Endothelium‐dependent relaxations in sheep pulmonary arteries and veins: resistance to block by NG‐nitro‐L‐arginine in pulmonary hypertension

B. K. Kemp, J. J. Smolich, B. C. Ritchie, T. M. Cocks

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The effect of the nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine (L‐NOARG), on endothelium‐dependent relaxation to a receptor‐independent agent, ionomycin, was examined in isolated pulmonary arteries and veins from control, short‐term and chronic pulmonary hypertensive sheep. All vessel segments were contracted to optimal levels of active force with endothelin‐1 to record endothelium‐dependent relaxation. Pulmonary hypertension was induced by continuous pulmonary artery air embolization for 1 day (short‐term) and 14 days (chronic) and was associated with a 2 and 3 fold increase in pulmonary vascular resistance respectively. L‐NOARG (0.1 mM) reduced the maximum relaxation (Rmax) to ionomycin in large and medium‐sized pulmonary arteries from control sheep by approximately 70%. By contrast, L‐NOARG (0.1 mM) did not inhibit the Rmax to ionomycin in matched vessels from short‐term and chronic pulmonary hypertensive sheep. Resistance of ionomycin‐induced relaxations to inhibition by L‐NOARG, was confined to the arterial vasculature in chronic pulmonary hypertensive animals, as relaxations to ionomycin in large and medium‐sized chronic pulmonary hypertensive veins were, like those in control veins, abolished by L‐NOARG. Both large and medium‐sized pulmonary veins from short‐term pulmonary hypertensive sheep, however, were resistant to block by L‐NOARG. Neither sensitivity (pEC50) nor Rmax, to ionomycin in large, short‐term pulmonary hypertensive arteries was affected when the extracellular concentration of K+ was increased isotonically to 30 mM. Nifedipine (0.3 μm) was present throughout to prevent high K+‐induced smooth muscle contraction. In the presence of this high extracellular K+, however, L‐NOARG (0.1 mM) caused complete inhibition of the relaxation to ionomycin, whereas in normal extracellular K+ (4.7 mM), L‐NOARG only weakly inhibited ionomycin relaxations. In conclusion, the onset of pulmonary hypertension in sheep following air embolization, is associated with the development of resistance of endothelium‐dependent relaxations to block by L‐NOARG. The mechanism of L‐NOARG resistance appears to be due to the up‐regulation of a K+ channel‐mediated backup vasodilator mechanism which can compensate for the loss of nitric oxide (NO)‐mediated relaxation. Although this mechanism remains functionally ‘silent’ in the presence of NO it is able to maintain adequate endothelium‐dependent vasodilatation during pulmonary hypertension if NO synthesis is compromised. 1995 British Pharmacological Society

Original languageEnglish
Pages (from-to)2457-2467
Number of pages11
JournalBritish Journal of Pharmacology
Issue number5
Publication statusPublished - 1995
Externally publishedYes


  • EDRF
  • endothelium
  • hyperpolarization
  • K channels
  • nitric oxide
  • pulmonary hypertension

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