Angiotensin Ii in Human Veins: Development of Rapid Desensitization and Effect of Indomethacin

Abstract

SUMMARY 1. The present study investigated whether rapid desensitization (tachyphylaxis) develops after exposure of human hand veins to angiotensin (Ang)II and whether pretreatment with indomethacin affects its development. 2. Venoconstrictor responses to increasing (2–256 ng/min) and constant (50 ng/min) doses of AngII and noradrenaline (NA) infusion were obtained in six healthy male subjects using the dorsal hand vein technique. After pretreatment with indomethacin and placebo, venoconstrictor responses to 50 ng/min AngII infusion were obtained in eight healthy male subjects. 3. The maximal mean (±SD) venoconstrictor response to NA (obtained with 256 ng/min NA) was 93.1±4.7%, whereas that to AngII (obtained with doses between 16 and 128 ng/min) was 43.8±12.2%. Continuous infusion of NA induced constant venoconstriction, whereas the venoconstrictor response to AngII peaked 3 min after the beginning of infusion and, thereafter, was attenuated. 4. Venoconstriction in response to constant AngII infusion after indomethacin pretreatment was significantly larger than that after placebo from 6 to 18 min after the initiation of infusion. 5. These findings show that rapid desensitization to AngII develops in human hand veins and this is compatible with the hypothesis that vasodilator prostaglandins are involved in the development of this desensitization.

Importance of the Angiotensin Type 1 Receptor in Angiotensin Ii–induced Bronchoconstriction and Bronchial Hyperresponsiveness in the Guinea Pig

“…In the present study, we first demonstrated tachyphylaxis of bronchoconstriction elicited by Ang II in vivo. Although pretreatment with indomethacin significantly inhibited tachyphylaxis of Ang IIinduced vascular constriction in human veins in vitro [13], indomethacin did not affect the tachyphylaxis of Ang II-induced bronchoconstriction in our study. This may be due to differences between in vivo and in vitro studies.…”

“…Although rapid desensitization (tachyphylaxis) to Ang II develops in human hand veins in vitro [13], it is unclear whether tachyphylaxis is a factor in bronchoconstriction. We therefore have developed models of Ang IIinduced bronchoconstriction and Ang II-induced bronchial hyperresponsiveness in guinea pigs.…”

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

“…All drugs, except for aspirin, were prepared aseptically from fresh opened vials, using 0.9% saline (Baxter, Norfolk, UK). Angiotensin II (Clinalfa, Laufelfingen, Switzerland) was infused intravenously at a dose of 50 pmol min −1 , as previous studies have reported tachyphylaxis with this dose [5]. Noradrenaline (Levophed, Abbott, Maidenhead, UK) was infused at a dose of 50 pmol min −1 [1].…”

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

“…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, AII-receptor signaling domains seem capable of triggering an internalization of AII receptors (23) in what have been described as "coated pits," which then internalize as vesicles that fuse with lysosomes for degradation (26). Recent evidence also suggests that vasodilator prostaglandins, which are released by AII, are involved in AII tachyphylaxis in humans because pretreatment with indomethacin reduces, but dose not abolish, the tachyphylaxis (27).…”