Mortality and cerebral metabolism after bilateral carotid artery ligation in normotensive and spontaneously hypertensive rats.

Mortality and cerebral glycolytic metabolism were studied after bilateral ligation of the common carotid artery in normotensive Wistar rats (NTR), and spontaneously hypertensive rats (SHR) derived from Wistar strain. In the first 24 hours after occlusion of carotid arteries, 72 per cent of 108 SHR died, whereas it was fatal in only 16 per cent of 43 NTR. In SHR, cerebral lactate and cerebral lactate/pyruvate ratio (L/P ratio) increased by 12.4 and 12.1 times the control, respectively at five to six hours after ligation, and remained raised even in rats surviving for two to three days thereafter. Changes in cerebral lactate and L/P ratio were minimal in NTR. Cerebral ATP decreased markedly at five to six hours after ligation in SHR studied. These results indicate that bilateral carotid artery ligation causes severe brain damage in SHR but not in NTR, suggesting hypertension per se to be operative for the development of cerebral ischaemia.     

An ultrastructural study of developing cerebral infarction following bilateral carotid artery occlusion in spontaneously hypertensive rats

Summary An ultrastructural study of cerebral infarcts in spontaneously hypertensive rats 1–5 h after bilateral carotid artery occlusion was performed. The alterations of the neocortex consisted of shrinkage of the neurons surrounded by swollen astrocytic processes. Distension of the rough endoplasmic reticulum of the neuronal cytoplasm appeared early, while changes of the mitochondria were slight. Though there appeared slight to moderate perivascular astrocytic swelling, endothelial swelling was rare and there was no severe narrowing of the capillary lumen. There were no filling defects of colloidal carbon injected to the blood vessels of the ischemic brains. Ischemic neuronal alterations were proved to develop in the absence of severe morphological changes of the microvasculature in the developing cerebral infarcts in the present experimental model.     

Disruption of blood-brain barrier following bilateral carotid artery occlusion in spontaneously hypertensive rats. A quantitative study

The present study was designed to clarify the relationship of cerebral blood flow (CBF) to blood-brain barrier (BBB) in the ischemic brains with or without recirculation, which were produced by clipping of both common carotid arteries in spontaneously hypertensive rats. CBF was measured by the hydrogen clearance method and BBB function was evaluated by the permeability of 131I-albumin and Evans blue dye. Cortical CBF was reduced from 48.8 +/- 9.5 to 4.0 +/- 1.2 ml/100 gm/min during 1 hr ischemia and further to 2.6 +/- 0.3 ml/100 gm/min during 3 hrs ischemia, while thalamic CBF was reduced much less from 50.0 +/- 3.6 to 17.9 +/- 6.5 ml/100 gm/min and to 17.5 +/- 11.0 ml/100 gm/min, respectively. There was no increase in permeability to protein tracers observed in such 1 hr or 3 hrs ischemic brain. Both cortical and thalamic CBF were markedly increased 2.5 to 6 fold of resting values at 5 min after recirculation in the 1 hr ischemic brain. In the 3 hrs ischemic brain, however, both CBF were only slightly increased but never restored to the resting level even at 30 min after recirculation. In such reperfused brains, exudation to Evans blue dye was observed in none of 16 animals with 1 hr ischemia, but in 18 of 23 with 3 hrs ischemia. Disruption of BBB was twice more frequent in the cortex (77.8%) than in either thalamus (33.3%) or hippocampus (33.3%). Permeability index of 131I-albumin (brain albumin/blood albumin) was significantly higher in the ischemic areas stained with blue dye (2.07 +/- 0.45%) than in non-ischemic control brain (0.10 +/- 0.01%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral vasomotor reactivity in normotensive and spontaneously hypertensive rats

Intravenously injected metaraminol induced a larger blood pressure increase in spontaneously hypertensive rats (SHR) than in normotensive controls (NR) when the pressure was raised from the same starting level. Cerebral blood flow (CBF) response in NR was either perfect autoregulation, partial autoregulation or "break-through." When present, the autoregulatory response was very rapid, i.e. the flow returned to the initial value within 10-15 sec. All SHR showed an initial prompt vasoconstrictor response which was followed after 30-40 sec by a gradual flow increase. The blood pressure elevation was highest in SHR when hypertension was induced by compression of the aorta, which supports the hypothesis that the enhanced response is, at least in part, a consequence of an increased vessel wall to lumen ratio. The characteristic CBF pattern observed in SHR after a metaraminol-induced rise in blood pressure was not seen when the blood pressure was increased by aortic compression, which suggests an effect of the drug separate from its pressor effect. During maximum vasodilatation the cerebrovascular resistance (CVR) was considerably higher in SHR than in NR. Assuming an equivalent vessel density in the 2 groups, our results suggest that structural changes in resistance vessels in SHR encroach on the lumen.     

Brain metabolism and arterial acid-base balance following bilateral carotid occlusion in normotensive and experimental hypertensive rats.

The effects of bilateral common carotid artery occlusion on brain metabolism and arterial acid-base balance were studied in normotensive and experimental renovascular hypertensive rats. One hour after carotid occlusion in hypertensive rats, supratentorial lactate increased to 383% and lactate-pyruvate ratio to 280% of the controls, while adenosine triphosphate (ATP) decreased to 69%. These metabolic changes were thought to be due to cerebral ischemia. Arterial pCO2 was lowered and the pH was raised in the hypertensive animals due to cerebral ischemia induced hyperventilation. In the normotensive rats, carotid occlusion had minimal effects on cerebral metabolism and arterial acid-base balance. These results suggest that hypertensive rats are more susceptible to cerebral ischemia caused by carotid occlusion than normotensive rats. Increased cerebrovascular resistance in hypertension is discussed as a causal factor in cerebral ischemia.     

Effect of bilateral common carotid artery ligation on prostaglandin levels (TXA2, PGI2) in spontaneously hypertensive rats (SHRSP, SHRSR) and normotensive rats (WKY)

Three different levels of global forebrain ischemia were induced in rats and their plasma levels of Thromboxane B2 (TXB2) and 6 Keto PGF1 alpha were determined to investigate the relation between severity of ischemia and eicosanoid production. Ischemia stimulates the activity of cellular lipase whose actions cause deacylation of brain phospholipids and release of free fatty acids. Arachidonic acid (A.A.) is one of the predominant fatty acids which is liberated in brain after ischemia. A.A. is the primary substrate for the synthesis of prostaglandins (PGs), Thromboxane A2 (TXA2) and Prostacyclin (PGI2), which play an important role in regulation of platelet aggregation and vasotonus. Thromboxane is a potent platelet aggregator and vasoconstrictor. On the other hand, PGI2 has the opposite nature. Therefore it can be considered that PGs and moreover, the balance of TXA2 and PGI2 may have an intimate relation to the development of cerebral ischemia. Three different levels of ischemia were produced by bilateral carotid artery ligation (BLCL) using three kinds of rats with different blood pressure ranges, namely, SHRSP (Stroke-prone spontaneously hypertensive rats), SHRSR (Stroke-resistant spontaneously hypertensive rats) and WKY (Wistar kyoto rats). It is known that higher pressure groups suffer severe ischemia by BLCL procedure. Hypertensive rats (SHRSP, SHRSR) were originally produced from WKY. The experimental animals used were about 300 gr and 16 weeks old male rats. The plasma and brain TXB2 and 6 Keto-PGF1 alpha, stable metabolites of TXA2 and PGI2 were measured by radioimmunoassay. The chronological changes of brain and plasma PGs levels after ischemia using SHRSR were also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of long-term antihypertensive treatment on brain metabolism after bilateral carotid artery occlusion in spontaneously hypertensive rats.

The effects of antihypertensive treatment on brain metabolism after bilateral carotid occlusion were studied in spontaneously hypertensive rats. The results indicate that an increase in metabolites of ischaemic brain such as lactate and the lactate/pyruvate ratio after carotid occlusion in spontaneously hypertensive rats is apparently suppressed by treating hypertension. This suggests that hypertension may play an important role in susceptibility to cerebral ischaemia.     

Different susceptibilities to cerebral infarction in spontaneously hypertensive (SHR) and normotensive Sprague-Dawley rats

Rapid occlusion of the middle cerebral artery (MCA) was undertaken in 5-6 week old rats to determine whether or not the young spontaneously hypertensive rat (SHR) or the normotensive Sprague-Dawley rat (SD) is protected against cerebral infarction by collateral circulation. Rats were killed 3 days after MCA occlusion and administration of Evans blue. As compared to SD, the SHR had elevated blood pressure prior to MCA occlusion, large cortical infarcts marked with Evans blue, and motor deficits contralateral to the occluded MCA. SHR did not develop an adequate collateral circulation, but SD were protected from infarction by it. Because the cerebral lesions were in young spontaneously hypertensive rats living prior to the established form of hypertension, the increased susceptibility to infarction was not secondary to it. Since normotensive rats usually do not infarct after sudden MCA occlusion, the infarction trait may be linked to the mechanism causing elevated blood pressure in spontaneously hypertensive rats.     

Regional cerebral blood flow changes after bilateral external carotid artery ligation in acute experimental infarction.

Regional cerebral blood flow (rCBF) was measured in baboons by intracarotid injection of 133Xe and a gamma camera after acute cerebral infarction was induced by occlusion of the middle cerebral artery (MCA). A steady state of rCBF was measured four hour after MCA occlusion and was followed by bilateral ligation of the external cartoid arteries (ECA). Subsequent rCBF measurements were obtained at 30, 60, and 120 minutes. After bilateral ECA ligation, flow in ischaemic and non-ischaemic areas was greatly enhanced and flow in the hyperaemic areas significantly reduced, presumably since they had provided collateral circulation to the ischaemic zone with a favourable redistribution.     

Cerebral microangiopathy in stroke-prone spontaneously hypertensive rats

Summary The morphology of cerebral microvessels was studied immunohistochemically and ultrastructurally in 6- to 9-month-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP) with a systolic blood pressure of 138±15 mm Hg, 189±9 mm Hg, and 258±30 mm Hg respectively. Regions with major opening of the blood-brain barrier (BBB) were revealed by an i. v. injection of Evans Blue. Multifocal BBB opening with massive leakage of plasma constituents rich in fibrinogen-fibrin-related antigen occurred in SHRSP with a blood pressure above 210–220 mm Hg. BBB-leakage sites were found in the cerebral cortex and the basal ganglia, most frequently in the arterial border zones. The perivascular tissue spaces were dilated within the BBB-leakage sites, in particular around arterioles. Damaged endothelial and smooth muscle cells were replaced by fibrin-like material, multiple layers of basement membranes and bundles of collagen fibrils surrounded by proliferated fibroblasts. The degenerative-infiltrative-proliferative disease process transformed short segments of single arterioles into severely thickened, tortuous and stenotic vessels. Fibrinoid degeneration, formation of microaneurysms and fibrin-rich vascular occlusions were observed. In contrast, only minor or no vascular alterations were seen in regions with preserved BBB in SHRSP and SHR. A severely increased intraluminal pressure load appears to be of major pathogenetic importance for breakdown of the BBB and initiation of the vascular disease process in SHRSP. However, since only short segments of a limited number of widely separated vessels are severely affected, and the number of affected vessels increase towards arterial end and border zones, additional predisposing and aggravating factors may play significant roles in the development of fibrinoid vascular lesions in arterial hypertension.Supported by the Swedish Medical Research Council (Projects 12P-6827, 14X-4968, 12X-07123, 12X-6238, 12X-03020), the Swedish National Association against Heart and Chest Diseases, the Medical Faculty, University of Lund, the MS-fund, Elsa Schmitz's Fund for Neurological and Neurosurgical Research, Rut and Erik Hardebo's Foundation     

Cerebral plasminogen activator activity in spontaneously hypertensive stroke-prone rats.

BACKGROUND AND PURPOSE: In the spontaneously hypertensive stroke-prone rat, it is unclear whether plasminogen activator plays a role in the development of stroke. The present study was undertaken to investigate brain levels of plasminogen activator activity in spontaneously hypertensive stroke-prone rats and Wistar-Kyoto rats. METHODS: Plasminogen activator was purified from the brains of rats of both strains. The purification involved used ammonium sulfate precipitation, gel filtration, a zinc chelate-Sepharose column, and a concanavalin A-Sepharose column. Fraction I (0.15 M KCl-soluble fraction) and fraction II (2 M KCl plus 6 M urea-soluble fraction) were purified from both strains. RESULTS: Total plasminogen activator activity in the original homogenates for fractions I and II derived from spontaneously hypertensive stroke-prone rats was increased to twice the level found in Wistar-Kyoto rats. The final product purified from fractions I and II in both strains of rats revealed single bands of plasminogen activator activity on enzymatic analysis with a molecular weight of 72,000. The purified product had stronger S-2288 amidolytic activity than S-2444 amidolytic activity, and it also displayed fibrin-binding ability. CONCLUSIONS: The study demonstrated that there is an increased content of plasminogen activator in the brains of spontaneously hypertensive stroke-prone rats that might be related to the development of stroke.     

Carotid and aortic bodies in chronically anemic normotensive and spontaneously hypertensive rats

Overactivity of the carotid body chemoreceptors along with the enlargement of chemoreceptor tissue were found in spontaneously hypertensive rats of Okamoto-Aoki strain (SHR). The purpose of the present study was to answer the question whether the aortic bodies were also enlarged in SHR. However, because aortic bodies, unlike carotid ones, are sensitive to oxygen content another question arose: do aortic bodies undergo hypertrophy in chronic anemia? Twenty-three spontaneously hypertensive rats of Okamoto-Aoki strain (SHR) and 24 normotensive Wistar rats (NCR) were maintained on low-iron food from the age of 3 weeks. In seven 10-week-old anemic SHR regular diet was substituted (transiently anemic SHR). Blood pressure measurements and hemoglobin were measured every second week. The animals were killed at the age of 18 weeks. Light microscopic studies of the carotid and aortic bodies were performed and volumes of chemoreceptor tissues were determined from serial sections. The eight SHR on low-iron diet exhibited lower hemoglobin concentration than their normotensive counterparts. In the anemic SHR blood pressure was lower than in control SHR, whereas blood pressure did not differ between the anemic and control NCR. Restoration of normal values of hemoglobin in the anemic SHR was followed by only a slight increase in blood pressure. The carotid bodies volumes were 2.5-3 times larger in the SHR than in NCR. The volumes of carotid bodies both of the SHR and NCR were influenced neither by blood pressure nor by hemoglobin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The results of carotid angiography in cerebral infarction in normotensive and hypertensive subjects

The results of carotid angiography in 304 cases of cerebral hemisphere infarction have been reviewed. Carotid occlusion was demonstrated in 19% and atheromatous vessel wall change in a further 28%. Hypertensive subjects showed a significantly lower prevalence of carotid occlusion, but a similar prevalence of vessel wall change. There was more likely to be angiographic abnormality if there was a neck bruit or if the ECG showed ischaemic changes.The findings support the concept that the pathogenesis of cerebral infarction differs in normotensive and hypertensive patients.     

Locomotor activity and catecholamine receptor binding in adult normotensive and spontaneously hypertensive rats

Summary The binding of³H-WB 4101, an ₁-adrenoceptor antagonist, to membranes of the cerebral cortex, the hypothalamus, and the lower brainstem was examined in adult spontaneously hypertensive (SH) rats and in normotensive Wistar Kyoto (WK) controls. The specific binding of³H-WB 4101 (0.33 nM) was significantly higher in homogenates from the cerebral cortex of SH rats as compared to WK rats. No differences were detected between SH and WK rats in the specific binding of³H-spiroperidol (0.25 nM), a dopamine receptor antagonist, to membranes from the corpus striatum and the limbic forebrain. The locomotor activity was significantly higher in SH rats as compared to WK controls, in all probability due to a lack of habituation to environmental change. It is suggested that the high reactivity of SH rats is related to a dysfunction in the noradrenergic neurons in the central nervous system.