系統:  SHRSP (Stroke-prone spontaneously hypertensive rat) 
キーワード:  脳卒中 
由来:  家森らにより高血圧を発症する SHR系ラットより作出された。SHR 系の A1-sbとA3 亜系統を 交雑して作出した基礎集団から、毎世代脳卒中で死亡した親からの仔を選抜・交配して1974 年に確立された。 
表現型・病態:  血圧は10 週齢で平均187mmHg に達する。祖先系統の SHRより40~50mmHg 高い血圧にまで達する。病理学的にヒトと極めて類似した脳卒中を発症する。脳出血と脳梗塞の両方を発症する。脳出血あるいは脳梗塞の発症率は雄では100日齢までに82%、雌では150日齢までに 58%。発生部位は anteriomedial and occipital cortex とbasal ganglia。  
病因(原因遺伝子):  SHR 系の高血圧に係る遺伝子マッピングは、SHRSP を用いて行われたものが最初である(SHR の項参照)。その後、SHRSP ラットと他系統ラットとの F2 ラットを用いた遺伝的連鎖解析により、高血圧を起こす遺伝子とは独立した、いくつかの脳卒中素因遺伝子の存在する染色体領域が見つかっている。脳血管障害を起こしやすくする遺伝子が第1 染色体に、逆に脳血管障害を起こしにくくする遺伝子が第4および第 5 染色体にあることが1996 年に報告されている。同じく1996 年に第4 染色体に脳卒中と関連した遺伝子の存在を確認した報告、また1997 年に脳虚血に対する脳組織の脆弱性と関連する遺伝子が第 5 染色体にあるとする報告が出された。しかしながらこれらの遺伝子の正体は明らかではない。 
臨床への応用、有用性:  脳卒中のモデルとして有用。 
維持機関:  京都大学大学院人間・環境学研究科 近畿大学医学部 島根医科大学 SHR等疾患モデル共同研究会 日本チャールスリバー (株)星野試験動物飼育所 (2001年5月25日現在) 
文献:  Negrin, CD., McBride, MW., Carswell, HV., Graham, D., Carr, FJ., Clark, JS., Jeffs, B., Anderson, NH., Macrae, IM., Dominiczak, AF. Reciprocal consomic strains to evaluate y chromosome effects. Hypertension 37: 391-397, 2001 Kato, N., Tamada, T., Nabika, T., Ueno, K., Gotoda, T., Matsumoto, C., Mashimo, T., Sawamura, M., Ikeda, K., Nara, Y., Yamori, Y. Identification of quantitative trait loci for serum cholesterol levels in stroke-prone spontaneously hypertensive rats. Arteriosclerosis, Thrombosis & Vascular Biology. 20: 223-229, 2000 Jeffs, B., Negrin, CD., Graham, D., Clark, JS., Anderson, NH., Gauguier, D., Dominiczak, AF. Applicability of a "speed" congenic strategy to dissect blood pressure quantitative trait loci on rat chromosome 2. Hypertension. 35:179-187, 2000 Rubattu S. Giliberti R. Russo R. Gigante B. Ganten U. Volpe M. Analysis of the genetic basis of the endothelium-dependent impaired vasorelaxation in the stroke-prone spontaneously hypertensive rat: a candidate gene approach. Journal of Hypertension. 18: 161-165, 2000 Intengan, HD., Schiffrin, EL. Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. Hypertension. 35: 1221-1225, 2000 Kimura, S., Saito, H., Minami, M., Togashi, H., Nakamura, N., Nemoto, M., Parvez HS. Pathogenesis of vascular dementia in stroke-prone spontaneously hypertensive rats. Toxicology 153:167-178, 2000 Collison, M., Glazier, AM., Graham, D., Morton, JJ., Dominiczak, MH., Aitman, TJ., Connell, JM., Gould, GW., Dominiczak, AF. Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat. Diabetes 49: 2222-2226, 2000 Carswell, HV., Anderson, NH., Clark, JS., Graham, D., Jeffs, B., Dominiczak AF., Macrae, IM. Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension. 33: 681-685, 1999 Brosnan, MJ., Clark, JS., Jeffs, B., Negrin, CD., van Vooren, P., Arribas, SM., Carswell, H., Aitman, TJ., Szpirer, C., Macrae, IM., Dominiczak, AF. Genes encoding atrial and brain natriuretic peptides as candidates for sensitivity to brain ischemia in stroke-prone hypertensive rats. Hypertension. 33: 290-297, 1999 Tagami, M., Yamagata, K., Ikeda, K., Fujino, H., Nara, Y., Nakagawa, K., Kubota, A., Numano, F., Yamori Y. Genetic vulnerability of cortical neurons isolated from stroke-prone spontaneously hypertensive rats in hypoxia and oxygen reperfusion. Hypertension Research. 22: 23-29, 1999 Yamori, Y. Implication of hypertensive rat models for primordial nutritional prevention of cardiovascular diseases. Clinical & Experimental Pharmacology & Physiology. 26: 568-572, 1999 Ikeda, K., Yamori Y. Gene related to stroke in stroke-prone spontaneously hypertensive rats. Clinical & Experimental Pharmacology & Physiology. 26: 566-567, 1999 Mizutani, K., Ikeda, K., Kawai, Y., Yamori, Y. Biomechanical properties and chemical composition of the aorta in genetic hypertensive rats. Journal of Hypertension. 17: 481-487, 1999 Hubner, N., Lee, YA., Lindpaintner, K., Ganten, D., Kreutz, R. Congenic substitution mapping excludes Sa as a candidate gene locus for a blood pressure quantitative trait locus on rat chromosome 1. Hypertension. 34: 643-648, 1999 Rubattu, S., Giliberti, R., Ganten ,U., Volpe, M. Differential brain atrial natriuretic peptide expression co-segregates with occurrence of early stroke in the stroke-prone phenotype of the spontaneously hypertensive rat. Journal of Hypertension. 17: 1849-1852, 1999 Rubattu, S., Lee-Kirsch, MA., DePaolis, P., Giliberti, R., Gigante, B., Lombardi, A., Volpe, M., Lindpaintner, K. Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat. Circ Res 85: 900-905, 1999 Mashimo, T., Nabika, T., Matsumoto, C., Tamada, T., Ueno, K., Sawamura, M., Ikeda, K., Kato, N., Nara, Y., Yamori, Y. Aging and salt-loading modulate blood pressure QTLs in rats. Am J Hypertens 12: 1098-1104, 1999 Russo, R., Vecchione, C., Cosentino, F., Natale, A., Mele, AF., Muscolo, M., Savoia, C., Ganten, D., Rubattu, S., Volpe, M. Impaired vasorelaxant responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats. Journal of Hypertension. 16: 151-156, 1998 Jeffs, B., Clark, JS., Anderson, NH., Gratton, J., Brosnan,MJ., Gauguier, D., Reid, JL., Macrae, IM., Dominiczak, AF. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat. Genet. 16: 364-367, 1997 Volpe, M., Iaccarino, G., Vecchione, C., Rizzoni, D., Russo, R., Rubattu, S., Condorelli, G., Ganten, U., Ganten, D., Trimarco, B., Lindpaintner, K. Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats. Journal of Clinical Investigation. 98: 256-261, 1996 Rubattu, S., Volpe, M., Kreutz, R., Ganten, U., Ganten, D., Lindpaintner, K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nature Genetics. 13: 429-434, 1996 Ikeda, K., Nara, Y., Matumoto, C., Mashimo, T., Tamada, T., Sawamura, M., Nabika, T., Yamori, Y. The region responsible for stroke on chromosome 4 in the stroke-prone spontaneously hypertensive rat. Biochemical & Biophysical Research Communications. 229: 658-662, 1996 Clark, JS., Jeffs, B., Davidson, AO., Lee, WK., Anderson, NH., Bihoreau, MT., Brosnan, MJ., Devlin, AM., Kelman, AW., Lindpaintner, K., Dominiczak AF. Quantitative trait loci in genetically hypertensive rats. Possible sex specificity. Hypertension 28: 898-906, 1996 Volpe, M., Rabattu, S. Pathophysiological aspects of genetically determined hypertension in rats, with special emphasis on stroke-prone spontaneously hypertensive rats. Handbook of Hypertension Vol. 16 Experimental and Genetic Models of Hypertension (Ganten D. and de Jong W., eds), pp. 365-394. Elsevier, 1994 Hubner, N., Kreutz, R., Takahashi, S., Ganten, D., Lindpaintner, K. Unlike human hypertension, blood-pressure in a hereditary hypertensive rat strain shows no linkage to the angiotensinogen locus. Hypertension 23: 797-801, 1994 Koike, G., Krieger, JE., Jacob, HJ., Mukoyama, M., Pratt, RE., Dzau, VJ. Angiotensin converting enzyme and genetic hypertension: cloning of rat cDNAs and characterization of the enzyme. Biochemical & Biophysical Research Communications. 198: 380-386, 1994 Hilbert, P., Lindpaintner, K., Beckmann, JS., Serikawa, T., Soubrier, F., Dubay, C., Cartwright, P., De Gouyon, B., Julier, C., Takahasi, S. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats [see comments]. Nature. 353: 521-529, 1991 Jacob, HJ., Lindpaintner, K., Lincoln, SE., Kusumi, K., Bunker, RK., Mao, YP., Ganten, D., Dzau, VJ., Lander, ES. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67: 213-224, 1991 Yamori, Y. Development of the Spontaneously Hypertensive Rat (SHR) and of various spontaneous rat models, and their implications. Handbook of Hypertension Vol. 4. Experimental and genetic models of hypertension (de Jong W., ed), pp. 224-239. Elsevier, 1984 Tanase, H., Yamori Y., Hansen C. T., Lovenberg, W. Heart size in inbred strains of rats. Part 1. Genetic determination of the development of cardiovascular enlargement in rats. Hypertension 4: 864-872, 1982 Yamori, Y., Nagaoka, A., Okamoto, K. Importane of genetic factors in hypertensive cerebrovascular lesions: An evidence obtained by successive selective breeding of stroke-prone and resistant SHR. Jpn. Circ. J. 38: 1095-1100, 1974 Okamoto, K., Yamori, Y., Nagaoka, K. Establishment of the stroke prone spontaneously hypertensive rats (SHR). Circ. Res. 34/35: 143-153, 1974 
執筆者記録:  森 政之(信州大学)2001年5月25日, TS:4/30/03 
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