Abstract 1815 Poster Session I, Saturday, 5/1 (poster 104)
Background: In most vascular beds, acidosis causes vasodilation. Hypercapnic acidosis is thought to mediate vasodilation by a direct effect of CO2 on the vascular smooth muscle (VSM). In the cerebral circulation, dilator prostanoids have been implicated in CO2-mediated vasodilation. In the pulmonary circulation, both hypercapnic and isocapnic (metabolic) acidosis evoke vasoconstriction. The signaling mechanisms responsible for the unique vasoconstrictor response of the lung to acidosis are unknown.
Hypotheses: (1) Isolated PRV mimic the vasoconstrictor response of the intact lung to acidosis. (2) Acidosis mediates vasoconstriction by acting directly on VSM (i.e. It is an endothelial-independent response.) (3) CO2 has a pH-independent vasodilator effect on PRV, such that the magnitude of the vasoconstriction at pH 6.8 will be greater in the absence than in the presence of CO2. (4) CO2 mediates vasodilation via release of dilator prostanoids.
Methods: Endothelium-intact and denuded PRV isolated from newborn piglets were cannulated and pressurized to 15 mm Hg for continous measurement of lumen diameter (LD). Prewarmed buffer was circulated through the vessel chamber at a rate of 30 ml/min. Changes in LD were measured after successively exposing the vessels to Hepes-based buffer at pH 6.8 (Hepes-6.8) and bicarbonate-based buffer containing 14% CO2 at pH 6.8 (bicarb-6.8). Indomethacin (indo), nitro-L-arginine (LNA) and tetraethylammonium (TEA) were used to assess the contribution of prostanoids, nitric oxide, and K+ channel activation, respectively, in the dilation response to CO2-containing buffer.
Results: PRV (n = 12) constricted by 11 ± 2.5% when a bicarbonate-based buffer was changed from pH 7.4 (5% CO2) to pH 6.8 (14% CO2). When the superfusate was changed to Hepes-6.8, an additional 13.7 ± 2.3 % constriction was observed. Removal of the endothelium had no effect on the constrictor response to acidosis in the presence or absence of CO2. When the superfusate was switched from Hepes-6.8 to bicarb-6.8, a significant dilation occurred, reversing 66% of the original constriction to Hepes-6.8. The CO2-mediated dilation was partially (≈50%) inhibited by removal of the endothelium and inhibition of K+ channels with TEA, but not by indo or LNA.
Conclusion: PRV mimic the response of the intact lung by constricting to acidosis (pH 6.8). Acidosis-mediated constriction of PRV is endothelium-independent. Addition of CO2 while maintaining pH at 6.8 causes vasodilation, suggesting that CO2 is a dilator stimulus in the pulmonary circulation. Although the dilation response to CO2 is, at least in part, dependent on an intact endothelium, neither dilator prostanoids nor nitric oxide mediate the effect. The mechanism of CO2-induced dilation in the pulmonary circulation involves K+ channel activation and membrane hyperpolarization, perhaps via release of an endothelial-derived hyperpolarizing factor.
(Spon by: David W. Busija)