PDE3，但不是 PDE4，可降低美托洛尔治疗患者衰竭心室中β₁-和β₂-肾上腺素能受体介导的变力和变时效应。
PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.
机构信息
Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
出版信息
Br J Pharmacol. 2013 Jun;169(3):528-38. doi: 10.1111/bph.12167.
BACKGROUND AND PURPOSE
PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.
EXPERIMENTAL APPROACH
Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁ adrenoceptors (β₂ adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂ adrenoceptors (β₁ adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC₅₀s.
KEY RESULTS
Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients.
CONCLUSIONS AND IMPLICATIONS
Metoprolol induces a control by PDE3 of ventricular effects mediated through both β₁ and β₂ adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β₂ adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.
背景与目的
PDE3 和/或 PDE4 控制几种物种的儿茶酚胺对心室的作用，但它们在衰竭人类心室中的相对作用尚不清楚。我们研究了 PDE3 选择性抑制剂西洛司特（0.3-1 μM）或 PDE4 抑制剂罗利普兰（1-10 μM）是否改变了儿茶酚胺对衰竭人心室的正性变力和变时作用。
实验方法
从 5 例未接受β-受体阻滞剂治疗和 15 例接受美托洛尔治疗的终末期心力衰竭患者新离体心脏的右和左心室小梁中，以 1 Hz 的频率起搏收缩。评估了 (-)-去甲肾上腺素（通过β₁肾上腺素受体介导，用 ICI118551 阻断β₂肾上腺素受体）和 (-)-肾上腺素（通过β₂肾上腺素受体介导，用 CGP20712A 阻断β₁肾上腺素受体）的作用，在没有和存在 PDE 抑制剂的情况下。从 -logEC₅₀s 估算儿茶酚胺的效力。
主要结果
西洛司特在未接受β-受体阻滞剂治疗的患者中并未显著增强儿茶酚胺的变力作用。与 (-)-去甲肾上腺素（0.47 ± 0.12 log 单位）相比，西洛司特在美托洛尔治疗的患者中引起更大的增强（P = 0.037），即对 (-)-肾上腺素（0.78 ± 0.12 log 单位）的正性变力作用。儿茶酚胺的变时作用也被西洛司特增强。罗利普兰对美托洛尔治疗患者的右和左心室小梁中 (-)-去甲肾上腺素或 (-)-肾上腺素的变力和变时效力没有影响。
结论和意义
美托洛尔诱导 PDE3 对通过β₁和β₂肾上腺素受体介导的心室作用的控制，从而进一步降低终末期心力衰竭患者的交感神经心脏刺激。PDE3 阻滞剂和美托洛尔的联合治疗可能会通过β₂肾上腺素受体促进肾上腺素引起的心脏刺激。PDE4 似乎不会降低衰竭人心室中儿茶酚胺的变力和变时作用。
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