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

Abstract

1. 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. 2. 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. 3. 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. 4. 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. 5. 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 microM) 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. 6. 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.

• Authors: B K Kemp, J J Smolich, B C Ritchie, T M Cocks
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 116 Issue 5 Pg. 2457-67 (Nov 1995) ISSN: 0007-1188 [Print] England
• PMID: 8581285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Ionophores
• Potassium Channels
• Vasodilator Agents
• Nitroprusside
• Nitroarginine
• Ionomycin
• Potassium Chloride
• Arginine
• Nitric Oxide Synthase

Topics

• Animals
• Arginine (analogs & derivatives, pharmacology)
• Blood Gas Analysis
• Endothelium, Vascular (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Female
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (physiopathology)
• In Vitro Techniques
• Ionomycin (pharmacology)
• Ionophores (pharmacology)
• Muscle Relaxation (drug effects)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Nitroarginine
• Nitroprusside (pharmacology)
• Potassium Channels (drug effects, metabolism)
• Potassium Chloride (pharmacology)
• Pulmonary Artery (drug effects, physiology)
• Pulmonary Veins (drug effects, physiology)
• Sheep
• Up-Regulation (drug effects)
• Vasodilator Agents (pharmacology)