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Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance

T Münzel1, A Giaid, S Kurz

  • 1Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 23, 1995
PubMed

Insights

Nitroglycerin tolerance increases blood vessel constriction by upregulating endothelin-1, a process mediated by protein kinase C. This explains hypersensitivity to various vasoconstrictors, except endothelin-1 itself.

Area of Science:

  • Vascular biology
  • Pharmacology

Background:

  • Nitroglycerin tolerance is a clinical issue reducing treatment efficacy.
  • The mechanisms underlying increased vasoconstriction during nitrate tolerance are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms behind enhanced vasoconstriction in nitroglycerin-tolerant rabbits.
  • To explore the role of endothelin-1 and protein kinase C in this phenomenon.

Main Methods:

  • Nitroglycerin patches were used to induce tolerance in rabbits.
  • Aortic segments were studied in organ chambers to assess relaxations and constrictions.
  • Protein kinase C antagonists were used to evaluate their effects on vascular responses.
  • Immunocytochemistry was employed to detect endothelin-1 and big endothelin-1.

Main Results:

  • Nitroglycerin tolerance led to reduced relaxation to nitroglycerin and increased sensitivity to angiotensin II, serotonin, phenylephrine, and KCl.
  • Protein kinase C antagonists reversed hypersensitivity in tolerant vessels.
  • Constriction to endothelin-1 was paradoxically decreased in tolerant vessels.
  • Increased endothelin-1-like immunoreactivity was observed in tolerant aortas.
  • Endothelin-1 mimicked and protein kinase C antagonists prevented the enhanced vasoconstriction.

Conclusions:

  • Increased autocrine endothelin-1 production in nitrate tolerance sensitizes vascular smooth muscle to vasoconstrictors via protein kinase C.
  • This mechanism contributes to the altered vascular reactivity observed during nitroglycerin tolerance.

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