Genetic Vulnerability of Cortical Neurons Isolated from Stroke-Prone Spontaneously Hypertensive Rats in Hypoxia and Oxygen Reperfusion

Motoki Tagami; Kazuo Yamagata; Katsumi Ikeda; Hideaki Fujino; Yasuo Nara; Kiyoshi Nakagawa; Akiyoshi Kubota; Fujio Numano; Yukio Yamori

doi:10.1291/hypres.22.23

Motoki Tagami, Kazuo Yamagata, Katsumi Ikeda, Hideaki Fujino, Yasuo Nara, Kiyoshi Nakagawa, Akiyoshi Kubota, Fujio Numano, Yukio Yamori

著者情報

Motoki Tagami
Department of Internal Medicine, Sanraku Hospital
Kazuo Yamagata
Division of Applied Life Science, Graduate School of Integrated Science and Art, University of East Asia
Katsumi Ikeda
Otsuka Department of International Preventive Medicine, Graduate School of Human and Environmental Studies, Kyoto University
Hideaki Fujino
Department of Internal Medicine, Sanraku Hospital
Yasuo Nara
Division of Applied Life Science, Graduate School of Integrated Science and Art, University of East Asia
Kiyoshi Nakagawa
Life Science, Environmental Conservation and Development, Graduate School of Human and Environmental Studies, Kyoto University
Akiyoshi Kubota
Department of Internal Medicine, Sanraku Hospital
Fujio Numano
The Third Department of Internal Medicine, Tokyo Medical and Dental University
Yukio Yamori
Life Science, Environmental Conservation and Development, Graduate School of Human and Environmental Studies, Kyoto University

キーワード: antioxidant, apoptosis, hypoxia, insulin-like growth factor, oxygen radical

ジャーナルフリー

1999 年 22 巻 1 号 p. 23-29

DOI https://doi.org/10.1291/hypres.22.23

詳細

Published: 1999 Received: - Available on J-STAGE: 2006/08/10 Accepted: - Advance online publication: - Revised: -
訂正情報
訂正日: 2006/08/10 訂正理由: - 訂正箇所: 論文受付日訂正内容: 訂正前 : 19980729

訂正日: 2006/08/10 訂正理由: - 訂正箇所: 論文タイトル訂正内容: Wrong : Impaired Nitric Oxide-Independent Dilation of Renal Afferent Arterioles in Spontaneously Hypertensive Rats
Right : Genetic Vulnerability of Cortical Neurons Isolated from Stroke-Prone Spontaneously Hypertensive Rats in Hypoxia and Oxygen Reperfusion

訂正日: 2006/08/10 訂正理由: - 訂正箇所: 論文抄録訂正内容: Wrong : Sustained hypertension alters vasomotor regulation in various vascular beds. We studied whether nitric oxide (NO)-dependent and NO-independent vasodilator mechanisms are altered in renal microvessels in hypertension. To directly visualize the renal microcirculation, the isolated perfused hydronephrotic rat kidney model was used. After pretreatment with indomethacin (100μmol/l), afferent arterioles were constricted by norepinephrine (NE) or by increasing renal arterial pressure (i.e., myogenic constriction; from 80 to 180mmHg). Acetylcholine (ACH) was then added, and the renal microvascular response was assessed by computer-assisted video image analysis. A similar protocol was conducted in the presence of nitro-L-arginine methylester (L-NAME; 100μmol/l). During NE constriction, ACH caused dose-dependent and sustained vasodilation of the afferent arteriole, similar in magnitude in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the presence of L-NAME, ACH (0.01-1μmol/l) elicited only transient dilation, and the degree of vasodilation was very low in SHR. During myogenic constriction, afferent arterioles from WKY and SHR kidneys responded to ACH with only transient vasodilation, which was unaffected by NO inhibition; the transient vasodilative responses elicited by ACH (0.1-1μmol/l) were smaller in SHR than in WKY. In conclusion, ACH has both sustained and transient vasodilative effects on the afferent arteriole. Sustained vasodilation is attributed to NO generation, which is similar in WKY and SHR. In contrast, transient vasodilation, mediated by NO-independent vasodilator factors, is impaired in SHR. Deranged vasodilatory mechanisms in hypertension may disturb the renal microcirculation, which may result in renal injury. (Hypertens Res 1999; 22: 31-37)
Right : Severe hypertension and cerebrovascular diseases develop in stroke-prone spontaneously hypertensive rats (SHRSP). Cortical neurons from SHRSP are more vulnerable than those from Wistar Kyoto rats (WKY) to the effects of nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, idebenone, and nilvadipine (a Ca²⁺ channel blocker) can reduce neuronal damage caused by hypoxia or neurotoxic agents. This study was designed to determine 1) whether cortical neurons from SHRSP are more vulnerable than those from WKY and 2) whether neuronal damage is minimized by the so-called neuroprotective agents in cells exposed to hypoxia and oxygen reperfusion. We demonstrated that 6 to 24h of hypoxia did not increase cell death in either WKY or SHRSP, whereas 36h of hypoxia significantly increased cell death in SHRSP (p<0.01). Furthermore, 6 to 36h of hypoxia and 1.5 to 5h of reperfusion heavily damaged cells from both strains of rats, and most cells became apoptotic or necrotic. We also verified that the ability to protect neurons in hypoxia and oxygen reperfusion was as follows: idebenone>insulin-like growth factor-1(IGF-1)>nilvadipine. These data indicate that oxygen radical generation occurs and the free radicals heavily damage neurons in hypoxia and oxygen reperfusion. SHRSP neurons are weaker than WKY neurons in these conditions. Furthermore, we surmise that idebenone, an antioxidant, decreases free radicals, and IGF-1 attenuates p⁵³-mediated apoptosis and thereby prevents cell death. We conclude that antioxidants are more potent than IGF-1 in protecting cortical neurons from damage caused by hypoxia and oxygen reperfusion, although both are very useful in minimizing damage to cortical neurons. (Hypertens Res 1999; 22; 23-29)

訂正日: 2006/08/10 訂正理由: - 訂正箇所: 著者情報訂正内容: Wrong : Koichi Hayashi¹⁾, Hiroto Matsuda¹⁾, Takahiko Nagahama¹⁾, Keiji Fujiwara¹⁾, Yuri Ozawa¹⁾, Eiji Kubota¹⁾, Masanori Honda¹⁾, Hirobumi Tokuyama¹⁾, Takao Saruta¹⁾
Right : Motoki Tagami¹⁾, Kazuo Yamagata²⁾, Katsumi Ikeda³⁾, Hideaki Fujino¹⁾, Yasuo Nara²⁾, Kiyoshi Nakagawa⁴⁾, Akiyoshi Kubota¹⁾, Fujio Numano⁵⁾, Yukio Yamori⁴⁾

訂正日: 2006/08/10 訂正理由: - 訂正箇所: 所属機関情報訂正内容: 訂正前 :
1) the Department of Internal Medicine, School of Medicine

訂正後 :
1) Department of Internal Medicine, Sanraku Hospital
2) Division of Applied Life Science, Graduate School of Integrated Science and Art, University of East Asia
3) Otsuka Department of International Preventive Medicine, Graduate School of Human and Environmental Studies, Kyoto University
4) Life Science, Environmental Conservation and Development, Graduate School of Human and Environmental Studies, Kyoto University
5) The Third Department of Internal Medicine, Tokyo Medical and Dental University

訂正日: 2006/08/10 訂正理由: - 訂正箇所: キーワード情報訂正内容: Wrong : hypertension, afferent arteriole, EDHF, nitric oxide, acetylcholine
Right : antioxidant, apoptosis, hypoxia, insulin-like growth factor, oxygen radical

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訂正日: 2006/08/10 訂正理由: - 訂正箇所: 論文受付日訂正内容: 訂正後 : 19980701

抄録

Severe hypertension and cerebrovascular diseases develop in stroke-prone spontaneously hypertensive rats (SHRSP). Cortical neurons from SHRSP are more vulnerable than those from Wistar Kyoto rats (WKY) to the effects of nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, idebenone, and nilvadipine (a Ca²⁺ channel blocker) can reduce neuronal damage caused by hypoxia or neurotoxic agents. This study was designed to determine 1) whether cortical neurons from SHRSP are more vulnerable than those from WKY and 2) whether neuronal damage is minimized by the so-called neuroprotective agents in cells exposed to hypoxia and oxygen reperfusion. We demonstrated that 6 to 24h of hypoxia did not increase cell death in either WKY or SHRSP, whereas 36h of hypoxia significantly increased cell death in SHRSP (p<0.01). Furthermore, 6 to 36h of hypoxia and 1.5 to 5h of reperfusion heavily damaged cells from both strains of rats, and most cells became apoptotic or necrotic. We also verified that the ability to protect neurons in hypoxia and oxygen reperfusion was as follows: idebenone>insulin-like growth factor-1(IGF-1)>nilvadipine. These data indicate that oxygen radical generation occurs and the free radicals heavily damage neurons in hypoxia and oxygen reperfusion. SHRSP neurons are weaker than WKY neurons in these conditions. Furthermore, we surmise that idebenone, an antioxidant, decreases free radicals, and IGF-1 attenuates p⁵³-mediated apoptosis and thereby prevents cell death. We conclude that antioxidants are more potent than IGF-1 in protecting cortical neurons from damage caused by hypoxia and oxygen reperfusion, although both are very useful in minimizing damage to cortical neurons. (Hypertens Res 1999; 22; 23-29)

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