Endogenous atrial natriuretic peptide inhibits endothelin-1
secretion in dogs with severe congestive heart failure.
Wada, Atsuyuki, Takayoshi Tsutamoto, Yukiharu Maeda, Toshiyuki
Kanamori, Yuzuru Matsuda, and Masahiko Kinoshita.
The First Department of Internal Medicine, Shiga University of
Medical Science Tsukinowa, Seta, Ohtsu 520-21, Japan
APStracts 2:0564H, 1995.
Atrial natriuretic peptide (ANP) has been shown to counteract the
response of endothelin-1 (ET-1), but whether endogenous ANP actually
inhibits the systemic release of ET-1 in vivo has not yet been
determined. We administered HS-142-1 (HS), a specific antagonist of
the guanylate cyclase-coupled ANP receptor, to conscious dogs with
severe congestive heart failure (CHF) produced by rapid right
ventricular pacing (n=5, for 22 days) at doses of 0.3, 1.0 and 3.0
mg/kg at 30 min intervals. In the present study, plasma ANP and ET-1
levels were significantly elevated in CHF (348+/-58, 4.54+/-0.60
pg/ml) compared with those in control dogs (65+/-4, p<0.01,
1.30+/-0.17 pg/ml, p<0.001). HS inhibited plasma cyclic GMP
(cGMP) levels, a biological marker of endogenous ANP activity, in a
dose-dependent manner from 21.8+/-2.2 to 7.2+/-1.4 pmol/ml
(p<0.001), with concomitant significant increases in plasma ET-1
levels from 4.54+/-0.60 to 6.60+/-0.72 pg/ml (p<0.05). There was
a significant negative correlation between the decrease in plasma
cGMP and the increment in plasma ET-1 (r= -0.64, p<0.01).
Despite these responses, mean arterial pressure and pulmonary
arterial pressure did not change significantly. Plasma angiotensin II
and arginine vasopressin levels, both of which have been reported to
stimulate ET-1 secretion in vitro, also showed no significant
changes. These results strongly suggest that endogenous ANP directly
inhibits endogenous ET-1 secretion through a cGMP-mediated pathway in
chronic severe CHF.
Received 31 March 1994; accepted in final form 29 November 1995.
APS Manuscript Number H294-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 December 95