Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure.
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 (1 mg/kg per day, n=5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270 beats/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.
First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Takashi
T
Yamamoto
Atsuyuki
A
Wada
Masato
M
Ohnishi
Takayoshi
T
Tsutamoto
Masanori
M
Fujii
Takehiro
T
Matsumoto
Tomoyuki
T
Takayama
Xinwen
X
Wang
Kiyoshi
K
Kurokawa
Masahiko
M
Kinoshita
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000032:analysis; D002304:Cardiac Pacing, Artificial; D006152:Cyclic GMP / Q000097:blood; D003864:Depression, Chemical; D004285:Dogs; D019332:Endothelin-1 / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood; D016232:Endothelins / Q000235:genetics; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D007546:Isoquinolines / Q000627:therapeutic use*; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D023421:Models, Animal; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011498:Protein Precursors / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D012964:Sodium / Q000652:urine; D014556:Urine
D019332:Endothelin-1; D016232:Endothelins; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D011498:Protein Precursors; D011725:Pyridines; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D012964:Sodium; D006152:Cyclic GMP; C412889:T 1032