Relative Effects of Cyclooxygenase and Nitric Oxide Synthase Inhibition on Vascular Resistances in Neonatal Lamb Lungs

Abstract

Effective attenuation of pulmonary vasoconstriction is essential during early postnatal development when increased pulmonary vascular resistance (PVR) may lead to a resumption of right-to-left shunting across fetal channels. In addition, modulation of venous resistance contributes to normal lung fluid balance. This study was designed to identify the relative modulating effects of endothelium-derived nitric oxide (EDNO) and dilator prostaglandins (PG) on normoxic and hypoxic pulmonary vasomotor tone in young newborns. Total and segmental PVR were measured using inflow-outflow and double occlusion techniques in isolated lungs of 6-h-old lambs studied under control conditions or after blocking PG and/or EDNO synthesis with indomethacin and/or N omega-nitro-L-arginine, respectively. During normoxia, both indomethacin and N omega-nitro-L-arginine were required to increase total PVR, but EDNO appeared to have the greater modulating effect. Indomethacin markedly enhanced hypoxic pulmonary vasoconstriction of large and small arteries and small veins, whereas N omega-nitro-L-arginine caused a lesser, but significant, increase in hypoxic pulmonary vasoconstriction of small arteries and veins, suggesting that dilator PG played the dominant modulating role during hypoxia. In addition, PG synthesis appeared to be enhanced after inhibition of EDNO synthesis. In contrast, indomethacin caused a decrease in venous resistance, suggesting that constrictor prostanoids had a greater effect than dilator PG on this segment. EDNO had a modest modulating effect on venous resistance in these lungs. These data suggest that dilator PG and EDNO exert complementary effects in attenuating total and segmental PVR during normoxia and hypoxia in 6-hold lamb lungs.

The effect of glibenclamide on acetylcholine and sodium nitroprusside induced vasodilatation in human cutaneous microcirculation

“…, 2004). On the contrary in neonatal lamb lung the inhibition of prostaglandin production increased the pulmonary vascular resistance (Gordon et al. , 1997).…”

“…Merkus et al proved that endogenous prostaglandins contribute significantly to systemic and coronary tone in conscious swine at rest but are not mandatory for the regulation of pulmonary resistance vessel tone (Merkus et al, 2004). On the contrary in neonatal lamb lung the inhibition of prostaglandin production increased the pulmonary vascular resistance (Gordon et al, 1997). Only a few studies of the role of prostaglandins on resting vascular tone were also performed on humans.…”

NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation

“…Abrupt increases in flow stimulate both NO and PG release in isolated endothelial cells in culture (5,8,11,13,24,32). In isolated neonatal lamb lungs, NOS inhibition during normoxia increased PVR more than COX inhibition, but during hypoxia, COX inhibition augmented PVR more than NOS inhibition (15). Barnard et al (6) compared the effects of NO and PG inhibition on the pulmonary vascular response to shear stress in isolated rat and dog lungs.…”

Maturational changes in ovine pulmonary vascular responses to inhaled nitric oxide

“…The cyclooxygenase inhibitor, indomethacin (40 g/mL perfusate), was added to block the potentially confounding effects of dilator prostaglandins, as previously described. 22 The perfusate exited the left atrium to a reservoir from which it was pumped (Varistaltic Roller Pump, Manostat, New York, NY) through a heat exchanger, filter/bubble trap, and flow probe (model EP 300 flow probe and model 501 flow meter, Carolina Medical Electronics, King, NC) to the pulmonary artery. Pulmonary artery pressure (Ppa), left atrial pressure (Pla), and airway pressure (Paw) were constantly measured (Statham 23id pressure transducers, Spectramed, Oxnard, CA) and recorded on a polygraph (model 7D, Grass Instrument Co., Quincy, MA).…”

“…Isolated lungs of 1-d-old and 1-m-old lambs were prepared as previously described. 4,18,22 Briefly, after anesthesia with ketamine (50 mg/kg, i.m), femoral venous and arterial catheters were inserted and the trachea was cannulated. Ventilation (Animal Ventilator model 713, Harvard Apparatus, So.…”