Endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) play important roles in the regulation of body fluid balance in congestive heart failure (CHF). Renal production of ET-1 increases in CHF and it is a significant independent predictor of sodium excretion. ANP inhibits the ET system through cGMP, a second messenger of ANP. However, in severe CHF, plasma cGMP levels reached a plateau despite the activation of ANP secretion. Thus, ANP does not seem to sufficiently oppose exaggerated ET-1 actions in severe CHF, partially due to the accelerated degradation of cGMP, through phosphodiesterase type 5 (PDE5). We examined the chronic effects of a PDE5 inhibitor, T-1032 (1mg/kg per day, n = 5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270beats/min). Vehicle dogs were given a placebo (n = 5) and normal dogs (n = 5) served as normal controls without pacing. In this experimentally produced CHF, plasma levels of ET-1, ANP and cGMP were elevated and renal production of cGMP was increased compared with the normal group, associated with increases in renal expression of preproET-1 mRNA and the number of ET-1-positive cells in glomeruli. In the T-1032 group, systemic and renal production of cGMP were further increased compared with the vehicle group despite no significant difference in plasma ANP levels between the two groups. Subsequently, the agent significantly improved urine flow rate, sodium excretion rate and glomerular filtration rate (GFR) associated with reductions in renal expression of preproET-1 mRNA and the number of ET-1-positive cells compared with the vehicle group. Moreover, there was a significant negative correlation between the number of ET-1-positive cells and GFR (r =-0.802 and P<0.001 respectively). Our results indicate that chronic PDE5 inhibition ameliorates the antagonistic relationship between renal ANP and ET-1 through the cGMP pathway, subsequently preventing renal dysfunction during the progression of CHF.
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September 2002
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September 01 2002
Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure
Takashi YAMAMOTO;
Takashi YAMAMOTO
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Atsuyuki WADA;
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
Dr A. Wada (e-mail [email protected]).
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Masato OHNISHI;
Masato OHNISHI
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Takayoshi TSUTAMOTO;
Takayoshi TSUTAMOTO
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Masanori FUJII;
Masanori FUJII
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Takehiro MATSUMOTO;
Takehiro MATSUMOTO
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Tomoyuki TAKAYAMA;
Tomoyuki TAKAYAMA
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Xinwen WANG;
Xinwen WANG
†Department of Vascular Surgery, First Teaching Hospital, China Medical University, Shenyang, People's Republic of China
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Kiyoshi KUROKAWA;
Kiyoshi KUROKAWA
‡Department of Anatomy, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Masahiko KINOSHITA
Masahiko KINOSHITA
*First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Publisher: Portland Press Ltd
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2002 The Biochemical Society and the Medical Research Society
2002
Clin Sci (Lond) (2002) 103 (s2002): 258S–262S.
Citation
Takashi YAMAMOTO, Atsuyuki WADA, Masato OHNISHI, Takayoshi TSUTAMOTO, Masanori FUJII, Takehiro MATSUMOTO, Tomoyuki TAKAYAMA, Xinwen WANG, Kiyoshi KUROKAWA, Masahiko KINOSHITA; Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure. Clin Sci (Lond) 1 September 2002; 103 (s2002): 258S–262S. doi: https://doi.org/10.1042/CS103S258S
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