Modification of Radiation Injury by Ramipril, Inhibitor of Angiotensin-Converting Enzyme, on Optic Neuropathy in the Rat

Abstract

Inhibitors of angiotensin-converting enzyme (ACE) have been used to reduce radiation-induced normal tissue injury. The present study was carried out to determine whether ramipril, one of the inhibitors of ACE, would ameliorate radiation-induced brain damage, using a well-characterized optic neuropathy model in the rat, one of the most critical and radiosensitive structures in the brain. The brains of adult Fischer rats were irradiated stereotactically with 30 Gy using a single collimated beam. Six months after irradiation and 1.5 mg/kg day(-1) ramipril (started 2 weeks after irradiation), rats were assessed for optic nerve damage functionally, using visual evoked potential, and histologically. Results show that ramipril conferred significant modification of radiation injury, since rats receiving radiation alone showed a threefold lengthening in the mean peak latency in the visual evoked potential, whereas 75% of rats receiving radiation followed by ramipril had evoked potentials that resembled those of normal untreated control rats. The histology of irradiated and ramipril-treated optic nerves appeared nearly normal, while there was significant demyelination in both optic nerves of irradiated rats. The study represents the first demonstration of prophylaxis of radiation injury by a carboxyl-containing ACE inhibitor, providing a pharmacological strategy designed to reduce radiation-induced normal tissue damage.

Can Angiotensin-Converting Enzyme Inhibitors Reduce the Incidence, Severity, and Duration of Radiation Proctitis?

“…Based on the propensity score matched analysis and the EORTC and RTOG grading classification our findings suggest that the use of ACEIs during prostate radical radiotherapy is significantly associated with a low grade proctitis. Our findings are in keeping with other studies that have identified the beneficial effects of concurrent use of ACEIs on reducing radiation induced injuries including radiation induced pneumonitis (12), nephritis (29), GI tract toxicity (37) and brain injury (30). A key advantage of our study was that propensity score matched analysis and the EORTC and RTOG grading classification of toxicity was used.…”

“…ACEIs have reported to decrease radiation-induced injuries in renal, brain, GI tract (29,30,37) in different models, although the underlying main, moderating and mediating mechanisms are yet to be unexplored. Various proposed mechanisms include the pharmacological component; that all type I angiotensin receptor blockers, L-158,809 and ACEIs containing sulphydryl radical were more effective in protection the lung against lung fibrosis (13).…”

“…Moreover, two animal studies (30,31) have demonstrated that the intake of ACEIs have reduced the prevalence of radiation induced brain injuries, including cognitive impairment and optic neuropathy. Other studies have explored the association between ACEIs and gastrointestinal (GI) toxicity.…”

The Management of Radiation-Induced Brain Injury

“…Intrathecal administration of the classic radioprotector WR-2721 (Amifostine) before spinal cord irradiation resulted in a dose-modifying factor of 1.3 and a prolongation of median latency to myelopathy by 63% at the ED 50 . 43 Fike et al observed that the polyamine synthesis inhibitor α-difluoromethylornithine reduced the volume of radionecrosis and contrast enhancement in the irradiated dog brain; 44 a delayed increase in microglia was also noted.…”

“…49 Administration of ramipril, an angiotensin converting enzyme inhibitor, from 2 weeks after stereotactic irradiation with a single dose of 30 Gy, until 6 months postirradiation, was associated with a reduction in the severity of optic neuropathy. 50 Attempts have been made to rectify the radiation-induced decrease in neurogenesis. Rezvani et al 51 transplanted neural stem cells 90 days after irradiation of the rat spinal cord with a single dose of 22 Gy.…”