Kim S Z, Cho K W, Kim S H
Department of Physiology, Medical School, and Institute for Medical Sciences, Jeonbug National University, Jeonju 561-180, Republic of Korea.
Am J Physiol. 1999 Dec;277(6):H2280-9. doi: 10.1152/ajpheart.1999.277.6.H2280.
Natriuretic peptide (NP) receptors (NPRs) located at the endocardial endothelium are suggested to be involved in regulating myocardial contractility. However, the characteristics and modulation of NPRs in relation to cardiac failure are not well defined. This study examined the properties of NPRs in ventricular endocardium using quantitative receptor autoradiography, RT-PCR, Southern blot analysis, and activation of particulate guanylyl cyclase (GC) by NPs. In control rats, specific 125I-labeled rat atrial NP (rANP)(1-28) binding sites were localized in right (RV) and left ventricular (LV) endocardium. Binding affinities of 125I-rANP(1-28) were remarkably higher in RV than LV endocardium. Radioligand binding at these sites was mostly inhibited by des[Gln18,Ser19,Gly20,Leu21, Gly22]ANP(4-23), a specific NP clearance receptor ligand. mRNAs for all three recognized NPRs were detected in endocardial cells by RT-PCR and confirmed by Southern blot analysis. Production of cGMP by particulate GC in endocardial cell membranes was stimulated by NPs with a rank order of potency of C-type NP(1-22) >> brain NP (BNP)(1-26) > ANP(1-28). We also examined the modulation of these NPRs during cardiac hypertrophy induced by monocrotaline (MCT). In MCT-treated rats with pulmonary hypertension, specific (125)I-rANP(1-28) binding to hypertrophied RV endocardium almost disappeared and cGMP production by NPs was significantly decreased. In rats with pulmonary hypertension, plasma levels of ANP and BNP were increased by fivefold compared with controls. The results indicate that there is a differential distribution of NPRs in the cardiac chambers, with the most abundant binding sites in RV endocardium, that NPR-B is the predominant GC-coupled NPR in ventricular endocardium, and that endocardial NPRs are downregulated with ventricular hypertrophy. Downregulation of NPRs may be associated with an increment of endogenous NP production caused by mechanical overload in hypertrophied ventricle.
位于心内膜内皮的利钠肽（NP）受体（NPRs）被认为参与调节心肌收缩力。然而，与心力衰竭相关的NPRs的特征和调节尚未明确界定。本研究使用定量受体放射自显影、逆转录-聚合酶链反应（RT-PCR）、Southern印迹分析以及NP对颗粒型鸟苷酸环化酶（GC）的激活，研究了心室心内膜中NPRs的特性。在对照大鼠中，特异性125I标记的大鼠心房NP（rANP）（1-28）结合位点定位于右心室（RV）和左心室（LV）心内膜。125I-rANP（1-28）在RV心内膜的结合亲和力明显高于LV心内膜。这些位点的放射性配体结合大多被des[Gln18,Ser19,Gly20,Leu21,Gly22]ANP（4-23）（一种特异性NP清除受体配体）抑制。通过RT-PCR在心肌内膜细胞中检测到所有三种已知NPRs的mRNA，并经Southern印迹分析证实。NP刺激心肌内膜细胞膜中的颗粒型GC产生cGMP，其效力顺序为C型NP（1-22）>>脑NP（BNP）（1-26）>ANP（1-28）。我们还研究了在由野百合碱（MCT）诱导的心肌肥大过程中这些NPRs的调节情况。在患有肺动脉高压的MCT处理大鼠中，特异性（125）I-rANP（1-28）与肥大的RV心内膜的结合几乎消失，NP产生的cGMP显著减少。在患有肺动脉高压的大鼠中，与对照组相比，ANP和BNP的血浆水平增加了五倍。结果表明，NPRs在心脏各腔室中存在差异分布，RV心内膜中结合位点最丰富，NPR-B是心室心内膜中主要的与GC偶联的NPR，并且心肌内膜NPRs随着心室肥大而下调。NPRs的下调可能与肥大心室中机械负荷导致的内源性NP产生增加有关。
