Production of Nitric Oxide, but Not Prostacyclin, Is Reduced in Klotho Mice

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A novel murine model of aging (kl/kl mice) has been developed by in vivo mutagenesis. We analyzed endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from 6- to 9-week old wild-type (+/+) and heterozygous (kl/+) klotho mice. The aortas of kl/+ mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) compared to +/+ mice. The response to sodium nitroprusside was unaltered in kl/+ mice. The contraction in response to norepinephrine was augmented by treatment with N G-nitro-<sc>L</sc>-arginine methyl ester (<sc>L</sc>-NAME, 10−5 M) to a greater extent in +/+ mice than in kl/+ mice. Treatment with <sc>L</sc>-NAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD. NO metabolites (NO2− and NO3−) and cGMP concentrations in the urine were significantly reduced in kl/+ mice compared to +/+ mice. However, the urinary excretion of 6-keto-prostaglandin F1α was unaltered. There was little immunostaining for NO synthase and vascular endothelial growth factor (VEGF) in the aorta of kl/+ mice. No immunostaining for NO synthase was noted in the aorta of kl/kl mice. The expression of the klotho gene product may have a role in the regulation of VEGF expression and is tightly linked to endothelial release of NO.
社団法人日本薬理学会の論文
2002-06-01