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CENTRAL NERVOUS SYSTEM

Alterations of Gene Expressions of PreproET-1 and ET Receptors in Brains of Endotoxemic Sprague-Dawley Rats

Nobutake Shimojo^*, Subrina Jesmin^*, Sohel Zaedi^*, Seiji Maeda^*, Satoshi Gando, Iwao Yamaguchi^*, Katsutoshi Goto and Takashi Miyauchi^*,1

^* Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine; and Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan; and Department of Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

To whom requests for reprints should be addressed at ¹ Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail: t-miyauc{at}md.tsukuba.ac.jp

Abstract

During severe sepsis, several immunological defense mechanisms initiate a cascade of inflammatory events leading to multiorgan failure, including septic encephalopathy and ultimately death. Endothelin-1 (ET-1) has recently been investigated in different cerebral pathologies. Some reports suggest the involvement of ET-1 in sepsis. However, no study to date has reported the alterations in expression of the genes encoding preproET-1 and ET receptors in the frontal cortex of the septic brain. Male Sprague-Dawley (SD) rats 8 weeks of age were administered either saline or 15 mg/kg lipopolysaccharide (LPS) at different time points (1, 3, 6, and 10 hrs). Rats that did not receive LPS were considered to be controls. The rats were sacrificed with ether, and the brain tissues were harvested. Systolic and diastolic blood pressure decreased 1 hr after LPS administration and then gradually returned to normal, without any change in the heart rate. We confirmed the induction of endotoxemia in the brains of SD rats by measuring the expression of nitric oxide synthase (NOS) mRNA induced in the cerebrum. The expression of inducible NOS (iNOS) mRNA in the brains of SD rat after LPS administration was 30-fold higher than that in the brains of control rats. mRNA expression of preproET-1 in the frontal cortex of SD rats after LPS administration was 2-fold higher than that in control rats. A time-dependent increase in the expression of the gene encoding the ET_A receptor (vasoconstrictive property) after LPS administration was observed in SD rat brain, whereas expression of the gene encoding the ET_B receptor (vasodilatatory property) showed an initial upregulation and then gradually decreased as sepsis progressed. In conclusion, we report for the first time that expressions of the genes encoding ET-1 and ET receptors are altered in the endotoxemic brain and that these alterations are time-dependent in SD rats. The alterations in the ET system in brain tissue observed in the present study may contribute to the understanding of the pathophysiological changes in the endotoxemic brain.

Key Words: endothelin-1 • endothelin receptors • endotoxemia • brain • blood pressure