Chronic regulation of arterial blood pressure in ANP transgenic and knockout mice: Role of cardiovascular sympathetic tone

Objective: Atrial natriuretic peptide (ANP) lowers arterial blood pressure (ABP) chronically, in association with vasodilation of the resistance vascu lature, The mechanism mediating the chronic relaxant effect of ANP is likel y indirectly mediated by interactions with tonic vasoeffector mechanisms, i nasmuch as the resistance vasculature is relatively insensitive to direct c GMP-mediated relaxation by ANP. On the basis of evidence that ANP has wides pread sympatholytic activity, the current study investigated whether the ch ronic hypotensive effect of ANP is mediated by attenuation of tonic cardiov ascular sympathetic tone. Methods: Total plasma catecholamine concentration and changes in basal ABP and heart rate (HR) following autonomic ganglioni c blockade were measured as indices of underlying sympathetic nerve activit y in hypotensive ANP-overexpressing transgenic mice (TTR-ANP), hypertensive ANP knockout mice (-/-) and the genetically-matched wild type (NT and +/+, respectively) control mice. Presser and chronotropic responses to norepine phrine infusion were measured in ganglion-blocked mice of all genotypes, an d norepinephrine receptor binding was assessed in representative tissues of -/- and +/+ mice, in order to determine whether peripheral adrenergic rece ptor responsiveness is altered by ANP-genotype. Results: Basal ABP was sign ificantly lower in TTR-ANP and higher in -/- compared to their wild-type co ntrols. Basal HR did not differ significantly between mutant and control mi ce. Autonomic ganglionic blockade reduced ABP and HR in all genotypes, howe ver, the relative decrease in ABP was significantly smaller in TTR-ANP and greater in -/- mice than in their respective controls. Total plasma catecho lamine was significantly higher in -/- than in +/+ mice but did not differ significantly between TTR-ANP and NT mice. Norepinephrine infusion during g anglionic blockade elicited quantitatively similar presser and chronotropic responses in mutant and control mice. Tissue norepinephrine binding did no t differ significantly between -/- and +/+ mice. Conclusions: The present s tudy shows that differences in endogenous ANP activity in mice, resulting i n chronic alterations in ABP are accompanied by directional changes in unde rlying cardiovascular sympathetic tone, and suggests that the chronic vasod ilator effect of ANP is, at least partially, dependent on attenuation of va scular sympathetic tone, possibly at a prejunctional site(s). (C) 1999 Else vier Science B.V. All rights reserved.