Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure.
Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure.
复制标题
长期服用 5 型磷酸二酯酶抑制剂可抑制患有充血性心力衰竭的狗肾脏产生内皮素-1。
DOI：
10.1042/cs103s258s
复制
发表时间：
2002
期刊：
影响因子：
6
通讯作者：
M. Kinoshita
中科院分区：
文献类型：
--
作者：
Takashi Yamamoto;A. Wada;M. Ohnishi;T. Tsutamoto;M. Fujii;Takehiro Matsumoto;T. Takayama;Xinwen Wang;K. Kurokawa;M. Kinoshita
内皮素-1（ET-1）和心钠素（ANP）在充血性心力衰竭（CHF）体液平衡调节中起重要作用。CHF时肾脏ET-1的产生增加，是钠排泄的重要独立预测因子。ANP通过其第二信使cGMP抑制ET系统。然而，在严重的CHF，血浆cGMP水平达到一个平台，尽管激活ANP分泌。因此，ANP似乎不足以对抗严重CHF中过度的ET-1作用，部分原因是cGMP通过磷酸二酯酶5型（PDE 5）加速降解。我们研究了PDE 5抑制剂T-1032（1 mg/kg/d，n=5）对快速心室起搏（270次/min）诱导的CHF犬肾功能和肾脏ET-1产生的慢性影响。给予溶媒犬安慰剂（n=5），正常犬（n=5）作为无起搏的正常对照。在实验性CHF中，与正常组相比，血浆ET-1、ANP和cGMP水平升高，肾脏cGMP产生增加，与肾脏preproET-1 mRNA表达和肾小球ET-1阳性细胞数量增加有关。在T-1032组中，与溶剂组相比，cGMP的全身和肾脏产生进一步增加，尽管两组之间的血浆ANP水平无显著差异。随后，与溶媒组相比，该药物显著改善了尿流率、钠排泄率和肾小球滤过率（GFR），并降低了肾脏preproET-1 mRNA的表达和ET-1阳性细胞的数量。ET-1阳性细胞数与GFR呈显著负相关（r=-0.802，P<0.001）。我们的研究结果表明，慢性PDE 5抑制通过cGMP途径改善肾脏ANP和ET-1之间的拮抗关系，从而防止CHF进展过程中的肾功能不全。
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.