Cross tachyphylaxis to endothelin isopeptide‐induced hypotension: a phenomenon not seen with proendothelin
Authors: de Gouville Anne‐Charlotte Le Monnier , Cavero Icilio 
Published: July 2012

In anaesthetized rats, an i.v. injection of endothelin‐1 (0.25 nmol kg−1) evoked a rapidly appearing (maximal effect within 15 s) and short lasting (3 min) fall in blood pressure with tachyphylaxis occurring so that it was reduced by 50% by the last of 4 injections given 10 min apart. This property was also shared by endothelin‐2, endothelin‐3 and vasoactive intestinal contractor (VIC).

Cross tachyphylaxis between the isopeptides occurred. However, under the same experimental conditions the hypotensive effects of acetylcholine, adenosine, atrial natriuretic peptide (ANP) and substance P were reproducible and not modified in animals in which endothelin‐1 no longer lowered blood pressure. Thus, the mechanism of the hypotensive action of endothelin peptides is different from that of acetylcholine, adenosine, ANP, and substance P.

In pithed rats, endothelin‐1 (0.25 nmol kg−1) and its precursor human proendothelin (h‐proendothelin) (0.5 nmol kg−1) induced pressor responses of a similar magnitude, which for h‐proendothelin (up to 5.0 nmol kg−1) were not preceded by a hypotensive phase. The pressor effects of endothelin‐1, like those of vasopressin, were reproducible upon repeated i.v. injections.

Rats given a 10 min infusion (0.1 nmol kg−1 min−1) of endothelin‐1 showed no hypotensive response to an i.v. bolus injection of endothelin‐1, whereas animals pretreated with an equipressor infusion of h‐proendothelin did not develop tachyphylaxis to endothelin‐1.

In pithed rats, endothelin‐1, at a dose inducing the same maximal increase in blood pressure as h‐proendothelin, was approximately 3 fold more potent as a mesenteric vasoconstrictor than h‐proendothelin. These results suggest that if h‐proendothelin is processed to endothelin‐1, this transformation is not uniform throughout the vascular system.

The pressor response of h‐proendothelin in pithed rats was dose‐dependently inhibited by phosphoramidon (2.5–5.0 mg kg−1). However, this compound did not antagonize the effects of endothelin‐1 (0.25 nmol kg−1) or those of h‐proendothelin (0.5 nmol kg−1) once developed.

Although some of these results may suggest that h‐proendothelin does not undergo in vivo conversion to endothelin‐1, the results obtained with phosphoramidon suggest that h‐proendothelin is converted into endothelin‐1. Therefore, the amount of endothelin‐1 so produced can elicit pressor responses or regional vasoconstriction, but is insufficient to lower blood pressure and to inhibit endothelin‐1‐induced hypotension.

The mechanism of the tachyphylaxis does not appear to be depletion of endothelium‐derived relaxing factor, since agents coupled to the latter endogenous vasorelaxant substance do not exhibit cross‐tachyphylaxis with endothelin‐1. It is suggested that upon repeated or sustained exposure to endothelin‐1, the endothelin‐1 receptors mediating hypotension decrease in number and/or undergo conformational changes making them refractory to activation. Alternatively, the depletion of a blood‐borne agent responsible for the hypotension could be involved.