Vasodilator activity of endothelin-1 and endothelin-3: rapid development of cross-tachyphylaxis and dependence on the rate of endothelin administration
In pentobarbital anesthetized cats, i.v. bolus injections of endothelin-1 (ET-1, 1 microgram) and ET-3 (3 micrograms) produced a rapidly appearing but short-lasting fall in aortic blood pressure followed in the case of ET-1 only by a small pressor response. When these peptides were administered repe...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 254; no. 3; pp. 1024 - 1028 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.09.1990
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Subjects | |
Online Access | Get full text |
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Summary: | In pentobarbital anesthetized cats, i.v. bolus injections of endothelin-1 (ET-1, 1 microgram) and ET-3 (3 micrograms) produced
a rapidly appearing but short-lasting fall in aortic blood pressure followed in the case of ET-1 only by a small pressor response.
When these peptides were administered repeatedly after 10- to 12-min intervals, there was a gradual attenuation of the hypotension
that by the fourth injection was replaced by a monophasic pressor response. The i.v. infusion of ET-1 (0.3 microgram/min)
or ET-3 (0.9 microgram/min) for 20 min produced sole systemic vasoconstriction. The decrease in blood pressure produced by
an i.v. bolus injection of ET-1 and ET-3 was no longer observed 5 min after the end of the ET-1 or ET-3 infusion. In contrast,
the hypotensive activity of bradykinin was not modified after the depressor responses to ET-1 and ET-3 had disappeared. Thus,
the failure of i.v. bolus injections of ET-1 and ET-3 to lower blood pressure under these experimental conditions cannot be
attributed to the development of tachyphylaxis to endogenous endothelium-derived relaxant factor, which is known to mediate
the effects of bradykinin. These results suggest that ET-1 and ET-3 share a single vascular receptor for vasodilation, which
becomes refractory upon repeated or maintained exposure to these peptides. Alternatively, this refractoriness may be due to
depletion of an intracellular mediator(s) that is jointly used by the membrane binding sites of ET-1 and ET-3. Moreover, the
present data suggest that the vasodilator activity of ETs depends on the rate of the peptide administration. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |