Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes

Abstract

The purpose of the present study was to determine the relationship between hypertensive pulmonary vascular remodelling and the changes in mean pulmonary artery pressure (mPAP) during low-dose nitric oxide (NO) inhalation.Rats were exposed to chronic hypobaric hypoxia (air at 50.5 kPa (380 mmHg), 10% oxygen, for 5-29 days) to induce chronic pulmonary hypertension (PH) with pulmonary vascular structural changes. After the chronic hypoxic exposure, the rats had an indwelling pulmonary artery catheter inserted and changes in mPAP with NO were correlated to morphometrical analysis of pulmonary vascular changes.All concentrations of inhaled NO (0.1-2.0 parts per million) reduced mPAP with a similar per cent reduction from baseline mPAP in PH rats, while no changes were observed in control rats. During NO inhalation in PH rats, the absolute value of the decrease in mPAP, but not per cent reduction in mPAP, significantly correlated with baseline mPAP, the percentage of muscularised arteries at the alveolar wall level and at the alveolar duct level, and the per cent medial wall thickness of muscularised arteries.In the chronic hypoxic pulmonary hypertension model, the severity of pulmonary vascular remodelling did not alter the reactivity of the pulmonary arteries to nitric oxide and might, in part, determine the magnitude of nitric-oxide induced absolute reduction in mean pulmonary artery pressure. In all conditions causing pulmonary hypertension (PH), vascular changes include new muscularisation of normally non-muscular peripheral pulmonary arteries and medial muscle hypertrophy of normally muscular arteries. Abnormal muscular pulmonary vasculature might have a heightened reactivity [1, 2], which may explain the effect of nitric oxide (NO) inhalation in hypertensive pulmonary disease, because NO dilates constricted pulmonary vasculature. Although inhaled NO can dilate these structurallyremodelled pulmonary arteries, the degree of response to inhaled NO was quite variable in patients with congenital heart disease [1], primary pulmonary hypertension (PPH) [3], limited scleroderma and isolated PH [4] and severe acute respiratory distress syndrome (ARDS) [5]. The differences in severity of pulmonary vascular structural changes might explain the differences in inhaled NO-induced reduction in pulmonary artery pressure (PAP) among patients.Chronic hypoxia induces PH and hypertensive pulmonary vascular changes in rats [6][7][8]. With increasing exposure to hypoxia, there is a progressive increase in the severity of the hypertensive pulmonary vascular changes [7]. These findings allowed the authors to make a rat model of experimentally different degrees of PH and hypertensive pulmonary vascular changes. To determine the relationship between the hypertensive pulmonary vascular changes and response to inhaled NO, NO inhalation was carried out in a rat model of chronic PH induced by chronic hypoxic exposure of varying durations. Quantitative morphometrical analysis was applied to determine the severity of hypertensive pu...

Comparison of mechanical behavior among the extrapulmonary arteries from rats

“…Commercially available computer software was used to incrementally increase pressure every 1.38 kPa. A review of the literature showed that mean pulmonary arterial pressure (mPAP) in healthy rats can range from 2.57 kPa (Jiang et al, 2002) in Sprague-Dawley rats to 3.84 kPa (Deten et al, 2003) in Long-Evans rats. A maximum inflation pressure of 17.9 kPa was chosen to mimic extreme hypertension in the pulmonary artery.…”

Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics

“…Under normoxic conditions, inhaled NO has little vasodilatory effect on the adult pulmonary vasculature, suggesting perhaps a maximally vasodilated state at baseline or a non-responsiveness to NO (Jiang et al, 2002; Koizumi et al, 1994; Pison et al, 1993). In models of hypoxia-, thromboxane-, or endotoxin-induced pulmonary hypertension or acute lung injury associated pulmonary hypertension, NO blunts vasoconstriction and lowers pulmonary arterial pressure (Bottiger et al, 1996; Frostell et al, 1993; Rich et al, 1993; Rossaint et al, 1993; Weitzberg et al, 1993).…”

Acute Vasodilator Effect of Fasudil, a Rho-kinase Inhibitor, in Monocrotaline-Induced Pulmonary Hypertension in Rats

“…27 An aortic catheter was also passed from the left carotid artery into the ascending aorta to measure arterial pressure. At 24 to 48 hours after the catheterization and under conscious conditions in which the animals were calm and free-moving, a single oral administration of fasudil (3, 10, and 30 mg/kg) or vehicle was performed, and hemodynamic variables were continuously monitored with a polygraph system (AP-601G; Nihon Kohden, Tokyo, Japan) before and after the fasudil administration at 0.5, 1, 3, 5, 7, and 24 hours.…”