Endogenous atrial natriuretic peptide inhibits endothelin-1 secretion in dogs with severe congestive heart failure.
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-minutes intervals. In the present study, plasma ANP and ET-1 levels were significantly elevated in CHF(348 +/-58 and 4.54 +/- 0.60 pg/ml, respectively compared with those in control dogs (65 +/- 4, P < 0.01, 1.30 +/- 0.17 pg/ml, P < 0.001). HS inhibited plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels, a biological market 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.
Wada
A
A
First Department of Internal Medicine, Shiga University of Medical Science, Ohtsu, Japan.
Tsutamato
T
T
Maeda
Y
Y
Kanamori
T
T
Matsuda
Y
Y
Kinoshita
M
M
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology*; D004285:Dogs; D004702:Endocrine Glands / Q000187:drug effects / Q000503:physiopathology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood; D011134:Polysaccharides / Q000494:pharmacology
D019332:Endothelin-1; C072551:HS 142-1; D006728:Hormones; D011134:Polysaccharides; D009320:Atrial Natriuretic Factor