Cerebrovascular consequences of repeated exposure to NG-nitro-L-arginine methyl ester.
1. Acute treatment with the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produces cerebral oligaemia. The effects of repeated exposure to L-NAME upon cerebral blood flow were examined to determine whether the enhanced NOS inhibition reported following chronic treatment might reduce cerebral perfusion to ischaemic levels. 2. Rats were treated with L-NAME (75 mg kg-1, i.p.) once daily for 10 days. Local cerebral blood flow and glucose utilization were measured by [14C]-iodoantipyrine and [14C]-2-deoxyglucose quantitative autoradiography respectively, either 1 h or 15 h after the last injection. A second group of rats was injected (i.p.) only once with L-NAME, either 1 h or 15 h prior to the measurement procedures. 3. Mean arterial blood pressure (MABP) was significantly increased (+35%) 1 h after a single injection of L-NAME. Although the hypertension was reduced 15 h after the injection (+13%), MABP remained significantly higher than control. 4. Local cerebral blood flow was significantly decreased 1 h after a single injection of L-NAME (ranging from -45% to -54%), and remained so even after 15 h (-39% to -48%). At neither time-point was there any change in glucose utilization. 5. At 15 h after the final injection of the chronic L-NAME treatment protocol, MABP was significantly elevated from control (+58%) and was also significantly higher than at 1 h following a single injection (+20%). There was no effect upon the established hypertension when rats treated chronically with L-NAME were challenged with a further injection of the drug and MABP was measured 1 h later, suggesting saturation of NOS inhibition. 6. Although reduced, cerebral blood flow was not significantly different from control when measured 15 h after the last injection of the chronic L-NAME treatment. When rats treated chronically with L-NAME were subjected to a further challenge with the drug, cerebral blood flow was reduced when measured 1 h after the acute injection (ranging from -34% to -41%). There was however evidence of some attenuation in the response when compared to that measured 1 h after a single injection of L-NAME (ranging from -45% to -54%). Thus, the cerebral circulation shows no evidence of either sustained L-NAME-induced vasoconstriction or saturated NOS inhibition following 10 daily injections of L-NAME. Chronic L-NAME treatment had no effect upon cerebral glucose use. 7. The trend towards re-establishment of cerebrovascular dilator tone and the normalization of cerebral flow-metabolism relationships could explain the lack of any ischaemic damage found in chronically treated rats, but the loss of an extended autoregulatory range afforded by acute L-NAME treatment may be responsible for an increased incidence of stroke.
Kelly
P A
PA
Department of Clinical Neuroscience, University of Edinburgh.
Ritchie
I M
IM
Collins
F M
FM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000633:toxicity; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004791:Enzyme Inhibitors; D001120:Arginine; D019001:Nitric Oxide Synthase; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester