Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart
Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart
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DOI：
10.1016/j.jacc.2006.08.066
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发表时间：
2007-03-13
影响因子：
24
通讯作者：
Kass, David A.
中科院分区：
文献类型：
--
作者：
Forfia, Paul R.;Lee, Myung;Kass, David A.
本研究的目的是测试西地那非（SIL）对急性磷酸二酯酶5 （PDE5）的抑制是否模拟和/或增强外源性利钠肽（NP）输注的心肾作用。心衰（HF）常伴有NP分泌升高而反应迟钝。这种NP抗性部分可能与PDE5增加的环鸟苷单磷酸（cGMP）分解代谢有关。方法对7只狗进行速搏诱发心衰前后对比研究。b型利钠肽（BNP）输注30分钟（2 μ g/kg, 0.02 μ g/kg/min），另一天注射SIL （1 mg/kg，静脉注射），然后注射BNP （SIL + BNP）。测定肺、血管和肾脏中磷酸二酯酶5的活性。结果在基线（非衰竭）时，BNP降低中心静脉压、肺毛细血管楔压、舒张压、平均肺动脉压和平均动脉压。西地那非无影响，SIL + BNP与单独BNP相似。相比之下，SIL降低心力衰竭犬的肺动脉压与BNP相似，SIL + BNP比单独BNP更能进一步降低肺动脉压。血浆cGMP/血浆BNP比值随HF显著降低，提示NP耐药。西地那非加BNP增加了心力衰竭动物的这一比例，但对非衰竭动物没有影响。西地那非没有独立的利尿/利钠作用，也没有增强基线或HF条件下BNP的作用。在HF患者中，PDE5活性在全身、肺血管和肾脏中显著升高。结论HF患者全身和肺血管中的PDE5活性增加，使PDE5抑制的血流动力学反应与BNP输注相同。心衰患者的利钠肽脱敏部分与PDE5活性增加有关，支持PDE5抑制的治疗作用。
Objectives The aim of this work was to test whether acute phosphodiesterase 5 (PDE5) inhibition via sildenafil (SIL) mimics and/or potentiates cardiorenal effects of exogenous natriuretic peptide (NP) infusion.Background Heart failure (HF) is often accompanied by elevated NP secretion yet blunted responsiveness. Such NP resistance may, in part, relate to increased cyclic guanosine monophosphate (cGMP) catabolism by PDE5.Methods Dogs (n = 7) were studied before and after tachypacing-induced HF. Animals received 30-min infusion of B-type natriuretic peptide (BNP) (2 mu g/kg bolus, 0.02 mu g/kg/min), and on a separate day SIL (1 mg/kg, intravenous), followed by BNP (SIL + BNP). Phosphodiesterase 5 activity was measured in lung, vasculature, and kidney.Results At baseline (non-failing), BNP lowered central venous, pulmonary capillary wedge, diastolic, mean pulmonary artery, and mean arterial pressure. Sildenafil had no effects, and SIL + BNP was similar to BNP alone. In contrast, SIL lowered these pressures similarly to BNP in dogs with HF, and SIL + BNP was additive in further reducing pulmonary pressures over BNP alone. Plasma cGMP/plasma BNP ratio was markedly reduced with HF, indicating NP resistance. Sildenafil plus BNP increased this ratio in HF, but had no effect in non-failing animals. Sildenafil had no independent diuretic/natriuretic effects nor did it enhance BNP effects under baseline or HF conditions. In HF, PDE5 activity was significantly increased in the systemic and pulmonary vasculature and in the kidney.Conclusions The PDE5 activity in systemic and pulmonary vasculature increases in HF rendering hemodynamic responses to PDE5 inhibition identical to those from BNP infusion. Natriuretic peptide desensitization in HF relates, in part, to increased PDE5 activity, supporting a therapeutic role for PDE5 inhibition.