Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
PLoS One. 2012;7(9):e45489. doi: 10.1371/journal.pone.0045489. Epub 2012 Sep 20.
A positive inotropic responsiveness to serotonin, mediated by 5-HT(4) and 5-HT(2A) receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT(4), 5-HT(2A) and 5-HT(2B) serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-β (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function exvivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT(4) mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT(2A) and 5-HT(2B) receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT(2A) receptor mediated a positive inotropic response. We suggest that the 5-HT(4) receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure.
在梗塞后充血性心力衰竭（HF）和压力超负荷诱导的肥厚的大鼠心室中，5-HT（4）和 5-HT（2A）受体介导的血清素正性变力反应出现。HF 的一个特征是向胎儿基因型的转变，这与心脏功能的丧失相关。因此，我们想研究胎儿和新生儿的心室是否显示出血清素反应性。收集 Wistar 大鼠在预期出生前 3 天和 1 天（-3 天和-1 天）以及出生后 1、3、5 和 113 天（与 Sham 和 HF 年龄匹配）的心脏。还收集了梗塞后 HF 和假手术（Sham）处理动物的心脏。检查 5-HT（4）、5-HT（2A）和 5-HT（2B）血清素受体、5-HT 转运体、心房利钠肽（ANP）和肌球蛋白重链（MHC）-α和 MHC-β 的 mRNA 表达（实时定量 RT-PCR）以及 5-HT-受体介导的收缩功能体外增加（电刺激胎儿和新生儿心室条带以及成年大鼠左心室乳头肌在器官浴中）。5-HT（4）mRNA 表达和功能反应在-3 天最高，逐渐降低至 5 天，然后降低至成年水平。在 HF 中，受体 mRNA 水平和功能反应再次出现，但低于胎儿心室。5-HT（2A）和 5-HT（2B）受体 mRNA 水平在出生后立即增加到最大值，但其中只有 5-HT（2A）受体介导正性变力反应。我们认为 5-HT（4）受体是胎儿心脏基因程序的代表，在晚期胎儿发育中具有功能，并在心力衰竭中重新激活。
