Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats.

Abstract

1. The effect of blockade of nitric oxide synthesis in pulmonary endothelium by two L-arginine analogues was tested in isolated blood-perfused lungs of normal rats and rats exposed chronically to 10% O2. 2. In both groups of rats the analogues (N-monomethyl-L-arginine (L-NMMA) and N-nitro-L-arginine methyl ester (L-NAME)) enhanced hypoxic vasoconstriction. In normal rats, with rare exceptions, these analogues had little or no effect on pulmonary artery pressure (Ppa) at constant blood flow during normoxia. However, chronically hypoxic rats have pulmonary hypertension and in these rats the analogues always raised Ppa; the rise in Ppa after L-NMMA but not L-NAME could be partially reversed by L-arginine. L-NAME was more potent than L-NMMA. 3. To see whether the difference between rat groups was due to the high Ppa in chronically hypoxic rats, in control rats we raised Ppa passively by lung inflation to values higher than found in chronically hypoxic rats. L-NAME did not alter the effects of lung inflation on Ppa. 4. Ppa was also raised passively by plotting pressure-flow lines up to high flow rates; the lines were changed minimally by both analogues in control rats but in chronically hypoxic rats the lines were raised to higher pressures and steepened substantially. 5. In control rats, during vasoconstriction caused by hypoxia, endothelin 1 and almitrine, L-NAME caused further rises in pressure. We conclude that a stimulus for nitric oxide release in control rats is the narrowing of vessels caused by vasoconstriction rather than passive increases in intravascular pressure. 6. In chronically hypoxic rats arterioles are narrowed by growth of new muscle and there is some muscle tone even in normoxia. Thus narrowing of the vascular lumen is the stimulus common to both groups of rats which leads to nitric oxide synthesis and attenuation of Ppa by a negative feedback process. Narrowing is associated with a large increase in shear stress due to two factors; the pressure drop along a vessel segment is increased and the surface area of the lining of the affected segment is decreased. 7. Atrial natriuretic peptide caused dose-dependent pulmonary vasodilation in both rat groups but had a greater effect in chronically hypoxic rats. The action persisted and was enhanced after blockade of NO synthesis.

Role of Nitric Oxide Synthase and Cyclooxygenase in Pulmonary Vascular Control in Isolated Perfused Lungs of Ferrets, Rats and Rabbits

“…As described earlier, we and others found that NOS blockade did not raise Ppa in normoxic isolated perfused rat lungs (Mazmanian et al 1989;Archer et al 1990;Hasunuma et al 1991;Barer et al 1993). However, we found that it did raise Ppa during relatively mild hypoxia (7% Oµ ventilation; Barer et al 1993). Thus, in vivo, the mixed venous POµ may be sufficiently low to cause slight constriction and activation of NOS.…”

“…The circumstances which cause their release are not fully worked out and may differ with species. In isolated rat lungs perfused at constant flow, blockade of either NOS with the ¬_arginine analogues (Mazmanian et al 1989;Archer et al 1990;Hasunuma et al 1991;Barer et al 1993) or COX with sodium meclofenamate (Russell et al 1993) caused little or no rise in pulmonary artery pressure (Ppa); however, if the vasculature was in a state of vasoconstriction caused by vasoconstrictor agents or chronic exposure to hypoxia, ¬_NAME did cause a substantial rise in Ppa. These results suggest that, in these circumstances, there is no constant release of NO or dilator prostaglandins in the rat.…”

Vitamin C supplementation influences the antioxidant response and nitric oxide handling of erythrocytes and lymphocytes to diving apnea

“…As the half-life of NO is very short, we can suspect that the high rate of NO production is attained after diving. Hypoxic conditions are known to induce NO synthesis by endothelial cells (Barer et al, 1993;Swenson et al, 2005) in accordance with the increased plasma nitrite levels after diving apnea session. The lack of differences between placebo and supplemented groups could indicate that endothelial cells are saturated with ascorbate in both groups.…”

Effects of Moderate Altitude on Exhaled Nitric Oxide, Erythrocytes Lipid Peroxidation and Superoxide Dismutase Levels.

“…NO is also continuously released in the systemic circulation and attenuates the arterial pressure [17]. Shear stress is a probable stimulus for NO release.…”

“…Shear stress is a probable stimulus for NO release. Hypoxic vasoconstriction may also provoke NO release in proportion to its severity [17]. The end metabolic product of NO is nitrite and nitrate.…”