CEREBROVASCULAR CONSEQUENCES OF REPEATED EXPOSURE TO N-G-NITRO-L-ARGININE METHYL-ESTER

1 Acute treatment with the nitric oxide synthase (NOS) inhibitor N-G-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 [C-14]-iodoantipyrine and [C-14]-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.