Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide

Nancy L. Kanagy, John R. Charpie, Jamie Dananberg, R. Clinton Webb

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Nitric oxide (NO) has been postulated as a regulator of vascular reactivity, and the current study tested the hypothesis that NO-induced decreased sensitivity to vasoconstrictors persists following removal of NO. Endothelium-denuded segments of rat aorta were incubated 2-4 h at 37°C with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Incubation produced rightward shifts in concentration response curves for phenylephrine [i.e., half-maximum effective concentration (EC50; in μM): control = 0.016, NO 0.14], aluminum fluoride (i.e., EC50 in mM: control 1.66, NO = 2.29), and KCI (i.e., EC50 in mM: control = 5.9, NO = 23.9). Similar shifts were seen for two other NO donors. The SNAP-induced shift was not attenuated by a guanylyl cyclase inhibitor, LY-83583 (10 μM) and was not mimicked by 8- bromoguanosine 3',5'-cyclic monophosphate (100 μM). It was attenuated by 1,4-naphthoquinone (50 μM), an inhibitor of endogenous mono-ADP ribosyltransferases. NO incubation increased cGMP content (4.6 ± 0.8 vs. 1.5 ± 0.15 pmol/mg protein), an increase unaffected by 1,4-naphthoquinone (3.3 ± 1.0 pmol/mg protein) but prevented by LY-83583 (1.6 ± 0.36 pmol/mg protein). ADP ribosylation of three proteins was observed in membranes from HEK 293 cells: 88, 66, and 38 kDa. ADP ribosylation of the 38-kDa protein was stimulated in a concentration-dependent manner by NO but was not decreased by 1,4-naphthoquinone. In conclusion, NO produces a long-lasting inhibition of vascular contractility by both a cGMP-dependent and -independent mechanism. Based on the observations of 1,4-naphthoquinone, we conclude that the cGMP- independent mechanism is not stimulation of endogenous ADP ribosylation but some other covalent modification in the pathway that mediates contraction.

Original languageEnglish (US)
Pages (from-to)253-260
Number of pages8
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume271
Issue number1 Pt 2
StatePublished - Jul 1 1996

Keywords

  • adenosine 5'-monophosphate ribosylation
  • guanosine 3',5'-cyclic monophosphate
  • guanylyl cyclase
  • vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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