Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection

Neil K. Worrall, Kathy Chang, Gloria M. Suau, Wanda S. Allison, Thomas P. Misko, Patrick M. Sullivan, Ronald Tilton, Joseph R. Williamson, T. Bruce Ferguson

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

NO is produced during cardiac allograft rejection by expression of inducible NO synthase (iNOS) in the rejecting heart. Recent evidence indicates that NO modulates vascular permeability under both physiological and pathophysiological conditions. The present study explored the effects of early acute cardiac allograft rejection, and specifically the effects of NO, on myocardial and systemic vascular barrier function using a quantitative double-tracer permeation method in a rat cardiac transplant model. Early allograft rejection increased albumin permeation twofold to fivefold in the allograft heart and systemic vasculature (brain, lung, sciatic nerve, diaphragm, retina, muscle, kidney, and uvea) compared with isografts and controls. There were no detectable differences in regional blood flow or hemodynamics, suggesting that increased albumin permeation resulted from increased vascular permeability. iNOS mRNA was expressed in the allograft heart and native lung and was associated with increased serum nitrite/nitrate levels. iNOS inhibition with aminoguanidine prevented or attenuated allograft heart and systemic vascular barrier dysfunction and reduced allograft serum nitrite/nitrate levels to isograft values. Aminoguanidine did not affect the mild histological changes of rejection present in allografts. These data demonstrate the novel observations that (1) endothelial barrier function is compromised in the systemic vasculature, particularly in the brain, remote from the site of allograft rejection; (2) allograft vascular barrier dysfunction is associated with increased NO production and iNOS mRNA expression in the affected tissues (eg. native lung and grafted heart); and (3) inhibition of NO production by iNOS prevents vascular barrier dysfunction in the allograft heart and systemic vasculature.

Original languageEnglish (US)
Pages (from-to)769-779
Number of pages11
JournalCirculation Research
Volume78
Issue number5
StatePublished - May 1996
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type II
Allografts
Blood Vessels
Nitric Oxide Synthase
Isografts
Capillary Permeability
Nitrites
Nitrates
Lung
Albumins
Uvea
Messenger RNA
Regional Blood Flow
Brain
Sciatic Nerve
Diaphragm
Serum
Retina
Hemodynamics
Transplants

Keywords

  • blood-brain barrier
  • capillary permeability
  • cardiac transplantation
  • endothelium
  • nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Worrall, N. K., Chang, K., Suau, G. M., Allison, W. S., Misko, T. P., Sullivan, P. M., ... Ferguson, T. B. (1996). Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection. Circulation Research, 78(5), 769-779.

Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection. / Worrall, Neil K.; Chang, Kathy; Suau, Gloria M.; Allison, Wanda S.; Misko, Thomas P.; Sullivan, Patrick M.; Tilton, Ronald; Williamson, Joseph R.; Ferguson, T. Bruce.

In: Circulation Research, Vol. 78, No. 5, 05.1996, p. 769-779.

Research output: Contribution to journalArticle

Worrall, NK, Chang, K, Suau, GM, Allison, WS, Misko, TP, Sullivan, PM, Tilton, R, Williamson, JR & Ferguson, TB 1996, 'Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection', Circulation Research, vol. 78, no. 5, pp. 769-779.
Worrall, Neil K. ; Chang, Kathy ; Suau, Gloria M. ; Allison, Wanda S. ; Misko, Thomas P. ; Sullivan, Patrick M. ; Tilton, Ronald ; Williamson, Joseph R. ; Ferguson, T. Bruce. / Inhibition of inducible nitric oxide synthase prevents myocardial and systemic vascular barrier dysfunction during early cardiac allograft rejection. In: Circulation Research. 1996 ; Vol. 78, No. 5. pp. 769-779.
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