Chronic regulation of arterial blood pressure by atrial natriuretic peptide, role of endothelial factors, sympathetic nervous system and renin-angiotensin system

Atrial Natriuretic Peptide (ANP) exerts a chronic hypotensive effect that is mediated by relaxation of the resistance vasculature. Two functionally opposite mouse models of chronic ANP activity; an ANP-over expressing hypotensive transgenic mouse (TTR-ANP) characterized by reduced peripheral vascular resistance (TPR) and an hypertensive ANP gene knockout mouse (-/-), were used to evaluate the relative contribution of endothelial factors and tonic sympathetic nervous activity to the chronic vasodilatory effect of ANP. The general hypothesis that was tested is that the chronic ANP-dependent vasodilation is mediated by potentiation of vasodilatory nitric oxide (NO) and C-type natriuretic peptide (CNP) and inhibition of vasoconstrictor endothelin-1 (ET-1) from the vascular endothelium (VE) of the resistance vasculature, and by attenuation of tonic vascular sympathetic tone. The consequences of life-long deficiency in ANP activity on renal and hormonal adaptations to increased dietary salt intake were also evaluated in order to test the hypothesis that chronic deficiency in ANP activity leads to salt sensitivity of arterial blood pressure (ABP). Characterization of systemic hemodynamics in -/- and +/+ using the thermal dilution technique indicated that the hypertension in -/- mice is specifically due to an elevation of basal TPR, thus confirming that the chronic hypotensive effect of ANP is mediated primarily by vasodilation of the resistance vasculature. Steady-state concentrations of ET-1, CNP and endothelial cell nitric oxide synthase (ecNOS) and ecNOS activity, measured in whole organ homogenates from TTR-ANP, -/- and the genetically-matched control (NT, +/+) mice as an index of local synthesis from resistance vessel endothelium, and responsiveness of ABP and HR to acute inhibition of endogenous ET-1, CNP and NO in -/- and +/+ did not differ significantly between the mutant and wild-type control mice. This indicates that the chronic vasodilatory effect of ANP is not mediated by alterations in the activity of these endothelial vasoregulatory modulators. The hypotensive response to acute autonomic ganglionic blockade (AGB), taken as an indirect index of tonic sympathetic tone, was quantitatively smaller in TTR-ANP and greater in -/- mice relative to their respective wild-type controls. These differences were paralleled by directional differences in total plasm catecholamine concentration, and were not attributable to altered peripheral adrenergic receptor responsiveness. These findings suggest that the chronic hypotensive effect of ANP is, at least partially, dependent on attenuation of cardiovascular sympathetic tone. Prolonged maintenance (3-4 weeks) on high dietary salt (HS, 8% NaCl) exacerbated the hypertension in -/- mice while having no effect on +/+. The hypertensive effect of salt in the -/- mice was not accompanied by salt retention, despite an inherent reduced capacity for renal excretion of salt Instead, it was associated with failure to downregulate plasma renin activity (PRA) and total plasma catecholamine concentration. Chronic treatment with the angiotensin II (ANG II) receptor antagonist Losartan during HS intake abolished the salt-induced increases in ABP and plasma catecholamine concentration, indicating the dependency of the hypertensive effect of salt on ANG II activity. In conclusion, the results of this thesis show that ANP exerts a chronic vasodilatory effect that is mediated by attenuation of vascular sympathetic tone. In the absence of endogenous ANP activity, an ANGII-dependent salt-sensitive component of hypertension develops in -\- mice, which is due to the removal of antagonism by ANP on renin synthesis.