To determine whether exposure to chronic hypoxia and subsequent development of pulmonary hypertension induces alterations of endothelium-dependent relaxation in rat pulmonary vascular bed, we studied isolated lung preparations from rats exposed to either room air (controls) or hypoxia (H) during 1

Fax + 33 1 60 92 21 25 rious effects of NO derived from neuronal or inducible Abstract. Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features isoforms. New neuroprotective strategies have been leading to neuronal death in cerebral ischemia, trau-proposed with selective NOS inhibitors for the neuronal matic brain injury, Parkinson's disease, Huntington's (ARL17477) or the inducible (1400W) isoforms or with disease, Alzheimer's disease and amyotrophic lateral compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in sclerosis. Nitric oxide (NO) alone or in cooperation experimental ischemia-induced acute neuronal damage. with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of The efficacy of these new strategies is well established in NO synthase (NOS) inhibitors and mutant mice lacking acute neuronal injury but remains to be determined in each NOS isoform have provided evidence for the inju-more chronic neurological diseases.

To define the relationship between plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) and hemodynamic parameters in patients with chronic pulmonary artery hypertension, we measured plasma concentrations of the peptide in 15 patients during right heart catheterization. Eleven patients had chronic obstructive pulmonary disease and 4 had pulmonary vascular disease of diverse etiology. At rest, plasma concentrations of IR-ANP positively correlated with mean pulmonary artery pressure (r = 0.70, p less than 0.01) and pulmonary vascular resistance (r = 0.88, p less than 0.001), but not with right atrial pressure. Nine of these patients, all with chronic obstructive pulmonary disease, were also evaluated during exercise. Plasma concentrations of IR-ANP increased from 131 +/- 22 to 191 +/- 30 pg/ml (p less than 0.003) at maximal exercise, whereas pulmonary artery pressure increased from 29 +/- 1.5 to 56 +/- 2.5 mm Hg and right atrial pressure from 5 +/- 1 to 13 +/- 2 mm Hg. Increases of plasma IR-ANP concentrations correlated with changes in pulmonary artery pressure and right atrial pressure but not with changes in pulmonary capillary wedge pressure. These findings suggest that ANP is released in response to an increase in pulmonary artery pressure and are consistent with the hypothesis that ANP could modulate the pulmonary vascular tone in patients with pulmonary artery hypertension.

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The influence of endogenous and exogenous atrial natriuretic factor (ANF) on pulmonary hemodynamics was investigated in anesthetized pigs during both normoxia and hypoxia. Continuous hypoxic ventilation with 11% O2 was associated with a uniform but transient increase of plasma immunoreactive (ir) ANF that peaked at 15 min. Plasma irANF was inversely related to pulmonary arterial pressure (Ppa; r = -0.66, P less than 0.01) and pulmonary vascular resistance (PVR; r = -0.56, P less than 0.05) at 30 min of hypoxia in 14 animals; no such relationship was found during normoxia. ANF infusion after 60 min of hypoxia in seven pigs reduced the 156 +/- 20% increase in PVR to 124 +/- 18% (P less than 0.01) at 0.01 microgram.kg-1.min-1 and to 101 +/- 15% (P less than 0.001) at 0.05 microgram.kg-1.min-1. Cardiac output (CO) and systemic arterial pressure (Psa) remained unchanged, whereas mean Ppa decreased from 25.5 +/- 1.5 to 20.5 +/- 15 mmHg (P less than 0.001) and plasma irANF increased two- to nine-fold. ANF infused at 0.1 microgram.kg-1.min-1 (resulting in a 50-fold plasma irANF increase) decreased Psa (-14%) and reduced CO (-10%); systemic vascular resistance (SVR) was not changed, nor was a further decrease in PVR induced. No change in PVR or SVR occurred in normoxic animals at any ANF infusion rate. These results suggest that ANF may act as an endogenous pulmonary vasodilator that could modulate the pulmonary pressor response to hypoxia.