Alexandra Holzmann

Effects of intravenous Zaprinast and Inhaled nitric oxide on pulmonary hemodynamics and gas exchange in an ovine model of acute respiratory distress syndrome

Methods The authors studied two groups of sheep with lung injury produced by saline lavage. In the first group, 0, 5, 10, and 20 ppm of inhaled NO were administered in a random order before and after an intravenous Zaprinast infusion (2 mg/kg bolus followed by 0.1 mg · kg−1 · min−1). In the second group, inhaled NO was administered at the same concentrations before and after an intravenous infusion of Zaprinast solvent (0.05 m NaOH). Results After lavage, inhaled NO decreased pulmonary arterial pressure and resistance with no systemic hemodynamic effects, increased arterial oxygen partial pressure, and decreased venous admixture (all P < 0.05). The intravenous administration of Zaprinast alone decreased pulmonary artery pressure but worsened gas exchange (P < 0.05). Zaprinast infusion abolished the beneficial ability of inhaled NO to improve pulmonary gas exchange and reduce pulmonary artery pressure (P < 0.05 vs. control). Conclusions This study suggests that nonselective vasodilation induced by intravenously administered Zaprinast at the dose used in our study not only worsens gas exchange, but also abolishes the beneficial effects of inhaled NO.

Inhibition of Nitric Oxide Synthase Prevents Hyporesponsiveness to Inhaled Nitric Oxide in Lungs from Endotoxin-challenged Rats

BACKGROUND Inhalation of nitric oxide (NO) selectively dilates the pulmonary circulation and improves arterial oxygenation in patients with adult respiratory distress syndrome (ARDS). In approximately 60% of patients with septic ARDS, minimal or no response to inhaled NO is observed. Because sepsis is associated with increased NO production by inducible NO synthase (NOS2), the authors investigated whether NOS inhibition alters NO responsiveness in rats exposed to gram-negative lipopolysaccharide (LPS). METHODS Sprague-Dawley rats were treated with 0.4 mg/kg Escherichia coli O111:B4 LPS with or without dexamethasone (inhibits NOS2 gene expression; 5 mg/kg), L-NAME (a nonselective NOS inhibitor; 7 mg/kg), or aminoguanidine (selective NOS2 inhibitor; 30 mg/kg). Sixteen hours after LPS treatment, lungs were isolated-perfused; a thromboxane-analog U46619 was added to increase pulmonary artery pressure (PAP) by 5 mmHg, and the pulmonary vasodilator response to inhaled NO was measured. RESULTS Ventilation with 0.4, 4, and 40 ppm NO decreased the PAP less than in lungs of LPS-treated rats (0.75+/-0.25, 1.25+/-0.25, 1.75+/-0.25 mmHg) than in lungs of control rats (3+/-0.5, 4.25+/-0.25, 4.5+/-0.25 mmHg; P < 0.01). Dexamethasone treatment preserved pulmonary vascular responsiveness to NO in LPS-treated rats (3.75+/-0.25, 4.5+/-0.25, 4.5+/-0.5 mmHg, respectively; P < 0.01 vs. LPS, alone). Responsiveness to NO in LPS-challenged rats was also preserved by treatment with L-NAME (3.0+/-1.0, 4.0+/-1.0, 4.0+/-0.75 mmHg, respectively; P < 0.05 vs. LPS, alone) or aminoguanidine (1.75+/-0.25, 2.25+/-0.5, 2.75+/-0.5 mmHg, respectively; P < 0.05 vs. LPS, alone). In control rats, treatment with dexamethasone, L-NAME, and aminoguanidine had no effect on inhaled NO responsiveness. CONCLUSION These observations demonstrate that LPS-mediated increases in pulmonary NOS2 are involved in decreasing responsiveness to inhaled NO.

Inhaled nitric oxide inhibits platelet-leukocyte interactions in patients with acute respiratory distress syndrome

INTRODUCTION In addition to its effects on platelet function, recent studies suggest that inhaled nitric oxide (NO) also influences the function of circulating leukocytes. Therefore, the aim of this work was to investigate the formation of platelet-leukocyte aggregates (PLAs) and platelet and leukocyte cell surface receptor expression during NO therapy in patients with acute respiratory distress syndrome. METHODS In 16 patients responding to NO therapy with an improvement in oxygenation (NO group) and in four nonresponders (control), platelet P-selectin expression, platelet fibrinogen binding, the expression CD11a on leukocytes, and the formation of PLAs were investigated at 0, 60, 120, and 180 mins of therapy or at corresponding time points by means of flow cytometry. In addition, PLA was investigated in 30 healthy volunteers during NO inhalation, in five mechanically ventilated patients without acute respiratory distress syndrome and without NO inhalation, and during NO incubation in platelet-rich plasma of ten healthy volunteers in vitro. RESULTS NO therapy inhibited PLA formation at 60 (13% +/- 4% in the NO group vs. 19% +/- 7% in the control group, p <.01) and 120 mins (14% +/- 4% vs. 18% +/- 7%, p <.05) and slightly decreased CD11a expression at 60 mins (152 +/- 22 arbitrary units vs. 187 +/- 36 arbitrary units, p <.05). Furthermore, besides inhibiting platelet fibrinogen binding, NO also led to a significant inhibition of P-selectin expression at 120 (38% +/- 4% vs. 43% +/- 5%, p <.05) and 180 mins (34% +/- 5% vs. 43% +/- 6%, p <.01), demonstrating a significant correlation between changes in P-selectin expression and PLA formation. In contrast, PLA formation was not influenced by mechanical ventilation in patients without acute respiratory distress syndrome. These results were further supported by additional studies showing inhibition of PLA formation in healthy volunteers as well. CONCLUSIONS NO-dependent inhibition of PLA formation in patients with acute respiratory distress syndrome can be explained by the inhibition in platelet P-selectin expression. Thus, this study provides rational evidence of systemic antileukocytic and antiplatelet properties of NO therapy in the clinical setting.

Selective pulmonary vasodilation by intravenous infusion of an ultrashort half-life nucleophile/nitric oxide adduct.

Background PROLI/NO (C5 H7 N3 O4 Na2 [center dot] CH3 OH) is an ultrashort‐acting nucleophile/NO adduct that generates NO (half‐life 2 s at 37 [degree sign] Celsius and pH 7.4). Because of its short half‐life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension. Methods In eight awake healthy sheep with pulmonary hypertension induced by 9,11‐dideoxy‐9 alpha,11 alpha‐methanoepoxy prostaglandin F sub 2 alpha, the authors compared PROLI/NO with two reference drugs‐inhaled NO, a well‐studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1 of SNP or 0.75, 1.5, 3, 6, and 12 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized. Results Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 micro gram [center dot] kg sup ‐1 [center dot] min sup ‐1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled). Conclusions The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.