and inhibitors of the renin-angiotensin system. and (observe review [2]). Some of these ET-antagonists selectively inhibit ETA-receptors whereas others block both ETA-and ETB-receptors [2]. Furthermore, newer, nonpeptidic orally available molecules are in medical evaluation and have already been analyzed in individuals with hypertension, coronary artery disease and heart failure [9C11]. The pressor systems, i.e. SNS, RAS and endothelin system (ETS) have important relationships under experimental conditions. The interactions between the SNS and the RAS are well analyzed, while data on the effects of the ETS on SNS and RAS are lacking; ETA-selective antagonism with BQ-123 attenuates the constrictor effects of angiotensin II, but not noradrenaline [14]. Furthermore, ET mediates part of Ly93 the vasoconstriction to angiotensin II in smaller vessels, an effect that can be blocked with the ETA-selective antagonist BQ-123 [15]. No data exist so far in the human being circulation under conditions. These potential relationships could be relevant for the forthcoming medical use of the nonpeptidic ET-antagonists; if mutual potentiation or synergism of the ETS with the SNS or RAS look like clinically relevant, this would possess therapeutic effects for the use of these medicines in combination therapy. Consequently, we analyzed the effects of the ETA-selective ET-antagonist BQ-123 and ETB-selective ET-antagonist BQ-788 on angiotensin II and noradrenaline induced vasoconstriction in the human being pores and skin microcirculation = 11 healthy volunteers because there was no additional effect on blood flow when compared with the lower dose (10?12 m); however, local side-effects (burning pruritus) were more pronounced. To study the effects of the ET-antagonists only, doseCresponse curves for BQ-123 and BQ-788 were performed (10?10?10?8 m). Control injections were made with saline. To assess the effects of an endothelin-independent vasodilator, the effects of Ly93 nitroprusside (10?10 m) about angiotensin II (10?16?10?12 m) and noradrenaline (10?16?10?12 m) were assessed inside a subgroup of six healthy volunteers. Injections had to be purely intradermal, producing a symmetrical wheel without visible distributing outside the wheel. If these criteria were not fulfilled, the injection site was excluded from analysis [18]. Agents were injected with 0.4-mm needles (Omnikan?30, B. Braun, Melsungen/FRG). No more than five injections per forearm were allowed. Blood flow was measured after 2, 5, 8, 10, Ly93 15, 20, 25 and 30 min. Each healthy volunteer was examined on 3 days to perform the whole study protocol Rabbit Polyclonal to BCAS2 under the same environmental conditions. The subjects were blinded for the compound injected. A high interday reproducibility of the ideals obtained has been shown previously [18]. Medicines Endothelin-1, angiotensin II, BQ-123 and BQ-788 were provided by Clinalfa, Laufelfingen, Switzerland). Noradrenaline, nitroprusside and saline (0.9% NaCl solution) were provided by the pharmacy of our hospital (University Hospital, Essen, Germany). Solutions were prepared immediately before use to avoid loss of effectiveness using saline to dilute the medicines to the related concentration [18]. Data analysis The mean between minimum and maximum value of a 20 s reading was determined. Results are indicated as difThe mean between minimum amount and maximum value of a 20 s reading was determined. Results are indicated as variations from baseline and control () in mean s.e. mean; the area under the timeCresponse curve was determined (AUC). The significance of variations was determined Ly93 by multiple steps analyses of variance (ANOVA) with the factors drug and time (95% confidence intervals). A Bonferroni test with correction for multiple comparisons was used to identify the statistical variations of the drug used. Results Effect of ET-antagonists The ETA-selective antagonist BQ-123 led to a dose-dependent vasodilatation (< 0.001 saline, Figure 1). In contrast, the ETB-selective antagonist BQ-788 at higher doses led to a slight vasoconstriction (< 0.01 saline, Number 1). Open in a separate window Number 1 DoseCresponse curve of the ETA-selective antagonist BQ-123 (?)and the ETB-selective antagonist BQ-788 (?) in the human being pores and skin microcirculation < 0.01/0.001 control. AUC: Area under.