Inhibition of Nitric Oxide Synthase 1 Induces Salt-Sensitive Hypertension in Nitric Oxide Synthase 1α Knockout and Wild-Type Mice

We recently showed that , , and splice variants of neuronal nitric oxide synthase (NOS1) expressed in the macula densa and NOS1 accounts for most of the NO generation. We have also demonstrated that the mice with deletion of NOS1 specifically from the macula densa developed salt-sensitive hypertension. However, the global NOS1 knockout (NOS1KO) strain is neither hypertensive nor salt sensitive. This global NOS1KO strain is actually an NOS1KO model. Consequently, we hypothesized that inhibition of NOS1 in NOS1KO mice induces salt-sensitive hypertension. NOS1KO and C57BL/6 wild-type (WT) mice were implanted with telemetry transmitters and divided into 7-nitroindazole (10 mg/kg/d)-treated and nontreated groups. All of the mice were fed a normal salt (0.4% NaCl) diet for 5 days, followed by a high-salt diet (4% NaCl). NO generation by the macula densa was inhibited by >90% in WT and NOS1KO mice treated with 7-nitroindazole. Glomerular filtration rate in conscious mice was increased by approximate to 40% after a high-salt diet in both NOS1KO and WT mice. In response to acute volume expansion, glomerular filtration rate, diuretic and natriuretic response were significantly blunted in the WT and knockout mice treated with 7-nitroindazole. Mean arterial pressure had no significant changes in mice fed a high-salt diet, but increased approximate to 15 mm Hg similarly in NOS1KO and WT mice treated with 7-nitroindazole. We conclude that NOS1, but not NOS1, plays an important role in control of sodium excretion and hemodynamics in response to either an acute or a chronic salt loading.