Effects of Noradrenaline and Prostaglandin F_2α on Angiotensin‐Induced Contraction and Tachyphylaxis in Rat Aortic Rings

Abstract

The aim of this study was to examine the effects of noradrenaline (NA) and prostaglandin F2 alpha (PGF2 alpha) on angiotensin II (AII)-induced contraction and tachyphylaxis in aortic rings of the rat. Neither NA (10(-9) M) nor PGF2 alpha (10(-7) M) had significant effect on the response of the rings to the spasmogenic concentrations (10(-10) to 10(-7) M) of AII, but lowered significantly the threshold response of the aortic rings to AII (from 10(-9) to 10(-12) M). In rings that were tachyphylatic to AII, both NA and PGF2 alpha attenuated significantly the tachyphylaxis of the rings to AII at the concentrations of 10(-10) and 10(-7) of the octapeptide; and also lowered the threshold of the tachyphylatic rings to AII (from 10(-9) to 10(-11) M for NA, and from 10(-9) to 10(-10) M for PGF2 alpha). The specific properties of noradrenaline and PGF2 alpha were not shared by the non-specific potassium chloride. Because the lowering of threshold and attenuation of tachyphylaxis occurred at the physiological levels of AII and NA, it is possible that the in vivo actions of AII are under constant modulation by circulating and localised (higher than circulating) levels (e.g. of PGF2 alpha) of spasmogens. The results also call into question the physiological significance of angiotensin tachyphylaxis and may suggest that it is only an in vitro phenomenon occurring in the absence of endogeneous spasmogens.

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

“…Changes at receptor sites have been proposed as a mechanism for the rapid desensitization (tachyphylaxis) of responses to AngII, including changes in receptor affinity, 13 internalization of the receptor 14 and the existence of a regulatory site (tachyphylactic site) that induces down-regulation of angiotensin receptors. 15 The present study did not yield any information as to whether the rapid desensitization of responses to AngII and the attenuation of this phenomenon by indomethacin in human hand veins is mediated by angiotensin (AT) receptors or not. However, results from several in vitro studies suggest that rapid desensitization 26,27 and the release of PG by AngII 28 are AT1 receptor-mediated events.…”

“…Sim et al 2 reported that tachyphylaxis to AngII‐induced elevation of blood pressure does not occur in freely moving rats, although they used doses of AngII equivalent to those that induced tachyphylaxis in aortic preparations in vitro , and suggested that this phenomenon is prevented from occurring in intact animals by circulating vasoactive substances, including NA. 15 There are also other data supporting the contention that this phenomenon does not occur in vivo . 16,17 When preparations are perfused with whole blood, plasma 16 or liquid that contains physiological amino acids, vasopressin and thyroid hormone, 17 tachyphylaxis to AngII is either attenuated or undetected.…”

“…Changes at receptor sites have been proposed as a mechanism for the rapid desensitization (tachyphylaxis) of responses to AngII, including changes in receptor affinity, 13 internalization of the receptor 14 and the existence of a regulatory site (tachyphylactic site) that induces down‐regulation of angiotensin receptors. 15 …”

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

“…In summary, tachyphylaxis to ANGII in dorsal hand veins is not accounted for by local NO generation. Although PG production may be responsible, in part, for the observed tachyphylaxis, alternative mechanisms such as changes in receptor density [10] or responsiveness [11], or the release of other modulatory factors may also be important.…”

Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

“…For instance, angiotensin II stimulates potent vasoconstriction with an accompanying tachyphylaxis (De Mey and Vanhoutte, 1981;Sim and Kuttan, 1992), which is considered a protective device. The mechanism behind this tachyphylaxis is possibly due to internalization and desensitization of angiotensin II-mediated intracellular signaling.…”