Cerebral ischemic response-like hemodynamic changes induced by telencephalic ischemia in Mongolian gerbils (Meriones unguiculatus)

Brain Research. 294 (1984) 367-369 Elsevier

367

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Cerebral ischemic response-like hemodynamic changes induced by telencephalic ischemia in Mongolian gerbils (Meriones unguiculatu$) MASAYASU MATSUMOTO, KAZUFUMI KIMURA. ATSUSHI FUJISAWA, TOMOHIRO MATSUYAMA, RYUZO FUKUNAGA, NOBUO HANDA, SHOTARO YONEDA and HIROSHI ABE Division of Angiology, First Department of Internal Medicine, Osaka University Medical School, Osaka 553 (Japan) (Accepted October 18th, 1983) Key words." cerebral ischemia - - systemic hemodynamics - - Mongolian gerbil - - cerebral ischemic response - - carotid sinus denervation

The effect of bilateral common carotid occlusion on systemic hemodynamics was investigated in the gerbil with and without bilateral carotid sinus denervation. Irrespective of the sinus denervation, telencephalic, severe ischemia produced significant changes in the heart rate and systemic arterial blood pressure, similar to those observed in cerebral ischemic response. These hemodynamic changes, associated with cerebral ischemia, may play an important role in affecting the pathophysiology of cerebral ischemia itself. It is unquestionably important for the m a n a g e m e n t of ischemic cerebrovascular disease to know the effects of cerebral ischemia on systemic h e m o d y n a m ics. Many investigators have r e p o r t e d that severe ischemia of the brain induces an extremely powerful pressor response in the systemic arterial pressure, known as the cerebral ischemic response 5-10 and this response has been r e p o r t e d to be due to a direct effect of ischemia on the brainstem2.3. In these reports, however, separate effects of telencephalic ischemia have not yet been investigated because telencephalic ischemia without brainstem ischemia could not be produced in dogs, cats and rabbits, usually used in the previous studies. In the present study, we used the Mongolian gerbil (Meriones unguiculatus) as a model animal. Since this animal lacks efficient connecting arteries between the carotid and vertebrobasilar arterial circulations when it is 5 weeks or older ~,'~, telencephalic ischemia can be easily produced without ambiguity by bilateral occlusion of the c o m m o n carotid arteries, rendering the brainstem continuously nourished by the basilar artery. Twenty-eight male Mongolian gerbils, weighing 65-75 g, were used. The animals were maintained

under standard l a b o r a t o r y conditions for at least 10 days prior to the experiment. F o o d and water were allowed ad libitum. All animals were anesthetized with ketamine hydrochloride, 100 mg/kg, intraperitoneally and placed in the supine position. A t a p e r e d polyethylene tube (PE-10; 0.28 x 0.61 mm in diameter, Clay A d a m s , Parsippany, U . S . A . ) was placed in the abdominal aorta via the tail artery, filled with heparinized saline solution (50 IU/ml) and sealed with melted polyethylene, as described previouslyT. The carotid arteries were exposed by a ventral midline incision and silk sutures were l o o p e d around the vessels to allow subsequent ligation, and thereby acute occlusion, of these vessels. In 13 gerbils, bilateral carotid sinus denervation ( B C S D ) was performed by vascular stripping of all the nervous and connecting tissue from the carotid bifurcation and sinus region and painting with a solution of 10% phenol in alcohol, as described by Krieger6. Sham operations, carried out in the remaining 15 gerbils, involved the same procedures for general anesthesia and exposure of the c o m m o n carotid artery on both sides of the neck but no attempt was made to dissect out the carotid bifurcation or any of the b a r o r e c e p t o r afferents.

Correspondence: M. Matsumoto, Division of Angiology, First Department of Internal Medicine, Osaka University Medical School, Fukushima, i chome, Fukushima-ku, Osaka 553 (Japan). 0006-8993/84/$03.00 © 1984 Elsevier Science Publishers B.V.

368 The animals were allowed to recover from the above p r o c e d u r e for at least 3 h and then lightly reanesthetized with ketamine hydrochloride, 50 mg/kg, i.p. Severe ischemia of the cerebral hemispheres was then p r o d u c e d in all the gerbils, with or without B C S D , by bilateral ligation of the c o m m o n carotid artery. Mean arterial blood pressure ( M A B P ) was r e c o r d e d from the tail artery cannula using a Statham P23Db transducer and heart rate was obtained by counting from the e l e c t r o c a r d i o g r a m (the bipolar standard lead 1). Changes in these parameters were m o n i t o r e d continuously and/or periodically for 15 min after bilateral c o m m o n carotid occlusion. Before bilateral c o m m o n carotid occlusion, M A B P and heart rate in the gerbils with or without B C S D were 79.5 + 2.9 mm Hg (mean + S . E . M . ) and

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T i m e A f t e r C a r o t i d Ligation(min) Fig. l. Changes in mean arterial blood pressure (MABP) and heart rate after bilateral common carotid ligation in gerbils

with (A, A) or without (0, O) carotid sinus denervation. The vertical dotted line indicates the time of bilateral common carotid ligation. Control values before carotid ligation are indicated on the left side of this line. The measurements of MABP and heart rate were performed 10, 20, 40, 90 s and every one minute after bilateral common carotid occlusion. All values are means + S.E.M. Open symbols (©, A) show the values significantly different (P < 0.05) from the control values, according to the paired t-test. %tatistically significant difference (P < 0.05) from the values obtained in the gerbils without carotid sinus denervation by the unpaired t-test.

367.8 _+ 7.8/min or 79. l ± 2.5 mm Hg and 348.0 ~:: 9.8/min, respectively and there were no significant differences. The sequence of changes, both in M A B P and heart rate, during complete cerebral ischemia is presented in Fig. 1. Irrespective of B C S D , occlusion of both c o m m o n carotids triggered i m m e d i a t e hypertensive response starting approximately 4 s after the onset of the carotid occlusion and reached the maximal effects, 10--20 s later. The rise of blood pressure was more steep m the gerbils without BCSD than in those with BCSD and a significant difference (P < 0.05) was noted in M A B P at 10 s after carotid occlusion between the animals with and without BCSD (1(19.3 ± 6.1 mm Hg and 122.5 .:~_ 2.8 mm Hg, respectively). In both groups of animals, a transient fall in M A B P , acc o m p a n i e d by bradycardia and alteration in the rate and amplitude of the respiration, was then noted at 1-2 min after carotid occlusiom The b l o o d pressure was higher than the control at least during the first 10 rain of ischemia and began to decrease to control values at 14 min of ischemia in the animals without BCSD and at 12 min in those with BCSD. With respect to the heart rate, a severe bradycardia was observed in the animals without B C S D , concomitantly with the pressor responses elicited by the common carotid occlusion. On the other hand, in the animals with B C S D , a mild tachycardia was noted transiently at 10-20 s after the onset of the carotid occlusion and a m o d e r a t e bradycardia was observed following this tachycardiac response. There were significant differences in heart rate at t0-20 s and 1.5-8 min of cerebral ischemia between the gerbils with and without BCSD. These results clearly show that irrespective ol BCSD, occlusion of both c o m m o n carotid arteries produced significant changes in heart rate and M A B P , similar to those observed in the cerebral ischemic responseS.H). It should be stressed, however. that the carotid sinus b a r o r e c e p t o r reflexes were active in the gerbils without BCSD. The presence of the reflex mechanisms (baro- and c h e m o r e c e p t o r s ) may explain why the pressor responses were more p r o m p t and higher in the gerbils without B C S D than in those with BCSD. As for the changes in heart rate after carotid occlusion, carotid sinus denervation increased the latency for the bradycardia and the bradycardiac response was p r e c e d e d by a slight tachycardia after

369 the procedure. This was thought to be mainly due to

rotids were only partially due to reflex mechanisms

the abolition of the chemoreceptor reflex (hyperten-

(baro- and chemoreceptors) from the sinus area and

sion and bradycardia) while no aortic denervation was performed. In such rodent species as the rat it

largely due to the cerebral ischemic response. Al-

has been reported that functional aortic chemorecep-

though the precise mechanism of the "telencephalic ischemic response ~, detected in the present study, re-

tors were absent although the carotid chemoreceptor

mains to be investigated, our results suggest that a ce-

function was normal~.

phalic mechanism, possibly determined by cerebral ischemia, might also have to be considered in the pro-

For many years, the mechanism of the cerebral ischemic response has been a matter of controversy.

duction of the so-called cerebral ischemic response.

The mechanisms under consideration include: action of cephalic baroreceptors to changes in cerebral perfusion pressureJ, cerebral ischemiaS.~0, and local

We thank Dr. T. Nukada (National Osaka South Hospital) and Dr. M. Imaizumi (National Osaka

stimulation of structures in the brainstem or spinal

Hospital) for their constant interest and guidance in

cord: 4. In the present study we have examined, for the first time, the hemodynamic effects of severe tel-

this investigation; Dr. I. Ninomiya (National Cardiovascular Center) for helpful discussions; Mr. Y. Su-

encephalic ischemia, using the adult gerbil which

zuki (Research Institute, Ono pharmaceutical, Osa-

lacks an interconnection between the carotid and vertebrobasilar arterial circulations. It was revealed that in this animal the systemic hemodynamic responses elicited by the occlusion of both common ca-

M. Wada and Miss T. Deno for their secretarial assistance.

1 Booth, N. H.. Bredeck, H. E. and Herin, R. A.. Baroreceptor reflex mechanisms in swine, Amer. J. Physiol., 199 (19611) 1189-1191. 2 Dampney, R. A. L., Kumada, M. and Reis, D. J., Central neural mechanisms of the cerebral ischemic response. Characterization, effect of brainstem and cranial nerve transections, and simulation by electrical stimulation of restricted regions of medulla oblongata in rabbit, Circulat. Res., 45 (1979) 48-62. 3 Dampney, R. A. L. and Moon, E. A., Role of ventrolateral medulla in vasomotor response to cerebral ischemia, Arner. J. Physiol., 239 (19801 H349-H358. 4 Doba, N. and Reis, D. J., l,ocalization within the lower brainstem of a receptive area mediating the pressor response to increased intracranial pressure (the Cushing response), Brain Research, 47 (1972) 487-491. 5 Guyton, A. C., Acute hypertension in dogs with cerebral ischemia, Amer. J. Physiol.. 154 (1948) 45-54. 6 Krieger, E. M.. Neurogenic hypertension in the rat, Circulat. Res., 15 (19641 511 521. 7 Matsumoto, M., Kimura, K., Fujisawa, A., Matsuyama, T.. Asai, T., Uyama, O., Yoneda, S. and Abe, H., Region-

ka) for thorough m a n a g e m e n t of animals; and Miss

al blood flows measured in Mongolian gerbil by a modified microsphere method. Amer. J. Physiol.. 242 (I982) H990-H995. 8 Matsumoto, M., Matsuyama, T., Fujisawa, A., Yoneda, S., Kimura, K. and Abe, H., Hemodynamic studies in the gerbil stroke model: age-related changes in incidence of cerebral ischemia and changes in systemic or regional hemodynamics after bilateral common carotid artery occlusion, J. cereb. Blood Flow Metabol., 3 Suppl. I, (1983) $337-$338. 9 Matsuyama, T., Matsumoto, M., Fujisawa, A., Handa, N., Tanaka, K., Yoneda, S., Kimura, K. and Abe, H., Why are infant gerbils more resistant than adults to cerebral infarction after carotid ligation? J. cereb. Blood Flow Metabol., 3 (1983) 381-385. 10 M'Dowall, R. J. S., A chemical control of the heart-rate, Quart. J. exp. Physiol., 23 (19331,269-276. 11 Sapru, H. N. and Krieger, A. J., Carotid and aortic chemoreceptor function in the rat, J. appl. Physiol., 42 (1977) 344-348.