Role of nNOS in Blood Pressure Regulation in eNOS Null Mutant Mice

Abstract

Abstract-The role of neural nitric oxide synthase (nNOS) in regulating blood pressure (BP) remains uncertain. Recently it was reported that in mice lacking functional endothelial NOS (eNOS) genes (Ϫ/Ϫ), acute administration 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 and when induced causes hypotension, we hypothesize that it is NO produced by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselective nNOS inhibitors on BP and cerebellar NOS activity in eNOS (Ϫ/Ϫ), wild-type (ϩ/ϩ), and heterozygous (ϩ/Ϫ) mice as well as in ϩ/ϩ mice with renovascular hypertension. Because it is not known whether the decrease in BP caused by acute NOS inhibition in Ϫ/Ϫ mice can occur chronically, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (Ϫ/Ϫ) mice had higher BP than ϩ/ϩ or ϩ/Ϫmice, and acute administration of the selective nNOS inhibitor 7-nitroindazole (7-NI) decreased their mean BP from 137Ϯ13 to 124Ϯ12 mm Hg (PϽ0.01). In ϩ/ϩ, ϩ/Ϫ, or renovascular hypertensive ϩ/ϩ mice, 7-NI caused a small but insignificant rise from 105Ϯ5 to 110Ϯ6 mm Hg, from 115Ϯ9 to 119Ϯ13 mm Hg, and from 146Ϯ6 to 150Ϯ6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebellar NOS activity decreased by 70%; however, this inhibitory effect was brief, since 2 hours after 7-NI administration NOS returned toward control values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME) decreased this activity by 50%. Therefore, we studied the effect of chronic L-NAME administration (4 weeks) on BP. In Ϫ/Ϫ mice, chronic L-NAME administration decreased BP from 135Ϯ4 to 120Ϯ3 mm Hg (PϽ0.05), whereas in ϩ/ϩ and ϩ/Ϫmice, as expected, it increased BP from 109Ϯ2 to 125Ϯ3 mm Hg (PϽ0.001) and from 107Ϯ6 to 119Ϯ5 mm Hg (PϽ0.02), respectively. After L-NAME administration was stopped, BP returned to baseline. These results suggest that in eNOS Ϫ/Ϫ mice, NO derived from nNOS increases BP both acutely and chronically. (Hypertension. 1998;32:856-861.) Key Words: nitric oxide Ⅲ blood pressure Ⅲ nitric oxide synthase, neural Ⅲ nitric oxide synthase, endothelial I t is well known that nitric oxide (NO) plays an important role in regulating blood pressure (BP).1-4 Three isoforms of the enzyme responsible for NO formation, nitric oxide synthase (NOS), have been identified: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS).4,5 eNOS is expressed in endothelial cells and produces NO, which dilates blood vessels. It is stimulated by a variety of receptor agonists and by shear stress produced by flowing blood.3,4 Recently, 2 groups acting independently developed mice lacking functional eNOS genes (eNOS Ϫ/Ϫ mice).6,7 These mutant mice showed elevated B...

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

“…Moreover, the nNOS inhibitor did not reduce blood pressure in the intact mRen2.Lewis strain by the end of the treatment period. Indeed, the role of nNOS in the regulation of blood pressure is far from established, as studies report either increased (4,28,31), decreased (21,22) or no change (1) in blood pressure after nNOS inhibition. In the rat, this may reflect the type, site, and duration of administration of the nNOS inhibitor (18).…”

“…The current study did not directly measure NOS-dependent production of NO in the kidney; however, cortical nitrate/nitrite levels were lower in the ovariectomized group and tended to further decline following L-VNIO administration. Whether the greater nitrate/nitrite levels in the treated intact group reflect greater eNOS activity is not known; however, nNOS null mice exhibit increased expression of eNOS (22), and the OVX-treated group may not be capable of upregulaitng eNOS. Although medullary mRNA levels of nNOS and NO x content increased after ovariectomy, protein levels were not altered.…”

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

“…This is the first animal model to exhibit resistance to the effects of L-NAME other than eNOSdeficient mice. 25,26 The systemic hypertension induced by long-term NOS inhibition is probably explained by both the acute loss of nitric oxide-dependent vasodilation and by the timedependent development of overt fibrotic structural changes in resistance vessels. [1][2][3] In the present study, after initiation of L-NAME, systolic blood pressure increased significantly in both groups at 2 weeks.…”

The Relationship between Vascular Function and the Autonomic Nervous System

“…Some studies attribute a physiologically relevant role for neuronal nitric oxide synthase (nNOS) in the modulation of systemic arterial pressure, 56) as nNOS produces NO that affects smooth muscle cell relaxation. 16) …”