Lung cGMP release subsequent to NO inhalation in pulmonary hypertension: responders versus nonresponders.

Inhalation of nitric oxide (NO) is widely employed for the assessment of pulmonary vasoresponsiveness in pulmonary hypertension (PH). However, the reasons for the huge differences in vascular reactivity to NO between patients are unknown, and the role of NO-induced cyclic guanosine monophosphate (cGMP) is unclear. Twenty patients with severe precapillary PH were investigated. Thirty-six Swan-Ganz catheter investigations were performed and the study subjects were tested for responses to NO inhalation. This included an assessment of pulmonary and systemic arterial plasma cGMP and atrial natriuretic peptide (ANP) levels. A significant NO response (pulmonary vascular resistance (PVR) decrease >20%) was noted in nine of 20 patients (45%) during the first catheterization. A highly significant correlation between baseline plasma cGMP and ANP levels with PVR was observed (r=0.62 and r=0.66, respectively; p<0.0001). In response to NO, systemic and mixed venous cGMP levels increased from 13.9 +/- 1.28 nM and 12.75 +/- 0.99 nM to 79.23 +/- 4.99 nM and 55.25 +/- 4.41 nM (p<0.001), respectively, accompanied by the appearance of a marked transpulmonary cGMP gradient. Although in the responder group ANP levels were significantly reduced after NO inhalation, no significant correlation was observed to the extent of PVR reduction. The magnitude of the NO-elicited cGMP response did not discriminate between haemodynamic responders and nonresponders. This study concludes that plasma cyclic guanosine monophosphate levels are significantly correlated with the severity of disease in pulmonary arterial hypertension. Nitric oxide inhalation provokes a prompt increase in cyclic guanosine monophosphate secretion, but the magnitude of this release is not linked with a decrease in pulmonary vascular resistance.

Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension: response to iloprost inhalation.

OBJECTIVES: The goal of this study was to assess atrial natriuretic peptide (ANP) levels during inhalation of iloprost in severe primary (PPH) and nonprimary pulmonary hypertension (NPPH). BACKGROUND: The ANP system is activated in pulmonary hypertension and may help protect from right ventricular (RV) decompensation. It is unknown if ANP regulation is the same in severe PPH and NPPH and if the dynamic regulation is intact in a highly activated ANP system. METHODS: In 11 patients with PPH and seven patients with NPPH, right heart catheter investigations were performed. Pulmonary and systemic artery ANP and cyclic guanosine monophosphate (cGMP) levels as well as hemodynamics were measured before and after iloprost inhalation. RESULTS: The baseline hemodynamics of patients with PPH and patients with NPPH were comparable (mean pulmonary artery pressure [mPAP]: 61 +/- 5 mm Hg vs. 52 +/- 5 mm Hg, pulmonary vascular resistance [PVR]: 1,504 +/- 153 dyne.s.cm(-5) vs. 1,219 +/- 270 dyne.s.cm(-5). Atrial natriuretic peptide and cGMP levels were increased about tenfold and fivefold compared with controls in both PPH and NPPH. Iloprost inhalation significantly decreased mPAP (-9.1 +/- 2.5 mm Hg vs. -7.9 +/- 1.5 mm Hg), PVR (-453 +/- 103 dyne.s.cm(-5) vs. -381 +/- 114 dyne.s.cm(-5)), ANP (-99 +/- 63 pg/ml vs. -108 +/- 47 pg/ml) and cGMP (-4.6 +/- 0.9 nM vs. -4.2 +/- 1.6 nM). Baseline ANP including all patients significantly correlated with PVR, right atrial pressure, cardiac index, RV ejection fraction, mixed venous oxygen saturation and cGMP. CONCLUSIONS: The ANP system is highly activated in patients with severe PPH and NPPH. Atrial natriuretic peptide levels are significantly correlated with parameters of RV function and pre- and afterload. Iloprost inhalation causes a rapid decrease in ANP and cGMP in parallel with pulmonary vasodilation and hemodynamic improvement.

NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation but may also result in chronic pulmonary hypertension. It has not been clarified whether acute HPV and the response to prolonged alveolar hypoxia are triggered by identical mechanisms. We characterized the vascular response to sustained hypoxic ventilation (3% O(2) for 120-180 min) in isolated rabbit lungs. Hypoxia provoked a biphasic increase in pulmonary arterial pressure (PAP). Persistent PAP elevation was observed after termination of hypoxia. Total blockage of lung nitric oxide (NO) formation by N(G)-monomethyl-L-arginine caused a two- to threefold amplification of acute HPV, the sustained pressor response, and the loss of posthypoxic relaxation. This amplification was only moderate when NO formation was partially blocked by the inducible NO synthase inhibitor S-methylisothiourea. The superoxide scavenger nitro blue tetrazolium and the superoxide dismutase inhibitor triethylenetetramine reduced the initial vasoconstrictor response, the prolonged PAP increase, and the loss of posthypoxic vasorelaxation to a similar extent. The NAD(P)H oxidase inhibitor diphenyleneiodonium nearly fully blocked the late vascular responses to hypoxia in a dose that effected a decrease to half of the acute HPV. In conclusion, as similarly suggested for acute HPV, lung NO synthesis and the superoxide-hydrogen peroxide axis appear to be implicated in the prolonged pressor response and the posthypoxic loss of vasorelaxation in perfused rabbit lungs undergoing 2-3 h of hypoxic ventilation.