Yasuo Nakatomi

Changes in local cerebral blood flow following bilateral carotid occlusion in spontaneously hypertensive and normotensive rats.

Local blood flow in the cortex and thalamus was measured by the hydrogen clearance method in spontaneously hypertensive rats (SHR) and normotensive rats (NTR) before and after bilateral carotid occlusion. There were no differences in the resting blood flow values between SHR and NTR. Following carotid occlusion cortical blood flow in SHR was markedly reduced to 17% of the resting level at 1 h and, further, to less than 10% at 3--5 h period, while in NTR it decreased only to 36--38% during 5 h occlusion. Thalamic blood flow in SHR was decreased to 39% at 1 hr and to below 20% at 3--5 h, while in NTR it remained approximately 40% of the resting level during 5 h occlusion. The blood flow reduction in either cortex or thalamus after carotid occlusion was much greater in SHR than in NTR. This difference was highly significant. The increased cerebral vascular resistance caused by persistent hypertension may play an important role in a greater reduction of blood flow in SHR after carotid occlusion. Relation of the blood flow reduction to the brain metabolism is discussed.

Stroke-prone spontaneously hypertensive rats as an experimental model of malignant hypertension

A light-microscopic study of various organs of stroke-prone spontaneously hypertensive (SHRSP) rats was performed. The rats characteristically developed fibrinoid necrosis of the wall and marked cellular thickening of the intima and media of the arterioles and small arteries of the kidney, testicle, mesentery, adrenal gland, brain, etc. Parenchymal damage of the organs, secondary to the vascular alterations took place. There were no accumulations of lipids in the vascular lesions. Though stroke has been stressed as a characteristic clinical feature of the SHRSP rats, the cerebral lesions are different from those seen in ordinary cerebrovascular disease. Furthermore, many organs are involved. The overall vascular changes in the brain and other organs are consistent with those seen in malignant hypertension; the SHRSP rat is an excellent model of this disease.

Influence of sex on cerebral ischemia following bilateral carotid occlusion in spontaneously hypertensive rats: a metabolic study.

Cerebral lactate, pyruvate and adenosine triphosphate (ATP), and acid-base balance were measured in male and female spontaneously hypertensive rats (SHR) before, and 1, 3 and 5 hours after bilateral carotid occlusion. In male SHR, cerebral lactate and the lactate/pyruvate (L/P) ratio progressively increased after occlusion, while cerebral ATP decreased. In female SHR, an increase in lactate and the L/P ratio was less marked than in male SHR. Cerebral ATP remained unchanged 5 hours after occlusion. These data suggest that bilateral carotid artery occlusion may cause more pronounced ischemic changes in the brain in male SHR than in female SHR, resulting in a greater increase in lactate with a concomitant decrease in ATP in male SHR. Results suggest that female SHR are more resistant to cerebral ischemia following bilateral carotid occlusion than male SHR. Blood pressure and gonads in the susceptibility to cerebral ischemia are discussed.

Cerebral ischaemia induced by bilateral carotid occlusion in spontaneously hypertensive rats

Abstract Following bilateral carotid occlusion in spontaneously hypertensive rats (SHR), the supratentorial tissue lactate and lactate/pyruvate (L/P) ratio increased and ATP concomitantly decreased at 1 hr, although the infratentorial lactate and L/P ratio increased by a lesser extent and ATP remained unchanged. At 6 hr, the increase in supratentorial anaerobic metabolites and the decrease in ATP was greater than at 1 hr. Similarly, the infratentorial lactate and L/P ratio increased further and ATP decreased at this time. Arterial pCO 2 was correlated with supratentorial lactate below the range of 20 m M /kg and more highly with infratentorial lactate below 8 m M /kg. Above each of these values, there was no correlation in the supratentorial compartment and an opposite trend in the infratentorial compartment. Arterial pCO 2 , determined hourly in animals without additional anaesthesia, fell immediately after bilateral carotid occlusion and remained unchanged or decreased further for the next 2 hr. This was followed by a gradual rise close to or exceeding the control level. The present results may suggest that bilateral carotid occlusion in SHR causes a marked ischaemic change in the supratentorial tissues and that this is time-related. On the other hand, it causes metabolic impairment in the infratentorial compartment after a certain period of time (at least 6 hr or more), had elapsed. The late-occurring metabolic changes in the infratentorial compartment seems due to ischaemic oedema of the supratentorial compartment which caused either haemodynamic derangements in or mechanical compression of the brain stem. Spontaneous hyperventilation, reflected as hypocapnia, might be due to activation of the brain stem respiratory centre by supratentorial ischaemic stimuli or by CSF lactic acidosis originating from supratentorial lactate accumulation. When infratentorial energy deprivation developed after a certain period of time following occlusion, hyperventilation tended to disappear and even respiratory insufficiency developed. The relationship between ventilation and brain metabolism is discussed.

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

SummaryAn 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.

Response of cortical and pial arteries to changes of arterial CO2 tension in rats — a morphometric study

Changes of the internal (d) and external diameter (D) of cerebral arteries in response to the various levels of arterial pCO2 were studied in anesthetized rats, of which brains were frozen in situ with isopentane cooled in liquid nitrogen. The parietal cortex was fixed with osmium tetroxide and stained with toluidine blue for morphometry of the cerebral arteries. In comparison with control animals (pCO2 = 41.2 mm Hg), the d/D ratio in animals with hypercapnia (pCO2 = 69.9 mm Hg) was increased by 11.7% in the pial arteries and 7.9% in the cortical arteries, indicating vasodilatation. In contrast, the d/D ratio in those with hypocapnia (pCO2 = 27.7 mm Hg) was decreased by 6.2% and 13.0%, respectively, indicating vasoconstriction. There was a significant linear correlation existing between the d/D ratio of either pial or cortical arteries and pCO2. It is concluded that the cortical arteries respond to changes of arterial pCO2 in a similar manner to the pial arteries.

Mortality and histological findings of the brain during and after cerebral ischemia in male and female spontaneously hypertensive rats

Mortality and pathological changes of the brain during and after cerebral ischemia induced by bilateral carotid artery occlusion (BCO) were studied in male and female spontaneously hypertensive rats (SHR). Systolic arterial blood pressure at rest was significantly higher in male SHR (228 +/- 13 mm Hg, mean +/- S.E.M.) than female (192 +/- 12) (P less than 0.05). The average survival time during permanent occlusion was 11 +/- 6 h (mean +/- S.D.) in male SHR and 17 +/- 7 in female (P less than 0.005), though the cumulative mortality during 24-h ischemia was not different between male (88%) and female SHR (84%). Severe ischemic changes of nerve cells in the brain, especially in the cortex and hippocampus, were observed in 50% of male SHR at 3-h ischemia, while only 15% was observed in female SHR even after 7-h ischemia. After the temporary ischemia followed by reperfusion for 24 h, the mortality was varied between male and female SHR; 0, 31 and 100% after 1-, 3- and 5-h ischemia, respectively, in male SHR and 0% after 1- to 3-h ischemia and 33% after 5- to 7-h ischemia, respectively, in female. Ischemic changes of the brain tissue, such as acidophilic cytoplasm, nuclear degeneration and intercellular edema, were more frequent and severe in male SHR than female after recirculation following 3- or 5-h ischemia. It is concluded that the mortality and post-ischemic viability seem to be determined by the duration of ischemia and also by the degree of the neuronal damage, and female SHR is more tolerated for ischemic insult in comparison to male SHR.

Experimental cerebral ischemia in spontaneously hypertensive rats (SHR): Importance of degree of hypertension.

To study the relationship between the degree of hypertension and experimentally-induced cerebral ischemia, brain metabolites, Including lactate, pyruvate and adenosine triphosphate (ATP) were determined one hour after bilateral carotid occlusion in 119 spontaneously hypertensive rats (SHR) with a variety of mean arterial pressures (MAP). Of these, 36 SHR were given antihypertenslve agents for 10 weeks to reduce blood pressure prior to the experiment. There was a significant linear correlation between MAP before and either supratentorial lactate (r = 0.482, p < 0.001) or the lactate/pyruvate ratio (r = 0388, p < 0.001) in the brain after carotid occlusion. An inverse correlation was observed between supratentorial lactate and either ATP (r = –0.627, p < 0.001) or arterial Pco2 (r = −0.477, p < 0.001) after carotid occlusion. The changes suggest that the animals with a higher MAP had a greater increase in ischemic metabolites with a decrease In ATP and a more pronounced hypocap-nia after carotid occlusion. This hypocapnia is believed to be due to hyperventilation induced by cerebral ischemia. It is concluded that hypertensive rats are more susceptible to cerebral ischemia and the susceptibility is related to the degree of hypertension. By long-term lowering of the blood pressure prior to carotid occlusion, the ischemic changes are lessened In this experimental model.

Effects of hyperventilation on cerebral blood flow and brain tissue metabolism in normotensive and spontaneously hypertensive rats.

Cerebral vascular carbon dioxide (CO2) reactivities were compared in normotensive (NTR) and hypertensive (SHR) rats. Cerebral blood flow (CBF) in cortex and thalamus were evaluated before and during one hour of hyperventilation. After one hour of hyperventilation brain lactate, pyruvate, and ATP concentrations were also determined. Significant and similar reductions of CBF due to hyperventilation induce hypocapnia were found in both NTR and SHR groups. In contrast the percent increase in cerebrovascular resistance (CVR) per unit decrease in paCO2 was significant, indicating that hypocapnia induced vasoconstriction is greater in NTR than in SHR groups. During hyperventilation the average value for lactate in the NTR group was 3.98 mM/kg. In contrast it was 3.15 mM/kg in the SHR group, a significant difference (p less than 0.05). When paCO2 fell below 15 mm Hg the cerebral lactate increased strikingly in the NTR group and cortical CVR was reduced suggesting that an accumulation of the ischemic metabolites caused dilatation of the constricted cerebral vessels. In contrast the SHR group disclosed no such changes. The increase CVR characteristic of SHR appeared to diminish the cerebral vasoconstrictive response to hypocapnia. As a result ischemic metabolites in the brain do not increase in this group to the degree that they do in NTR.

Effect of Recirculation on the Recovery of Cerebral Metabolism after Experimental Cerebral Ischemia in Male and Female Spontaneously Hypertensive Rats

Lactate, pyruvate and adenosine triphosphate (ATP) concentrations in the brain were measured at the end of various periods of cerebral ischemia induced by bilateral carotid occlusion at 1-hour recirculation after the ischemia in spontaneously hypertensive rates (SHR). In both male and female SHR, a progressive and consistent increase in lactate and lactate/pyruvate ratio and a concomitant decrease in ATP were observed in the ischemic periods of 1, 3 or 5 h. Changes of these cerebral metabolites in females were two thirds to one half of those in males at corresponding periods of ischemia. At 1 h after recanalization of the occluded carotid arteries, metabolic derangements of the ischemic brain were little recovered in male SHR exposed to only 1-hour ischemia, whereas in female SHR the decreased ATP levels were recovered close to the nonischemic control level even after 7-hour ischemia. Furthermore, the increased lactate in female was attenuated to only one sixth of that in male at 1-hour recirculation after 5-hour ischemia. It is concluded that the recovery of the cerebral ischemic metabolism by reperfusion is better in female than male SHR, probably because of the smaller metabolic changes during the ischemic insult, and the fact that the degree as well as the duration of ischemia seem to be important factors for sufficient recovery from ischemic impairment of the brain.