Tier 3 — preclinical

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor

Palmer RM, Ferrige AG, Moncada S
Nature 1987 Volume 327, Issue 6122, pages 524-526

Bibliography

PubMed
PMID 3495737
DOI
10.1038/327524a0

Study snapshot

DesignControlled laboratory bioassay and chemiluminescence detection study
ModelCultured endothelial cells (from pig aorta) and isolated rabbit aorta/bioassay tissue strips
SampleNot applicable (cell culture/bioassay study; N not reported as a subject count)
InterventionBradykinin-stimulated release of EDRF/NO from cultured endothelial cells, with NO quantified directly by chemiluminescence (reaction with ozone) and EDRF activity measured by parallel bioassay
DurationNot applicable (acute in vitro experiments)
EndpointsComparison of biological activity (bioassay-measured relaxation) between EDRF and NO released from endothelial cells; Bradykinin-stimulated quantitative release of NO from endothelial cells, measured by chemiluminescence; Effect of haemoglobin (inhibitor) and superoxide dismutase (potentiator) on EDRF- and NO-induced relaxation

What the study showed, in plain terms

Published within weeks of a companion paper from Louis Ignarro's group, this 1987 Nature study by Salvador Moncada's team provided the other pillar of proof that nitric oxide (NO), a simple and previously little-studied gas, is responsible for the blood-vessel-relaxing effects of "endothelium-derived relaxing factor" (EDRF), a substance released by the cells lining blood vessels.

The researchers used a highly sensitive chemical technique (chemiluminescence) to directly measure the actual amount of NO gas released from blood-vessel endothelial cells when stimulated by the hormone bradykinin, and showed that this amount was enough to fully account for the vessel-relaxing activity attributed to EDRF, with both substances responding identically to blocking and enhancing agents.

Together with the Ignarro group's concurrent paper, this study is credited with resolving the decade-long mystery of EDRF's chemical identity and establishing nitric oxide as a fundamental signaling molecule in the cardiovascular system. This body of work led to the 1998 Nobel Prize in Physiology or Medicine, awarded to Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide as a signaling molecule; Moncada's foundational contributions to this field, including this paper, are widely recognized in the scientific community even though he was not among the Nobel laureates.

Key findings

  • Bradykinin stimulated release of NO from cultured endothelial cells in amounts sufficient to account for the biological (relaxant) activity of EDRF.
  • Relaxation of bioassay tissue induced by EDRF was indistinguishable from that induced by authentic NO, and both were equally unstable.
  • Relaxations induced by both EDRF and NO were inhibited by haemoglobin and enhanced by superoxide dismutase to a similar degree.
  • The authors concluded that NO released from endothelial cells is indistinguishable from EDRF in biological activity, stability, and pharmacological susceptibility, and proposed that EDRF and NO are identical.

What this study can and cannot tell us

This is a preclinical, in vitro study using cultured endothelial cells and isolated tissue bioassays, not human or intact-animal cardiovascular measurements, so direct clinical extrapolation requires corroborating in vivo evidence.

No explicit funding source or competing-interest statement was identified for this article; the study's chemical evidence for NO also relied on chemiluminescence detection methods that, while direct, were state-of-the-art for the era rather than the more refined spectroscopic techniques available today.

Related papers in the corpus

Tier 3
The nature of endothelium-derived vascular relaxant factor
Griffith TM et al. · Nature · 1984
Tier 3
Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide
Ignarro LJ et al. · Proceedings of the National Academy of Sciences of the USA · 1987
Tier 2
Nitric Oxide: A Unique Endogenous Signaling Molecule in Vascular Biology (Nobel Lecture)
Ignarro LJ et al. · Angewandte Chemie International Edition · 1999
Tier 2
Nitric oxide as a unique signaling molecule in the vascular system: a historical overview
Ignarro LJ et al. · Journal of Physiology and Pharmacology · 2002

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology