Putative precursors of endothelin have less vasoconstrictor activity in vitro but a potent pressor effect in vivo

1 In anaesthetized rats, an i.v. injection of endothelin-1 (0.25nmolkg-') 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). 2 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. 3 In pithed rats, endothelin-1 (0.25 nmol kg-')and its precursor human proendothelin (h-proendothelin) (0.5nmolkg-') induced pressor responses of a similar magnitude, which for h-proendothelin (up to 5.0 nmol kg'-) were not preceded by a hypotensive phase. The pressor effects of endothelin-1, like those of vasopressin, were reproducible upon repeated i.v. injections. 4 Rats given a 10min infusion (0.1 nmol kg-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 hproendothelin did not develop tachyphylaxis to endothelin-1. 5 In pithed rats, endothelin-1, at a dose inducing the same maximal increase in blood pressure as hproendothelin, was approximately 3 fold more potent as a mesenteric vasoconstrictor than hproendothelin. These results suggest that if h-proendothelin is processed to endothelin-1, this transformation is not uniform throughout the vascular system. 6 The pressor response of h-proendothelin in pithed rats was dose-dependently inhibited by phosphoramidon (2.5-5.0mgkg '). However, this compound did not antagonize the effects of endothelin-1 (0.25 nmol kg-) or those of h-proendothelin (0.5 nmol kg-) once developed. 7 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. 8 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 crosstachyphylaxis 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.

Section: Discussionsupporting

confidence: 92%

“…administration of endothelin-1 or its isopeptides, to rats, evokes a rapidly appearing and short lasting fall in blood pressure, followed by a moderate pressor effect. In contrast, p-proendothelin produces only a monophasic pressor response (Kashiwabara et al, 1989). Additionally, when a series of i.v.…”

Section: Introductionmentioning

confidence: 99%

Cross tachyphylaxis to endothelin isopeptide‐induced hypotension: a phenomenon not seen with proendothelin

Gouville

Cavero

1991

“…Similarly to endothelin-1, big-endothelin-1 is also a potent pressor and bronchoconstrictor agent (Kashiwabara et al, 1989;Fukuroda et al, 1990;D'Orleans-Juste et al, 1991b). Yet, unlike endothelin-1, both effects of big-endothelin-1 are suppressed by phosphoramidon, suggesting that the latter peptide must be converted to its active metabolite via an endothelin-converting enzyme (ECE) which is sensitive to this neutral endopeptidase inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Different pressor and bronchoconstrictor properties of human big‐endothelin‐1, 2 (1–38) and 3 in ketamine/xylazine‐anaesthetized guinea‐pigs

Gratton

Rae

Claing

et al. 1995

Texas 75235-9050, U.S.A.1 In the present study, the precursors of endothelin-1, endothelin-2 and endothelin-3 were tested for their pressor and bronchoconstrictor properties in the anaesthetized guinea-pig. In addition, the effects of big-endothelin-l and endothelin-l were assessed under urethane or ketamine/xylazine anaesthesia. 2 When compared to ketamine/xylazine, urethane markedly depressed the pressor and bronchoconstrictor properties of endothelin-1 and big-endothelin-1. 3 Under ketamine/xylazine anaesthesia, the three endothelins induced a biphasic increase of mean arterial blood pressure. In contrast, big-endothelin-1, as well as big-endothelin-2 (1-38), induced only sustained increase in blood pressure whereas big-endothelin-3 was inactive at doses up to 25 nmol kg-'. 4 Big-endothelin-1, but not big-endothelin-2, induced a significant increase in airway resistance. Yet, endothelin-1, endothelin-2 and endothelin-3 were equipotent as bronchoconstrictor agents. 5 Big-endothelin-l, endothelin-l and endothelin-2, but not big-endothelin-2, triggered a marked release of prostacyclin and thromboxane A2 from the guinea-pig perfused lung. 6 Our results suggest the presence of a phosphoramidon-sensitive endothelin-converting enzyme (ECE) which is responsible for the conversion of big-endothelin-1 and big-endothelin-2 to their active moieties, endothelin-1 and 2. However, the lack of bronchoconstrictor and eicosanoid-releasing properties of big-endothelin-2, as opposed to endothelin-2 or big-endothelin-1, suggests the presence of two distinct phosphoramidon-sensitive ECEs in the guinea-pig. The ECE responsible for the systemic conversion of big-endothelins possesses the same affinity for big-endothelin-l and 2 but not big-endothelin-3. In contrast, in the pulmonary vasculature is localized in the vicinity of the sites responsible for eicosanoid release, an ECE which converts more readily big-endothelin-1 than big-endothelin-2.

“…Since big-endothelin-I has only 1/100th of the rat aorta contractile activity of endothelin-I (Kashiwabara et al, 1989), inhibition of the ECE should effectively block the biological activities involving conversion of bigendothelin-I to endothelin-1. This was the case in functional studies in vitro (D'Orleans-Juste et al, 1991a,b;Hisaki et al, 1991) and in vivo (Fukuroda et al, 1990;Matsumura et al, 1990b;Pollock & Opgenorth, 1991;McMahon et al, 1991;Pons et al, 1991;Mattera et al, 1992a,b).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the cardiovascular and neural activity of endothelin‐1, −2, −3 and respective proendothelins: effects of phosphoramidon and thiorphan

Mattera¹,

Eglezos²,

Renzetti³

et al. 1993

1 In the anaesthetized, ganglion-blocked rat, intravenous boluses of endothelin-1, endothelin-2 and endothelin-3 induced a transient hypotensive effect followed by a potent long lasting pressor response (ED_sommHg: 0.72 ± 0.05, 1.8 ± 0.2 and 2.7 ± 0.3 nmol kg-', respectively). The maximal effect for the three peptides was of a similar order of magnitude (,&MAP: 84 to 89 mmHg). Neither of these effects was influenced by phosphoramidon or thiorphan (10 mg kg-', i.v.).2 Intravenously administered big-endothelin-1 and -2 induced a transient (1-2 min) hypotension followed by a potent long lasting (>25 min) vasopressor effect (ED50,.Hg: 1.8 ± 0.2 and 6.7 ± 0.4 nmol kg-', respectively), with a similar maximal activity (A MAP: 85 ± 4 and 81 ± 2.4 mmHg, respectively). The onset of the big-endothelin-l vasopressor effect was more rapid (5-6 min) than that of big-endothelin-2 (10-13 min). Big-endothelin-3 was found to induce only a potent, long lasting (>35 min) hypertension, with a maximal effect of 75 ± 4.6 mmHg at 10 nmol kg-' and an ED50,,,,Hg of 6.5 ± 0.4 nmol kg-'. The onset of this effect was much slower (20-25 min) than that of the other proendothelins. Pressor responses induced by big-endothelin-1, -2 and -3 (3, 15 and 10 nmol kg-', respectively) were markedly reduced (60, 80 and 100%) in the presence of phosphoramidon (10 mg kg-', i.v.). Thiorphan (10 mg kg', i.v.) did not inhibit the effects of big-endothelin-1, -2 and -3. 3 In the electrically stimulated rat vas deferens, endothelin-I and -2 were found to be equipotent enhancers of the twitch response (EC,00%: 4.0 ± 0.4 nm and 7.9 ± 4.8 nm, respectively), both about 3-4 fold as active as endothelin-3 (EC,00%: 19 ± 2.5 nM). Endothelin-1 and -3 showed a comparable maximal stimulatory effect (Emax: 296 ± 30 and 262 ± 24%) while endothelin-2 was less active (Em,,: 194 ± 30%).4 Big-endothelin-l and -2 were potent enhancers of the twitch reponse too (EC 1o,%: 10.0 ± 2.6 nM and 21.6 + 3.2 nM, respectively), with a comparable maximal stimulatory effect (Ema: 254 ± 22 and 264 ± 24%). Big-endothelin-3 was found to be less potent (EC,0o%: 275 ± 21 nM), but retained a marked potentiating effect (Emax: 200 ± 38%). Phosphoramidon, but not thiorphan, concentration-dependently (10 and 100 JM) reduced big-endothelin-1 (58 and 86% respectively) and big-endothelin-2 (21 and 56%) -mediated responses. Conversely, the big-endothelin-3 effect was reduced by phosphoramidon only at 100#JM (-70%), while thiorphan acts concentration-dependently (31 and 71% at 10 and 100JIM respectively); thus, in the rat vas deferens, big-endothelin-I and -2 were as potent as their corresponding endothelins, while big-endothelin-3 was about 20 times less potent than endothelin-3. 5 The increasing effect of endothelin-2 (194 ± 30% over baseline) was significantly enhanced by either 10 JIM phosphoramidon (277 ± 42%) or thiorphan (318 ± 15%). The endothelin-I and endothelin-3-mediated twitch enhancement was not affected by the two protease inhibitors (10JIM). 6 These results suggest that in vivo big-endoth...