The role of nitric oxide in the development of neurogenic pulmonary edema in spinal cord-injured rats: the effect of preventive interventions

Abstract

Neurogenic pulmonary edema (NPE) is an acute life-threatening complication following an injury of the spinal cord or brain, which is associated with sympathetic hyperactivity. The role of nitric oxide (NO) in NPE development in rats subjected to balloon compression of the spinal cord has not yet been examined. We, therefore, pretreated Wistar rats with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) either acutely (just before the injury) or chronically (for 4 wk prior to the injury). Acute (but not chronic) L-NAME administration enhanced NPE severity in rats anesthetized with 1.5% isoflurane, leading to the death of 83% of the animals within 10 min after injury. Pretreatment with either the ganglionic blocker pentolinium (to reduce blood pressure rise) or the muscarinic receptor blocker atropine (to lessen heart rate decrease) prevented or attenuated NPE development in these rats. We did not observe any therapeutic effects of atropine administered 2 min after spinal cord compression. Our data indicate that NPE development is dependent upon a marked decrease of heart rate under the conditions of high blood pressure elicited by the activation of the sympathetic nervous system. These hemodynamic alterations are especially pronounced in rats subjected to acute NO synthase inhibition. In conclusion, nitric oxide has a partial protective effect on NPE development because it attenuates sympathetic vasoconstriction and consequent baroreflex-induced bradycardia following spinal cord injury.

The role of sympathetic nervous system in the development of neurogenic pulmonary edema in spinal cord-injured rats

“…On contrary, the same procedure did not lead to NPE when deeper anesthesia with 3% isoflurane was employed (21). Our experiments also indicated that the prevention of any of these two decisive components-blood pressure elevation by ganglionic blocker pentolinium and/or reflex bradycardia by atropine pretreatment-abolished NPE development following spinal cord compression (27). This is in line with the fact that isoflurane exerts sympathoinhibitory effects (20) and attenuates baroreflex gain in the control of either sympathetic nerve activity (20) or heart rate (HR) (13).…”

“…Our data (Fig. 4, Table 1) indicate that both types of ␣-adrenoceptor blockade were able to prevent not only NPE occurrence but also HR reduction which is a hemodynamic change essential for NPE development (26,27). The similar effects of ␣ 1 -and ␣ 2 -adrenoceptor blockade are not so surprising if we consider that an extensive catecholamine stimulation of these two different types of ␣-adrenoceptors always leads to a major augmentation of calcium entry through L type voltage-dependent Ca 2ϩ channels (L-VDCC) (8,17,18).…”

“…NPE did not occur in rats in which spinal cord was compressed at the lumbar level (Table 1, group 10; ⌬MAP Ϫ25 Ϯ 8 mmHg; ⌬HR Ϫ4 Ϯ 13 beats/min; p-index ϭ 0.43 Ϯ 0.01). This is in accordance with our previous findings that different types of spinal cord lesion, such as lower thoracic spinal transection at the T 8 level (⌬MAP 23 Ϯ 4 mmHg; ⌬HR Ϫ16 Ϯ 14 beats/min; p-index ϭ 0.46 Ϯ 0.04) or slow spinal compression (⌬MAP 0 Ϯ 2 mmHg; ⌬HR Ϫ23 Ϯ 7 beats/min; p-index ϭ 0.49 Ϯ 0.03), did not induce NPE (25,27). Hemodynamic data from these experiments clearly demonstrate that only such spinal cord interventions, which cause a marked rapid baroreflex-induced bradycardia, have a potential to promote the development of neurogenic edema.…”

“…To evaluate the contribution of this hemodynamic factor in the pathogenesis of NPE we have induced a moderate blood loss (ϳ15% volume of circulating blood) before spinal cord compression. It is evident that this intervention successfully prevented NPE development, indicating the importance of augmented venous return and overfilling of pulmonary circulation during early stages of NPE development, when baroreflex-induced reduction of HR impairs actual cardiac performance (27).…”

“…We have recently demonstrated (27) that major activation of sympathetic nervous system together with pronounced baroreflex-induced bradycardia are necessary prerequisites for the development of severe NPE, which is experimentally induced by rapid epidural balloon compression of the thoracic spinal cord in rats anesthetized by 1.5% isoflurane in air (21,22). On contrary, the same procedure did not lead to NPE when deeper anesthesia with 3% isoflurane was employed (21).…”