Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: A systematic review

Nitric oxide produced by the neuronal or inducible isoform of nitric oxide synthase (nNOS, iNOS) is detrimental in acute ischemic stroke (IS), whereas that derived from the endothelial isoform is beneficial. However, experimental studies with nitric oxide synthase inhibitors have given conflicting results. Relevant studies were found from searches of EMBASE, PubMed, and reference lists; of 456 references found, 73 studies involving 2321 animals were included. Data on the effects of NOS inhibition on lesion volume (mm3, %) and cerebral blood flow (CBF; %, ml · min−1 · g−1) were analyzed using the Cochrane Review Manager software. NOS inhibitors reduced total infarct volume in models of permanent (standardized mean difference (SMD) −0.56, 95% confidence interval (95% CI) −0.86, −0.26) and transient (SMD −0.99, 95% CI −1.25, −0.72) ischemia. Cortical CBF was reduced in models of permanent but not transient ischemia. When assessed by type of inhibitor, total lesion volume was reduced in permanent models by nNOS and iNOS inhibitors, but not by nonselective inhibitors. All types of NOS inhibitors reduced infarct volume in transient models. NOS inhibition may have negative effects on CBF but further studies are required. Selective nNOS and iNOS inhibitors are candidate treatments for acute IS.