We studied ultrastructurally cerebral perforating arteries in 60 stroke-prone spontaneously hypertensive rats (SHRSP), which were sequentially killed at 4-52 weeks of age before showing symptoms of stroke. Another 24 SHRSP were killed soon after they showed symptoms of cerebral infarction. The initial vascular lesions observed in the asymptomatic group included focal cytoplasmic necrosis in the outer layers of the media. This change progressed to widespread medial necrosis with time. In the infarction group, numerous monocytes were seen adhering to the endothelium of the arteries having advanced medial damage. Following the adherence of monocytes to the endothelium, large amounts of plasma components were visible in the arterial wall. The accumulation of the plasma components (especially fibrin) thickened the wall, narrowed the lumen, and resulted in occlusion. These results suggest that monocytes may affect the endothelium, perhaps disturbing the so- T here are many studies on hypertensive vascular lesions in humans and experimental animals.'" 7 Only a few investigators, however, have focused on the long-term effects of hypertension on the perforating arteries in the brain.8 " 12 In the present study we sequentially analyzed the ultrastructure of the perforating arteries in stroke-prone spontaneously hypertensive rats (SHRSP) as developed by Okamoto et al in 1974. 13 We discovered numerous monocytes that adhered to the endothelium. We have therefore tried to clarify the characteristic changes that develop into occlusions and have attempted to explain the role of monocytes in arterial lesions, especially those resulting in occlusion. Materials and MethodsOkamoto et al 13 and Yamori et al 14 developed SHRSP in which stroke (cerebral hemorrhage and/or infarction) develops spontaneously in > 8 0 % of the rats. The cerebral lesions resemble those found in humans. Since the development of this rat strain, we have continued to inbreed them selectively. At present we have > 1,500 SHRSP in our laboratory. A group of 24 SHRSP 28-50 weeks of age with symptoms of stroke composed a cerebral infarction group, and 60 asymptomatic SHRSP 4-52 weeks of age served as controls. Almost half the rats in the infarction group were in an Received October 29, 1986; accepted March 24, 1987. irritable state denoted as "Stage 2," while the other half were lethargic, labelled "Stage 3." 15 Rats in the infarction group were anesthetized with pentobarbital, and the cerebral arteries were perfused with a 1 % formaldehyde-1 .25% glutaraldehyde fixative in 0.1 M cacodylate buffer at pH 7.6 at room temperature 16 via the descending aorta at 180 mm Hg pressure for 4-5 minutes. After perfusion, the brains were carefully removed and fixed with a 2% formaldehyde-2.5% glutaraldehyde mixture in 0.1 M cacodylate buffer for 1 hour at 4° C. The infarcted cortices were then taken out and placed in the same fixative for 3 hours at 4° C and then washed overnight at 4° C in 0.1 M cacodylate buffer. Afterwards, the infarcted cortices were sectioned into sma...

We examined the infrastructure of cerebral pericytes and astrocytes in 20 normotensive Wistar-Kyoto rats and 60 asymptomatic stroke-prone spontaneously hypertensive rats killed at 4-52 weeks of age. Another 30 stroke-prone spontaneously hypertensive rats were killed soon after they showed symptoms of stroke. We found two kinds of pericytes around the capillaries: granular pericytes and filamentous pericytes. Granular pericytes possibly serve as scavenger cells in the central nervous system and became active and grew in size with time. In contrast, filamentous pericytes degenerated during the development of hypertension. Degeneration of the filamentous pericytes was involved in an increase of endothelial permeability. Increased permeability caused focal and then circumferential swelling of the astrocytes around the capillaries. Swelling of the astrocytes seemed to accelerate the production of attachment plaques. Following this increase in the number of attachment plaques, numerous astrocytic filaments were produced within the cytoplasm. As a result, fibrous astrocytes were fully developed. Adjacent to the fibrous astrocytes we detected opening of the interendothelial junctions as well as dead neurons. From these observations we propose that astrocytes perform the main function in trophic interactions among cerebral endothelial cells, astrocytes, and neurons and that dysfunction of astrocytes disturbs the neural environment, resulting in neuronal death. (Stroke 1990;21:1064-1071) H ypertensive cerebrovascular lesions have been extensively studied using stroke-prone spontaneously hypertensive rats (SHRSP), which were developed by Okamoto and colleagues 12 in 1974. In a previous study 3 we sequentially analyzed the ultrastructure of the perforating arteries in SHRSP. We discovered that deficiencies of nutrients and oxygen were the possible causes of medial necrosis of the perforating arteries. In this study we have focused on the long-term effects of hypertension in the cerebral capillaries and astrocytes. We have tried to clarify the detailed disease processes in the pericytes around the capillaries and in the astrocytes and attempted to define the trophic interactions among cerebral vessels, astrocytes, and neurons during chronic severe hypertension in SHRSP. Materials and MethodsOkamoto and colleagues 12 developed SHRSP, in which stroke (cerebral hemorrhage and/or infarc- Received November 13, 1989; accepted March 5, 1990. tion) develops spontaneously in >80%; the cerebral lesions resemble those found in humans. Since the development of this rat strain we have continued to inbreed them selectively, and at present we have the main colony of this inbred strain. There are more than 1,500 of these rats in our laboratory. Thirty SHRSP aged 28-50 weeks with symptoms of stroke made up the stroke group, 60 asymptomatic SHRSP aged 4-52 weeks made up the asymptomatic group, and 20 normotensive Wistar-Kyoto rats (WKY) aged 4-50 weeks made up the control group. All rats in each group were anesthetized with pentobarbital, ...

Severe hypertensionand 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 Cat+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 24 h of hypoxia did not increase cell death in either WKY or SHRSP, whereas 36 h of hypoxia significantly increased cell death in SHRSP (p < 0.01). Furthermore, 6 to 36 h of hypoxia and 1.5 to 5 h 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)

In this study bovine aortic endothelial cells were co-cultured with astrocytes from fetal Wistar Kyoto rats. Endothelial cells growing on type-I collagen, co-cultured with astrocytes, showed various stages of development. Although some cells appeared to be mature, horseradish peroxidase penetrated within 1 min of incubation through the intercellular junctions of these endothelial elements maintained on type-I collagen. In contrast, endothelial cells on type-IV collagen, co-cultured with astrocytes, were well developed; their intercellular junctions were well established, and plasmalemmal vesicles reduced in number. As a result, horseradish peroxidase was unable to penetrate through the endothelial cells grown on type-IV collagen and co-cultured with astrocytes because of the reduced extent of the junctional and vesicular transport. These findings reveal that (1) type-IV collagen is essential for the differentiation of endothelial cells, (2) endothelial cell-astrocyte interactions occur during co-culture, and (3) endothelial permeability depends on astrocyte-produced factors, in addition to type-IV collagen.

These results suggest that the use of biological agents does not significantly increase the incidences of SSI and late infection after orthopedic surgery in patients with rheumatoid arthritis after total joint arthroplasty.