1-Aminocyclopropanecarboxylic acid, an antagonist of N-methyl-D-aspartate receptors causes hypotensive and antioxidant effects with upregulation of heme oxygenase-1 in stroke-prone spontaneously hypertensive rats

Abstract

1-Aminocyclopropanecarboxylic acid (ACPC) has been shown to protect neurons against glutamate-induced neurotoxicity by reducing N-methyl-D-aspartate (NMDA) receptor activation. Recent studies have demonstrated that several antagonists of NMDA receptors have important cardiovascular effects. In this study, we examined whether the cardiovascular effects of ACPC involve the role of heme oxygenase-1 (HO-1) and its antioxidant effect in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP were divided into two groups: a control group and an ACIPC group administered ACIPC at 50 mg/kg per day for 4 weeks by peritoneal injection. Systolic blood pressure (SBIP) and mortality of stroke were significantly lower in the ACPC group than in the control group. Urinary Na+ and Cl- excretion and plasma superoxide dismutase (SOD) activity were increased in the ACPC group. Western analysis detected proteins that were immunoreactive to anti-nitrotyrosine antibody and showed lower levels of expression in the cerebral cortex compared to that in the control group. Immunohistochemical analysis revealed that 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation in the hippocampus and cerebral cortex was reduced in the ACPC group. Quantitative reverse-transcription-polymerase chain reaction (RT-PCR) showed that administration of ACPC also significantly decreased the expression of neuronal nitric oxide synthase (nNOS) mRNA in the hippocampus and enclotherial nitric oxide synthase (eNOS) mRNA in the cerebral cortex, and drastically increased HO-1 mRNA in the cerebral cortex. Enhanced HO-1 staining on sections from the hippocampus and cerebral cortex was observed in the ACPC group. These data suggest that the normalization by ACPC of blood pressure elevation and mortality of stroke involves induction of the expression of HO-1, which exerts antioxidant and vascular relaxation effects, in SHRSP.