Kompa Andrew R, Samuel Chrishan S, Summers Roger J
Department of Pharmacology, Monash University, Victoria, 3800, Australia. Howard Florey Institute, University of Melbourne, Victoria, 3010, Australia.
Br J Pharmacol. 2002 Nov;137(5):710-8. doi: 10.1038/sj.bjp.0704922.
Relaxin produces powerful inotropic and chronotropic responses in isolated atria. The effect of relaxin has been examined in a rat model of cardiac failure, induced by myocardial infarction (MI). Maximum inotropic responses to isoprenaline (sham 5.4+/-0.3 mN; MI 2.6+/-0.3 mN; P<0.001) and relaxin (sham 5.1+/-0.6 mN; MI 2.8+/-0.5 mN; P=0.013) were reduced in left atria following MI. No change in chronotropic responsiveness was observed in right atria. Pertussis toxin (PTX) treatment restored inotropic responses to isoprenaline (sham 5.5+/-1.3 mN; MI 5.8+/-1.0 mN; P=0.850) but not to relaxin. Instead, PTX reduced inotropic responses to relaxin in sham animals to the same level seen in the MI group (sham 3.2+/-1.7 mN; MI 2.8+/-0.6 mN; P=0.847). In right atria, PTX treatment did not affect the maximum chronotropic response to isoprenaline, but reduced responses to relaxin in both sham and MI animals. R3 relaxin and relaxin receptor (LGR7) mRNA was present in atria and left ventricle (LV) from sham and MI animals. R3 relaxin mRNA expression was increased in atria but not LV from MI animals. LGR7 mRNA expression was reduced in atria and LV from MI animals. PTX treatment in unoperated rats increased chronotropic responses (vehicle 184.3+/-5.3 beats min(-1); PTX 211.3+/-9.5 beats min(-1); P=0.029) and produced a rightward shift in the concentration-response curve to isoprenaline in left atria. PTX reduced inotropic (vehicle 3.3+/-0.7 mN; PTX 0.8+/-0.2 mN; P=0.005) and chronotropic (vehicle 130.2+/-8.1 beats min(-1); PTX 90.6+/-11.1 beats min(-1); P=0.012) responses to relaxin. 6 In left atria, relaxin produced a small increase in cAMP compared to those produced by isoprenaline and forskolin. However, PTX treatment significantly reduced relaxin-, isoprenaline- and forskolin-stimulated cAMP accumulation. Cardiac failure in MI animals caused a reduced inotropic response to both relaxin and (-)-isoprenaline. In non-MI animals, PTX treatment also reduced inotropic responses to relaxin. Differences between responses to (-)-isoprenaline and relaxin can be explained by changes in coupling efficiency occurring at the level of adenylate cyclase.
松弛素可在离体心房中产生强大的变力性和变时性反应。在由心肌梗死（MI）诱导的心力衰竭大鼠模型中研究了松弛素的作用。心肌梗死后，左心房对异丙肾上腺素（假手术组5.4±0.3 mN；心肌梗死组2.6±0.3 mN；P<0.001）和松弛素（假手术组5.1±0.6 mN；心肌梗死组2.8±0.5 mN；P=0.013）的最大变力性反应降低。右心房的变时性反应性未观察到变化。百日咳毒素（PTX）处理可恢复对异丙肾上腺素的变力性反应（假手术组5.5±1.3 mN；心肌梗死组5.8±1.0 mN；P=0.850），但不能恢复对松弛素的变力性反应。相反，PTX将假手术动物对松弛素的变力性反应降低到心肌梗死组的相同水平（假手术组3.2±1.7 mN；心肌梗死组2.8±0.6 mN；P=0.847）。在右心房，PTX处理不影响对异丙肾上腺素的最大变时性反应，但降低了假手术和心肌梗死动物对松弛素的反应。R3松弛素和松弛素受体（LGR7）mRNA存在于假手术和心肌梗死动物的心房和左心室（LV）中。心肌梗死动物心房中的R3松弛素mRNA表达增加，但左心室中未增加。心肌梗死动物心房和左心室中的LGR7 mRNA表达降低。未手术大鼠的PTX处理增加了变时性反应（载体组184.3±5.3次/分钟；PTX组211.3±9.5次/分钟；P=0.029），并使左心房对异丙肾上腺素的浓度-反应曲线向右移位。PTX降低了对松弛素的变力性（载体组3.3±0.7 mN；PTX组0.8±0.2 mN；P=0.005）和变时性（载体组130.2±8.1次/分钟；PTX组90.6±11.1次/分钟；P=0.012）反应。6在左心房中，与异丙肾上腺素和福斯可林相比，松弛素使cAMP略有增加。然而，PTX处理显著降低了松弛素、异丙肾上腺素和福斯可林刺激的cAMP积累。心肌梗死动物的心力衰竭导致对松弛素和（-）-异丙肾上腺素的变力性反应降低。在非心肌梗死动物中，PTX处理也降低了对松弛素的变力性反应。对（-）-异丙肾上腺素和松弛素反应的差异可通过腺苷酸环化酶水平偶联效率的变化来解释。
