Treatment of Vasogenic Brain Edema with the Novel Cl⁻ Transport Inhibitor Torasemide

Abstract

The efficacy of the diuretic agent torasemide, which antagonizes the Na+/K+/Cl- cotransport and Cl- channels, was investigated to determine its inhibition of brain edema from a focal cerebral lesion. For this purpose, cold injury of the brain was induced in 50 Sprague-Dawley rats while monitoring arterial blood pressure. The brain was removed for gravimetric assessment of swelling of the traumatized hemisphere 24 h after trauma. The water content was also determined after drying the cerebral hemispheres for 24 h. Animals were divided into five groups. A control group with trauma received vehicle only; two other groups received 1.0 or 10.0 mg torasemide/kg body weight 30 minutes before and 6 h after trauma (n = 10-12). Administration of the drug after the insult was also investigated in animals with application of vehicle or 10.0 mg/kg of torasemide at 30 minutes and 6 h following the brain lesion (n = 8). Torasemide did not affect important physiologic variables, such as the arterial pO2, pCO2, pH, hemoglobin, hematocrit, or plasma osmolality, while increasing blood pressure (p < 0.01). The blood pressure response notwithstanding, treatment significantly attenuated hemispheric brain swelling from trauma. In control animals without treatment, cold injury led to hemispheric swelling of 8.89%. In animals with 1 mg torasemide/kg BW, brain swelling amounted to 8.51% and to 7.04% in animals receiving 10 mg/kg before and after the insult (p < 0.005). Treatment was also found to attenuate the increase in tissue water content from trauma, but without reaching statistical significance. Postinsult treatment with torasemide (10 mg/kg BW) at 30 minutes and 6 h after trauma was again associated with a significant reduction in hemispheric brain swelling, which in this group amounted to 7.46% compared with 9.76% in the untreated controls (p < 0.005). The increase in the cerebral water content from trauma was also significantly blunted in the latter experiments (p < 0.01). The present data indicate a remarkable therapeutic potential of the novel diuretic agent torasemide to reduce vasogenic brain edema from an acute cerebral lesion. It is surmised that the compound specifically interferes with Cl- transport mechanisms, which apparently are activated in edematous brain involving neuronal and glial cells, for example. This conclusion is supported by in vitro observations that torasemide inhibits the swelling of glial cells from acidosis. On the other hand, it is unlikely that gross dehydration of the brain secondary to the induction of diuresis by the agent played a role, because hematocrit and plasma osmolality were not found to be affected.

Bumetanide Inhibition of the Blood-Brain Barrier Na-K-Cl Cotransporter Reduces Edema Formation in the Rat Middle Cerebral Artery Occlusion Model of Stroke

“…Similarly, torasemide reduced brain swelling and attenuated the increase in brain water after cold injury-induced focal ischemia in rat (Staub et al, 1994). These findings are consistent with our present results.…”

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

“…Many results imply that NKCC1 contributes to ischemic neuronal damage by facilitating excessive Na + and Cl -entry during the NMDA-mediated excitotoxicity. Inhibition of NKCC1 activity reduces NMDA-induced swelling and glutamate-mediated neurotoxicity and significantly attenuates OGD-induced neuronal death [24] . In addition, a substantial number of studies using neuronal cells have reported that excitotoxic glutamate increases the influx of extracellular Ca 2+ , resulting in intracellular acidification, which stimulates several pH-regulating systems, including the Na + -H + exchanger (NHE).…”

Na-K-Cl Cotransporter-1 in the Mechanism of Ammonia-induced Astrocyte Swelling

“…The NKCC2 isoform is localized exclusively to the kidney (23,24). NKCC1 activation was shown to contribute to astrocyte swelling/brain edema in ischemia and to brain edema after traumatic brain injury (25)(26)(27)(28)(29)(30). Its role in astrocyte swelling after ammonia treatment and in the brain edema in fulminant hepatic failure, however, are not known.…”