Cerebrovascular consequences of repeated exposure to NG‐nitro‐L‐arginine methyl ester

Abstract

Acute treatment with the nitric oxide synthase (NOS) inhibitor NGnitro‐L‐arginine methyl ester (1‐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. 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. 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. 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. 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. 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. 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. 1995 British Pharmacological Society