Physiol. Genomics AJP: Gastrointestinal and Liver Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Physiol. Genomics 30: 69-73, 2007. First published February 27, 2007; doi:10.1152/physiolgenomics.00149.2006
1094-8341/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
30/1/69    most recent
00149.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yao, H.
Right arrow Articles by Nabika, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yao, H.
Right arrow Articles by Nabika, T.
Received 12 July 2006; accepted in final form 23 February 2007.
Physiological Genomics 30:69-73 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

Congenic removal of a QTL for blood pressure attenuates infarct size produced by middle cerebral artery occlusion in hypertensive rats

Hiroshi Yao 1,2, Zong-Hu Cui 3, Junichi Masuda 4 and Toru Nabika 3

1 Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Saga
2 Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
3 Department of Functional Pathology, School of Medicine, Shimane University, Izumo, Japan
4 Department of Laboratory Medicine, School of Medicine, Shimane University, Izumo, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A genome-wide screen found a blood pressure quantitative trait locus (QTL) on rat chromosome 1 in stroke-prone spontaneously hypertensive rats of a Japanese colony (SHRSP/Izm). In the present study, we investigated the effects of congenic removal of this QTL from SHRSP/Izm on infarct size produced by middle cerebral artery (MCA) occlusion. To establish the congenic strain (SHRSPwch1.0), the blood pressure QTL was introgressed from Wistar-Kyoto (WKY)/Izm to SHRSP/Izm by repeated backcrossing. Male SHRSP/Izm [10–12 wk old (young adult) n = 8, 5 mo old (adult) n = 17] and SHRSPwch1.0 (young adult n = 7, adult n = 15) were randomly assigned to distal MCA occlusion. Resting mean arterial blood pressure (MABP) was 212 ± 23 mmHg in adult SHRSPwch1.0, which was significantly lower than 241 ± 22 mmHg in SHRSP/Izm. Infarct volume in the congenic rats was significantly decreased compared with that in SHRSP/Izm (66.4 ± 21.5 mm3 vs. 103.4 ± 24.8 mm3). Cerebral blood flow (CBF), determined at collaterally-perfused cortex with laser-Doppler flowmetry after MCA occlusion, was significantly greater in adult SHRSPwch1.0 compared with CBF in adult SHRSP/Izm. In young adult rats, there were no significant differences in MABP or in infarct volume between SHRSPwch1.0 and SHRSP/Izm. The congenic removal of a blood pressure QTL lowered blood pressure and caused a substantial reduction in infarct volume (–36%) with increased collateral CBF after MCA occlusion in the congenic rat. We demonstrated for the first time that the congenic strategy is useful to investigate the effects of genetic hypertension on focal ischemia or stroke.

genetics; stroke; cerebral ischemia; focal; hypertension; models; animal; quantitative trait locus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
SPONTANEOUSLY HYPERTENSIVE RATS (SHR) and stroke-prone SHR (SHRSP) show a greater vulnerability to the middle cerebral artery (MCA) occlusion (i.e., an increased stroke sensitivity) compared with the normotensive strains (2, 7, 16, 20, 21). Hypertension in these rat strains obviously has a major contribution to the exaggerated vulnerability because chronic antihypertensive treatment protected these rats against MCA occlusion-induced infarction (7, 16). However, in prehypertensive young rats, the relative frequency of infarction in the segregating progenies (F1) supported a single locus recessive model of inheritance for the susceptibility to infarction after MCA occlusion (3), while another study implied a dominant model (8). Two substrains of SHR (SHR/Izm and SHR/ Kyushu) showed different susceptibility to MCA occlusion even though they shared a similar level of hypertension (2). All of these studies indicated that infarct size produced by MCA occlusion in SHR and SHRSP was determined both by the extent of hypertension and by blood pressure-independent genetic factors.

A congenic strategy using inbred rat strains that display genetic hypertension is a powerful method by which to examine the effects of polygenetic traits on the stroke phenotype. We identified a potent quantitative trait locus (QTL) for blood pressure on chromosome 1 of SHRSP and constructed a congenic strain for this QTL (10, 11, 13). To establish the congenic strain (SHRSPwch1.0), the blood pressure QTL region was introgressed from WKY/Izm to SHRSP/Izm by repeated backcrossing. The established congenic strain showed significantly lower blood pressure than that of SHRSP, confirming the effect of the QTL on blood pressure. No study so far has examined the effect of polygenic or essential hypertension gene(s) on the size of MCA occlusion-induced infarction. In the present study, we therefore investigated the effects of congenic removal of the blood pressure QTL from SHRSP/Izm on the infarct size after MCA occlusion and assessed the contribution of hypertension on the stroke vulnerability.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All procedures were done in accordance with the Animal Care Guidelines at Kyushu University and The Law (no. 105) and Notification (no. 6) of the Japanese Government.

Congenic rats.
A congenic strain [SHRSP.WKY-(D1Wox29-D1Arb21)/Izm, hereafter referred to as SHRSPwch1.0] used in the present study was established through the construction of subcongenic lines for the chromosome 1 QTL. Briefly, SHRSP.WKY-(Klk1-D1Rat116)/Izm constructed with the speed congenic strategy (10) was backcrossed to SHRSP to obtain F1 rats, which were then intercrossed to produce F2 rats. The F2 rats were genotyped with the markers distributed in the chromosome 1 QTL region, and adequate recombinants were selected. Homozygotes were obtained through mating these F2 rats. The SHRSPwch1.0 had a congenic segment spanning the microsatellite markers D1Wox29 and D1Arb21, which was identified to that of the reciprocal congenic strain, WKY.SHRSP-(D1Wox29-D1Arb21)/Izm (5). This segment covered the 100:1 confidence interval of the blood pressure QTL reported previously (11, 13) (Fig. 1).


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 1. The quantitative trait locus (QTL) regions on chromosome 1 introgressed into congenic strain derived from Wistar-Kyoto rats (WKY). The filled boxes represent regions homozygous to the donor (WKY), and the vertical bars indicate the maximal segments potentially introgressed in the congenic strain. Gray box represents the QTL region introgressed into congenic rats reported by Kato et al. (10, 11). SHRSP, stroke-prone spontaneously hypertensive.

 
Photothrombotic MCA occlusion.
The animals were not salt-loaded. Animals were housed three or four per cage with free access to regular rat chow "Western diet" (CLEA rodent diet CE2, containing 25% protein, Na+ 2.6 mg/g and K+ 10.6 mg/g per pellet) and tap water ad libitum. Male SHRSP/Izm (10–12 wk old [young adult] n = 8, 5 mo old [adult] n = 17) and SHRSPwch1.0 (young adult n = 7, adult n = 15) were used in this study. Details of our focal ischemia model were described previously (2, 20, 21). Briefly, rats were anesthetized with halothane (3% for induction, 1.5% during the surgical preparation with a face mask, 0.75% after intubation, and 0.5% for maintenance) in a mixture of 70% nitrous oxide and 30% oxygen. The right femoral artery and vein were cannulated using PE-50 tubing. The rats were endotracheally intubated with PE-240 tubing, pancuronium bromide (an initial dose of 0.3 mg followed by 0.1 mg every 30 min) was intravenously injected, and the rats were mechanically ventilated. Mean arterial blood pressure (MABP) was continuously monitored. Rats were mounted on a stereotaxic head holder in the prone position, and a burr hole 3 mm in diameter was made 1 mm rostral to the anterior junction of the zygoma and squamosal bone under an operating microscope (OPMI 111, Carl Zeiss), revealing the distal segment of the MCA. The anatomy of distal MCA was recorded by drawing under the operating microscope (x20) and was classified into three categories (simple/regular/complicated) as previously described (2).

A krypton laser operating at 568 nm (643-Y-A01, Melles Griot) was used to irradiate the distal MCA at a power of 20 mW for 4 min. The photosensitizing dye rose Bengal (15 mg/ml in 0.9% saline, Wako) was administered intravenously to a body dose of 20 mg/kg over 90 s starting simultaneously with 4 min of laser irradiation. The irradiated MCA was consistently occluded within 3 min. Three days after ischemic insult, the infarct volume was determined on 2,3,5-triphenyltetrazolium chloride-stained sections.

Measurement of the regional cerebral blood flow.
Cerebral blood flow (CBF) was determined with laser-Doppler flowmetry 30 min after MCA occlusion in adult SHRSP/Izm (n = 5) and SHRSPwch1.0 (n = 5). A laser-Doppler flowmetry probe was laterally scanned, and CBF of the distal MCA cortical territory was measured at five points (2 mm posterior and 2.0, 2.5, 3.0, 3.5, and 4.0 mm lateral to the bregma) as previously described (21). Five CBF values in one rat were transformed to an area under curve according to the trapezoidal rule.

Statistical analysis.
Values are means ± SD. Differences in physiological variables, infarct volume, and values of area under curve for CBF were analyzed with the unpaired t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Physiological variables were maintained within normal limits and were not different between SHRSPwch1.0 and SHRSP/Izm (Table 1). Resting MABP determined at 30 min of resting state was 212 ± 23 mmHg in adult congenic rats (SHRSPwch1.0), which was significantly lower than 241 ± 22 mmHg in adult SHRSP/Izm (P = 0.0070, unpaired t-test) (Fig. 2A). Unexpectedly, body weight of adult SHRSPwch1.0 was significantly greater than that of SHRSP/Izm (390 ± 26 g vs. 315 ± 30 g, respectively, P < 0.0001) (Fig. 2B). Five adult SHRSP/Izm and one SHRSPwch1.0 died within 3 days after MCA occlusion. The number of SHRSP and SHRSPwch1.0 with distal MCA patterns (simple/regular/complicated) was 3/13/4 and 4/16/1, respectively. More SHRSP appeared to have complicated distal MCA than SHRSPwch1.0, but the difference was not statistically significant. Infarct volume in the adult SHRSPwch1.0 was significantly reduced compared with that in SHRSP/Izm (66.4 ± 21.5 mm3 vs. 103.4 ± 24.8 mm3, P = 0.0065) (Fig. 3A). Infarct size in the young adult rats was substantially smaller than that in the adult rats, and infarct volumes were not significantly different between the young adult SHRSPwch1.0 and SHRSP/Izm (Fig. 3B). Mean CBF values were in the range of 33–69% of baseline in the SHRSP/Izm, whose values indicate the cortical area of CBF determination was collaterally perfused region partly including ischemic penumbra or region at risk for infarction. CBF determined at collaterally perfused cortex after MCA occlusion was significantly greater in adult congenic rats (SHRSPwch1.0) compared with CBF in adult SHRSP/Izm (Fig. 4, P = 0.0252).


View this table:
[in this window]
[in a new window]

  		Table 1. Physiological variables

 

Figure 2
View larger version (18K):
[in this window]
[in a new window]

  		Fig. 2. Mean arterial blood pressure (MABP) (A, C) and body weight (B, D) in adult and young adult SHRSP/Izm and SHRSPwch1.0. Resting MABP was determined at 30 min of resting state with a maintenance dose of anesthesia. Bars represent SD. *P = 0.0070 vs. SHRSP/Izm, **P < 0.0001 vs. SHRSP/Izm.

 

Figure 3
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 3. Infarct volume in adult (A) and young adult (B) SHRSP/Izm and SHRSPwch1.0. A: infarct volume in adult congenic rats (SHRSPwch1.0) was significantly smaller than that in adult SHRSP/Izm. *P = 0.0065 vs. SHRSP/Izm.

 

Figure 4
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 4. Cerebral blood flow (CBF) of the distal middle cerebral artery (MCA) cortical territory was measured at 5 points (2 mm posterior and 2.0, 2.5, 3.0, 3.5, and 4.0 mm lateral to the bregma being indicated as CBF2.0, CBF2.5, CBF3.0, CBF3.5, and CBF4.0, respectively) with scanning a laser-Doppler flowmetry probe. CBF was expressed as a percentage of the average of 2–3 baseline values (A). Five CBF values in 1 rat were transformed to an area under curve according to the following formula (trapezoidal rule): Area under curve = 1/2(CBF2.0 + CBF4.0) + CBF2.5 + CBF3.0 + CBF3.5. Ischemic CBF determined at collaterally perfused cortex (area under curve) was significantly attenuated in adult congenic rats (SHRSPwch1.0) compared with that in adult SHRSP/Izm (*P = 0.0252) (B). Values are means ± SD.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The congenic removal of a QTL for blood pressure substantially reduced infarct size by 36%, while it decreased blood pressure by 12% (–29 mmHg) in adult rats. In young adult rats (10–12 wk old), both blood pressure and infarct size were not different between SHRSP/Izm and the congenic rats (SHRSPwch1.0). These results indicated that the absence of one of the blood pressure QTLs protected SHRSP against brain infarction principally through decreasing blood pressure and through the mechanism of increased collateral CBF after distal MCA occlusion.

Increased sensitivity to cerebral ischemia in SHR and SHRSP is, at least in part, determined by genetic factors independent of hypertension (14). This was supported by several observations: 1) Larger infarction was observed in SHRSP than WKY after MCA occlusion even at a prehypertensive age before hypertension and vascular hypertrophy were fully established (3). 2) The infarct volume after MCA occlusion was significantly different between the two substrains of SHR (i.e., SHR/Izm and SHR/Kyushu) despite the fact that they shared a similar blood pressure level (2). Furthermore, infarct volumes were almost the same between SHRSP/Izm and SHR/Kyushu, although MABP was higher in SHRSP/Izm by ~40 mmHg than that in SHR/Kyushu (18). 3) A genome-wide screening performed by Jeffs et al. (9) found a highly significant QTL on rat chromosome 5 that contributed to an infarct size after MCA occlusion, in F2 hybrids of SHRSP and WKY. In particular, this genetic study demonstrated that the infarct volume induced by MCA occlusion was not correlated with blood pressure in the F2 population. However, we found a significant attenuation in the infarct volume after MCA occlusion in adult congenic rats compared with SHRSP with higher blood pressure. Furthermore, 10- to 12-wk-old congenic rats showed an infarct size similar to that of SHRSP/Izm in the present study. Under the assumption of another QTL for susceptibility to ischemic insult in the chromosome 1 region, even young SHRSPwch1.0, of which the blood pressure level was the same as SHRSP, should have had a smaller infarct size. Thus, it is unlikely that the congenic fragment on rat chromosome 1 includes a gene contributed to the vulnerability to MCA occlusion. However, we cannot entirely exclude the possibility of interaction between two separate QTLs as an explanation for our results. For example, a gene on chromosome 1 may regulate possible effects depend on factors related to aging but independently of difference in blood pressure such as oxidative stress that normally accompanies aging (6). Interestingly, Rubattu et al. (15) showed that a QTL on rat chromosome 1 derived from an SHR background introgressed into the SHRSP background influenced stroke proneness without affecting blood pressure levels. We would suggest potential candidate genes [NTRK3 or TrkC (1), Homer2 (17), and Nox4 (19)] within the congenic segment as shown in Fig. 1.

In most studies of focal ischemia, one-point CBF measurement with laser-Doppler flowmetry frequently showed no significant differences between the groups. However, it may be that a true difference in CBF is missed because of a type II error as Macleod et al. pointed out (12). If we had done one-point measurement, for example at 4 mm lateral to the bregma, the conclusion would be that there is no significant difference in CBF after MCA occlusion between SHRSP and SHRSPwch1.0, suggesting some "genetic" effects on infarct size. As shown in our study (Fig. 4), none of the five one-point measurements find significant differences between SHRSP/Izm and the congenic rats, whereas the scanning method and area under curve revealed a clear difference in CBF between the two groups. This scanning method of CBF measurement would reduce the risk that reduction in infarct volume due to an effect of blood pressure reduction on CBF might be incorrectly attributed to some genetic traits.

Despite many pharmacological studies on effects of blood pressure reduction on the susceptibility to ischemic insult (7, 16), we often have problems interpreting the data, because antihypertensive drugs used in such studies had a variety of pharmacological effects in addition to lowering blood pressure. The present study, in which blood pressure of the rats was reduced by a genetic manipulation, is a unique complement to such pharmacological studies. Fujii et al. (7) demonstrated in their pharmacological study that the mean infarct volume in SHRSP was significantly reduced by 30–40% after 3 mo of a strict antihypertensive treatment with either cilazapril or hydralazine combined with hydrochlorothiazide. Although these drugs decrease blood pressure through different mechanisms, both treatments were equally effective in reducing infarct volume, implying that the extent of blood pressure reduction per se accounted for the decrease in infarct volume. However, the extent of protection was much more striking by congenic removal of a hypertension gene than by pharmacological blood pressure reduction. Protection against infarction was considered to be due to increased CBF through collateral vessels (Fig. 4). The mechanism by which lowering blood pressure increases collateral CBF may include reversal of structural changes or remodeling in cerebral arterioles, restoration of endothelium-dependent responses, and decreased vascular resistance (4).

Finally, body weight of adult congenic rats (SHRSPwch1.0) was greater than that of SHRSP. Rubattu et al. (15) made a similar interesting observation that SHRSP-derived congenic lines with a major stroke resistance had increased body weight. The mechanisms are not clear, and it could be a secondary nonspecific effect, but the introgressed chromosome 1 interval may contain QTLs influencing metabolic traits.

In summary, we have demonstrated for the first time the detrimental effects of genetic hypertension in the context of polygenes on collateral CBF and size of subsequent infarction after MCA occlusion in SHRSP.


   ACKNOWLEDGMENTS
 
The authors thank Drs. A. Shiraishi and T. Nakahara for critical comments on this manuscript.


   FOOTNOTES
 
Address for reprint requests and other correspondence: H. Yao, Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Kanzaki 842-0192, Saga, Japan (e-mail: hyao{at}hizen2.hosp.go.jp).

Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Bates B, Hirt L, Thomas SS, Akbarian S, Le D, Amin-Hanjani S, Whalen M, Jaenisch R, Moskowitz MA. Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals. Neurobiol Dis 9: 24–37, 2002.[CrossRef][Web of Science][Medline]
  2. Cai H, Yao H, Ibayashi S, Uchimura H, Fujishima M. Photothrombotic middle cerebral artery occlusion in spontaneously hypertensive rats: influence of substrain, gender and distal middle cerebral artery patterns on infarct size. Stroke 29: 1982–1987, 1998.[Abstract/Free Full Text]
  3. Coyle P, Odenheimer DJ, Sing CF. Cerebral infarction after middle cerebral artery occlusion in progenies of spontaneously stroke-prone and normal rats. Stroke 15: 711–716, 1984.[Abstract/Free Full Text]
  4. Coyle P, Feng X. Spatial features of focal infarction after hydralazine treatment in stroke-prone spontaneously hypertensive rats. Stroke 24: 253–257, 1993.[Abstract/Free Full Text]
  5. Cui ZH, Ikeda K, Kawakami K, Gonda T, Masuda J, Nabika T. Exaggerated response to cold stress in a congenic strain for the quantitative trait locus for blood pressure. J Hypertens 22: 2103–2109, 2004.[CrossRef][Web of Science][Medline]
  6. Dominiczak AF, Graham D, McBride MW, Brain NJR, Lee WK, Charchar FJ, Tomaszewski M, Delles C, Hamilton CA. Cardiovascular genomics and oxidative stress. Hypertension 45: 636–642, 2005.[Abstract/Free Full Text]
  7. Fujii K, Weno BL, Baumbach GL, Heistad DD. Effect of antihypertensive treatment on focal cerebral infarction. Hypertension 19: 713–716, 1992.[Abstract/Free Full Text]
  8. Gratton JA, Sauter A, Rudin M, Lees KR, McColl J, Reid JL, Dominiczak AF, Macrae IM. Susceptibility to cerebral infarction in the stroke-prone spontaneously hypertensive rat is inherited as a dominant trait. Stroke 29: 690–694, 1998.[Abstract/Free Full Text]
  9. 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.[CrossRef][Web of Science][Medline]
  10. Kato N, Mashimo T, Nabika T, Cui ZH, Ikeda K, Yamori Y. Genome-wide searches for blood pressure quantitative trait loci in the stroke-prone spontaneously hypertensive rat of a Japanese colony. J Hypertens 21: 295–303, 2003.[CrossRef][Web of Science][Medline]
  11. Kato N, Nabika T, Liang YQ, Mashimo T, Inomata H, Watanabe T, Yanai K, Yamori Y, Yazaki Y, Sasazuki T. Isolation of a chromosome 1 region affecting blood pressure and vascular disease trait in the stroke-prone rat model. Hypertension 42: 1191–1197, 2003.[Abstract/Free Full Text]
  12. Macleod M, O'Collins T, Howells D, Donnan G. Nicotinamiide attenuate focal ischemic brain injury: meta-analysis or mechanism of protection. Response Stroke 35: 2758, 2004.
  13. 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.[CrossRef][Web of Science][Medline]
  14. Rubattu S, Giliberti R, Volpe M. Etiology and pathophysiology of stroke as a complex trait. Am J Hypertens 13: 1139–1148, 2000.[CrossRef][Web of Science][Medline]
  15. Rubattu S, Hubner N, Ganten U, Evangelista A, Stanzione R, Di Angelantonio E, Plehm R, Langanki R, Gianazza E, Sironi L, D'Amati G, Volpe M. Reciprocal congenic lines for a major stroke QTL on rat chromosome 1. Physiol Genomics 27: 108–113, 2006.[Abstract/Free Full Text]
  16. Slivka A. Effect of antihypertensive therapy on focal stroke in spontaneously hypertensive rats. Stroke 22: 884–888, 1991.[Abstract/Free Full Text]
  17. Szumlinski KK, Dehoff MH, Kang SH, Frys KA, Lominac KD, Klugmann M, Rohrer J, Griffin W III, Toda S, Champtiaux NP, Berry T, Tu JC, Shealy SE, During MJ, Middaugh LD, Worley PF, Kalivas PW. Homer proteins regulate sensitivity to cocaine. Neuron 43: 401–413, 2004.[CrossRef][Web of Science][Medline]
  18. Takaba H, Fukuda K, Yao H. Substrain differences, gender, and age of spontaneously hypertensive rats critically determine infarct size produced by distal middle cerebral artery occlusion. Cell Mol Neurobiol 24: 589–598, 2004.[CrossRef][Web of Science][Medline]
  19. Vallet P, Charnay Y, Steger K, Ogier-Denis E, Kovari E, Herrmann F, Michel JP, Szanto I. Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 132: 233–238, 2005.[CrossRef][Web of Science][Medline]
  20. Yao H, Ibayashi S, Sugimori H, Fujii K, Fujishima M. Simplified model of krypton laser-induced thrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats. Stroke 27: 333–336, 1996.[Abstract/Free Full Text]
  21. Yao H, Sugimori H, Fukuda K, Takada J, Ooboshi H, Kitazono T, Ibayashi S, Iida M. Photothrombotic middle cerebral artery occlusion and reperfusion laser system in spontaneously hypertensive rats. Stroke 34: 2716–2721, 2003.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 HypertensionHome page
K. Iigaya, H. Kumagai, T. Nabika, Y. Harada, H. Onimaru, N. Oshima, C. Takimoto, T. Kamayachi, T. Saruta, and H. Itoh
Relation of Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 to Hyperactivity of Rostralventrolateral Medulla
Hypertension, January 1, 2009; 53(1): 42 - 48.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
30/1/69    most recent
00149.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yao, H.
Right arrow Articles by Nabika, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yao, H.
Right arrow Articles by Nabika, T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.