Endothelium-dependent relaxations in sheep pulmonary arteries and veins: resistance to block by NG-nitro-L-arginine in pulmonary hypertension.
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.
Kemp
B K
BK
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Smolich
J J
JJ
Ritchie
B C
BC
Cocks
T M
TM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001784:Blood Gas Analysis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D009599:Nitroprusside / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007476:Ionophores; D015221:Potassium Channels; D014665:Vasodilator Agents; D009599:Nitroprusside; D019335:Nitroarginine; D015759:Ionomycin; D011189:Potassium Chloride; D001120:Arginine; D019001:Nitric Oxide Synthase