Endothelin-1 and endothelin-2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries

M. G. Compeer, G. M. J. Janssen, J. G. R. De Mey

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background and PurposeEndothelin (ET)-1 and ET-2 cause potent long-lasting vasoconstrictions by tight binding to smooth muscle ETA receptors. We tested the hypotheses that different mechanisms mediate initiation and maintenance of arterial contractile responses to ET-1 and ET-2 and that this differs among vascular beds. Experimental ApproachSegments of rat mesenteric resistance artery (MRA) and basilar artery (BA) were studied in wire myographs with and without functional antagonists. Key ResultsSensitivity and maximum of MRA contractile responses to ET-1 were not, or only moderately, reduced by stimulation of soluble GC, AC or K+-channels and by an inhibitor of receptor-operated ion channels. However, each of these reduced maintenance of ET-1 effects and relaxed ET-1-induced contractions in MRA. A calcium channel antagonist did not alter sensitivity, maximum and maintenance of ET-1 effects, but relaxed ET-1-induced contractions in MRA. A PLC inhibitor prevented contractile responses to ET-1 and ET-2 in MRA and BA, and relaxed ET-1- and ET-2-induced responses in MRA and ET-1 effects in BA. A Rho-kinase inhibitor did not modify sensitivity, maximum and maintenance of responses to both peptides in both arteries but relaxed ET-2, but not ET-1, effects in MRA and ET-1 effects in BA. Conclusions and ImplicationsPLC played a key role in arterial contractile responses to ETs, but ET-1 and ET-2 initiated and maintained vasoconstriction through different mechanisms, and these differed between MRA and BA. Selective functional antagonism may be considered for agonist- and vascular bed selective pharmacotherapy of ET-related diseases.
Original languageEnglish
JournalBritish Journal of Pharmacology
Volume170
Issue number6
Pages (from-to)1199-1209
ISSN0007-1188
DOIs
Publication statusPublished - 2013

Keywords

  • endothelin-1 endothelin-2 ETA receptors PLC RhoK vasoconstrictions vasospasms mesenteric resistance artery basilar artery vascular smooth muscle GENE-RELATED PEPTIDE SOLUBLE GUANYLATE-CYCLASE RESISTANCE ARTERIES SIGNAL-TRANSDUCTION ETA-RECEPTOR IN-VIVO CARDIOVASCULAR-DISEASE ALLOSTERIC MODULATION ARRIVE GUIDELINES CALCIUM-CHANNELS

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