CEREBRAL BLOOD-FLOW DURING INHIBITION OF BRAIN NITRIC-OXIDE SYNTHASE ACTIVITY IN NORMAL, HYPERTENSIVE, AND STROKE-PRONE RATS

Background and Purpose Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). Methods Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of N-G-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of N-omega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. Results Baseline MABP was greater in SHR-SP (185+/-3, n=38) and SHR (169+/-3, n=38) compared with WKY rats (101+/-2 mmHg, n=38, P<.05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16+/-0.09, n=27) and SHR (1.94+/-0.07, n=27) compared with WKY rats (1.23+/-0.06 mm Hg/mL per minute per 100 g, n=27, P<.05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n=9 each) in response to 20 mg/kg L-NMMA (SHR, 85+/-6 to 67+/-6; SHR-SP, 87+/-7 to 69+/-5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WRY rats. Administration of L-NA (n=5 each) produced similar reduction of CBF (WKY rats, 67+/-6%; SHR, 49+/-94%; SHR-SP, 61+/-6% of baseline) and inhibition of NO synthase in each strain (approximate to 80% inhibition). Conclusions There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and nonstroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.