ROLE OF NNOS IN BLOOD-PRESSURE REGULATION IN ENOS NULL MUTANT MICE

The role of neural nitric oxide synthase (nNOS) in regulating blood pr essure (BP) remains uncertain. Recently it was reported that in mice l acking functional endothelial NOS (eNOS) genes (-/-), acute administra tion of a nonselective NOS inhibitor, N-w-nitro-L-arginine, decreased mean BP, suggesting that NO released by non-eNOS isoforms increases BP . Because the inducible NOS isoform is not constitutively expressed an d when induced causes hypotension, we hypothesize that it is NO produc ed by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselec tive nNOS inhibitors on BP and cerebellar NOS activity in eNOS (-/-), wild-type (+/+), and heterozygous (+/-) mice as well as in +/+ mice wi th renovascular hypertension. Because it is not known whether the decr ease in BP caused by acute NOS inhibition in -/- mice can occur chroni cally, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (-/-) mice had higher BP than +/+ o r +/- mice, and acute administration of the selective nNOS inhibitor 7 -nitroindazole (7-NI) decreased their mean BP from 137+/-13 to 124+/-1 2 mm Hg (P<0.01). In +/+, +/-, or renovascular hypertensive +/+ mice, 7-NI caused a small but insignificant rise from 105+/-5 to 110+/-6 mm Hg, from 115+/-9 to 119+/-13 mm Hg, and from 146+/-6 to 150+/-6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebella r NOS activity decreased by 70%; however, this inhibitory effect was b rief, since 2 hours after 7-NI administration NOS returned toward cont rol values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inh ibitor NG-nitro-L-arginine methyl ester (L-NAME) decreased this activi ty by 50%. Therefore, we studied the effect of chronic L-NAME administ ration (4 weeks) on BP. In -/- mice, chronic L-NAME administration dec reased BP from 135+/-4 to 120+/-3 mm Hg (P<0.05), whereas in +/+ and /- mice, as expected, it increased BP from 109+/-2 to 125+/-3 mm Hg (P <0.001) and from 107+/-6 to 119+/-5 mm Hg (P<0.02), respectively. Afte r L-NAME administration was stopped, BP returned to baseline. These re sults suggest that in eNOS -/- mice, NO derived from nNOS increases BP both acutely and chronically.