Local nitric oxide release does not affect tachyphylaxis to angiotensin II in dorsal hand veins in man in the presence of prostaglandin synthesis inhibition

Abstract

Aims Local prostaglandin (PG) production contributes to tachyphylaxis to angiotensin II (ANGII) in veins. Our aim was to assess the hypothesis that local nitric oxide (NO) generation is also, in part, responsible for tachyphylaxis to ANGII in veins, using the Aellig dorsal hand vein technique. Methods Eight healthy male volunteers received 600 mg of aspirin (orally) to inhibit PG production. The venoconstrictor effects of ANGII and noradrenaline (NA) were then compared in dorsal hand veins during co-infusion of the NO synthase inhibitor L-NMMA or saline, on separate occasions. Results ANGII and NA produced a similar degree of initial venoconstriction. However, the response to ANGII was signi®cantly attenuated by 12 min compared with NA (AUC 147t38 vs 196t40, respectively; [95% con®dence interval for difference: 7, 92], P=0.02). Infusion of L-NMMA did not in¯uence the response to ANGII or NA (P=0.2 and P=0.3, respectively). Conclusions Tachyphylaxis to ANGII in dorsal hand veins is not dependent on local NO release.

Marked synergism between vasopressin and angiotensin II in a human isolated artery

“…Moreover, in marked contrast to the stimulation observed when AII was administered alone, the enhanced response induced by the AII ϩ NE mixture showed no evidence of tachyphylaxis during six successive applications. A similar AII ϩ NE synergism has been reported in a number of other vascular preparations, including human coronary and digital arteries (9,10,30), with previous investigators also noting that the tachyphylaxis observed with AII alone was eliminated by co-application of NE with the AII (24,25). Our experiments with a selective AT 1 -type vascular-receptor antagonist demonstrated that this synergism between AII and NE in human gastroepiploic arteries is dependent on activation of the AT 1 -receptor subtype.…”

“…In our preparations, repeated exposure to AII led to a rapid fading of the induced contraction, whereas the VP-and NE-induced contractions remained more or less constant throughout the same exposure protocols. We cannot shed additional light on the mechanism underlying this AII tachyphylaxis, although our results confirm that this phenomenon is not dependent on endothelium-derived vasodilators such as nitric oxide (24). At present, it seems that AII tachyphylaxis may involve receptor desensitization, with decreased activation of phospholipase C (25).…”

“…To judge from the present results, the synergistic interaction between AII and either VP or NE may be boosted in hemorrhagic shock through the precipitous releases of large amounts of these hormones. Such important examples of synergism between vasoactive hormones in the maintenance of vascular homeostasis may, in part, explain the conflicting in vivo and in vitro response profiles of AII, as demonstrated by other investigators (23)(24)(25)(26)(27), although this hypothesis could be tested in further experiments.…”

“…Moreover, there are little data regarding the use of AII as a pressor agent under hemorrhagic conditions, although in two case reports, AII seemed effective at increasing blood pressure in vasodilatory septic shock that was otherwise refractory to high-dose catecholamine infusion (11,33). Interestingly, some investigators found that in vivo, the responses to AII in human resistance arteries, such as forearm arteries, do not exhibit rapid tachyphylaxis (24). This finding is not surprising because, in humans, some amounts of VP or NE are being continuously released to maintain homeostasis, and as shown in our study, the presence of a suboptimal response to AII alone does not prevent AII being effective when combined with either VP or NE.…”