Mediators of alkalosis-induced relaxation in pulmonary arteries from normoxic and chronically hypoxic piglets

Abstract

Alkalosis-induced relaxation was measured in precontracted arterial rings from 1-wk-old piglets exposed to normoxia or to 3 days of chronic hypoxia. In normoxic piglet arteries, alkalosis-induced relaxation was blunted in arteries without functional endothelium and in arteries treated with nitric oxide synthase or guanylate cyclase inhibitors but not in arteries treated with cyclooxygenase inhibitors or Ca2+- and ATP-dependent K+-channel inhibitors. Inhibition of voltage-dependent K+ channels with 10−3 M 4-aminopyridine also failed to block alkalosis-induced relaxation. 4-Aminopyridine at 10−2 M did block the response, but this may have been due to sustained vascular smooth muscle depolarization. Arteries from hypoxic piglets exhibited greater contraction to the thromboxane mimetic U-46619, decreased endothelium-dependent relaxation, and blunted alkalosis-induced relaxation. The residual relaxation was eliminated by nitric oxide synthase but not by cyclooxygenase or voltage-dependent K+-channel inhibition. Alkalosis-induced relaxation of newborn piglet pulmonary arteries appears to be mediated by the nitric oxide-cGMP pathway and is attenuated after 3 days of hypoxia, likely because of decreased nitric oxide activity.

Alkalosis stimulates endothelial nitric oxide synthase in cultured human pulmonary arterial endothelial cells

“…Our results not only confirm that alkalosis activates eNOS (5,13,14,28) but also demonstrate that alkalosis and acidosis increase expression of eNOS mRNA and protein. Interestingly, the nuclear effect of pH on eNOS was not in line with L-citrulline production with acidification, although it fits in the case of alkalization.…”

“…Inversely, acidosis elevates pulmonary vascular tone. Recent studies have shown that changes in pH affect the production of endothelium-derived relaxing factor (4,13,19). Mechanisms by which acidosis and alkalosis affect pulmonary vascular tone have been suggested to be involved with stimulation of NO release via Ca 2ϩ influx into the endothelium by extracellular alkalosis (5,28,29), as well as a close relationship between Ca 2ϩ uptake into endothelial cells and activation of the Na ϩ / Ca 2ϩ exchanger (NCX).…”

Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension

“…It demonstrates early changes in hemodynamic parameters and pulmonary vascular morphology consistent with the development of PAH in human infants exposed to hypoxia at birth (23, 26 -28, 53). In earlier studies (23,24,37), elevated PVRI was detected by 10 -14 days of hypoxia. In our study, the first sign of PAH was an increased medial thickening in 3-day CH piglets, which suggested vascular wall hypertrophy instead of the normal thinning of the pulmonary arterial musculature that occurs after birth (28).…”

“…Piglets were paired in environmental chambers at 3-4 days of age and exposed to N (FI O 2 ϭ 0.21) or CH (FIO 2 ϭ 0.10) for 3, 10, or 21 days. Ambient CO 2 was maintained at Ͻ0.5% by a combination of high gas flow in the chamber and CO 2 scrubbing with CaCO 3 (24). Piglets were removed from the chamber for Ͻ1 h each day for cleaning and replacement of feed and were allowed to feed ad libitum.…”

Effects of acid-base imbalance on vascular reactivity

“…In contrast, prostacyclin or K + channel activation contributed to the response of in situ pulmonary vessels. A study that sought to identify factors contributing to the difference in reactivity between isolated and in situ pulmonary vessels found that NOS inhibition fully blocked alkalosis-induced relaxation of piglet artery and vein rings in isolated pulmonary preparations ventilated with a gas mixture containing 3% CO 2 (pH ~7 .6) (26,27). In contrast, NOS inhibition alone had no effect on alkalosis-induced pulmonary vasodilation in isolated piglet lungs ventilated with gas mixture containing 0% CO 2 (pH ~7 .6) (28).…”