Involvement of local ischemia in endothelin-1 induced lesions of the neostriatum of the anaesthetized rat.
The present study examines the possibility that lesions induced by intrastriatal injections of endothelin-1 (ET-1, 0.43 nmol/0.5 microliter) are ischemic in nature due to a vasoconstriction of the cerebral microvessels. In time course and dose-response experiments with ET-1 and in comparisons with ET-3, the volume of the lesions has been determined based mainly on the disappearance of striatal nerve cells, using a computer assisted morphometrical analysis. The blood flow in the neostriatum close to the site of injection of ET-1 was determined acutely by Laser-Doppler flowmetry. The acute metabolic effects of ET-1 were also studied on striatal superfusate levels of lactate, pyruvate, dopamine and its metabolites DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) using an intrastriatal microdialysis probe. Dose related striatal lesions were observed with ET-1 (0.043-0.43 nmol) with a peak lesion volume after 24-48 h and the possible existence of a penumbra area. ET-3 showed a reduced potency to produce striatal lesions compared to ET-1. The lesions induced by ET-1 were prevented by coinjection with dihydralazine, a vasodilator drug. Acutely ET-1 (0.43 nmol/0.5 microliter) produced a prolonged reduction of the cerebral blood flow down to 40% of control values and temporary increases of striatal lactate and DA efflux, the latter change being very marked. Also a significant reduction of DOPAC and HVA was observed. These neurochemical changes were all prevented by treatment with dihydralazine.(ABSTRACT TRUNCATED AT 250 WORDS)
Fuxe
K
K
Department of Histology and Neurobiology, Karolinska Institutet, Stockholm, Sweden.
Kurosawa
N
N
Cintra
A
A
Hallström
A
A
Goiny
M
M
Rosén
L
L
Agnati
L F
LF
Ungerstedt
U
U
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003342:Corpus Striatum / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D003956:Dialysis; D004078:Dihydralazine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D016232:Endothelins / Q000008:administration & dosage / Q000633:toxicity*; D006719:Homovanillic Acid / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D013238:Stereotaxic Techniques; D014661:Vasoconstriction
D016232:Endothelins; D007773:Lactates; D011773:Pyruvates; D015102:3,4-Dihydroxyphenylacetic Acid; D004078:Dihydralazine; D004298:Dopamine; D006719:Homovanillic Acid