CHRONIC REGULATION OF ARTERIAL BLOOD-PRESSURE BY ANP - ROLE OF ENDOGENOUS VASOACTIVE ENDOTHELIAL FACTORS

Atrial natriuretic peptide (ANP) exerts a chronic hypotensive effect d ue to a decrease in total peripheral resistance (TPR). This study exam ines if chronic ANP-dependent vasodilation is attributable to differen ces in the cardiovascular regulatory activity of vascular endothelium (VE), based on evidence that; ANP affects synthesis/release and target cardiovascular effects of endothelin-l (ET-1), C-type natriuretic pep tide (CNP), and nitric oxide (NO). To determine if the synthetic activ ity of resistance vasculature VE is chronically altered by plasma ANP activity, we measured ET-1, CNP, and endothelial constitutive NO synth ase (ecNOS) concentration and total NOS enzyme activity in homogenates of kidney, heart, lung, hindquarter skeletal muscle, and brain from h ypotensive transgenic mice with elevated plasma ANP, hypertensive knoc kout mice (-/-) characterized by the absence of ANP, and the correspon ding normotensive wild-type (NT, +/+) mice. Tissue distribution and ab undance patterns of ET-1, CNP, ecNOS, and NOS enzyme activity were com parable between the different genotypes and did not differ significant ly between mutant and control mice. Antagonism of ETA/B receptors in - /- and +/+ mice in vivo with SB-209670 reduced arterial blood pressure (ABP) significantly and comparably in both genotypes (-27 +/- 4 and - 25 +/- 28 change for -/- and +/+ mice, respectively) independent of an y significant changes in heart rate (HR) (-6 +/- 8 and -4 +/- 4% chang e for +/- and +/+ mice, respectively). Immunoneutralization of CNP-spe cific guanylate cyclase-linked receptors (GC-B) with monoclonal antibo dies (3G12) increased ABP slightly, but not significantly, by similar relative amounts in both -/- (10 +/- 6% change) and +/+ mice (8 +/- 3% change), without changing HR significantly (4 +/- 1% change for both +/+ and -/- mice). Inhibition of NOS activity (by N-G-nitro-L-arginine methyl ester) significantly increased ABP, but; the changes were comp arable between -/- (53 +/- 5% change) and +/+ mice (50 +/- 6% change) and occurred in the absence of significant changes in HR (-1 +/- 5 and 7 +/- 5% change for -/- and +/+ mice, respectively). We conclude that the differences in ABP associated with chronic variations in endogeno us ANP activity are not due to alterations in synthesis or responsiven ess of the cardiovascular system to the effects of ET-1, CNP, or NO.