Tremblay J, Huot C, Willenbrock R C, Bayard F, Gossard F, Fujio N, Koch C, Kuchel O, Debinski W, Hamet P
Centre de Recherche Hôtel-Dieu de Montréal, Université de Montréal, Québec, Canada.
J Clin Invest. 1993 Nov;92(5):2499-508. doi: 10.1172/JCI116858.
Atrial natriuretic peptide (ANP) specifically stimulates particulate guanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been recognized as its second messenger. Spontaneously hypertensive rats (SHR) have elevated plasma ANP levels, but manifest an exaggerated natriuretic and diuretic response to exogenous ANP when compared to normotensive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normotensive strains (Wistar 13 +/- 2; Wistar-Kyoto 12 +/- 2; Sprague-Dawley 14 +/- 2) while a maximal 33 +/- 3-fold elevation occurs in SHR (P < 0.001). This hyperresponsiveness of cGMP is reproducible in intact glomeruli from SHR from various commercial sources. Furthermore, this abnormality develops early in life, even before hypertension is clearly established, and persists despite pharmacological modulation of blood pressure, indicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in membranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor subtypes between normotensive and hypertensive strains, as assessed by competitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate guanylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactivation analysis does not evoke a disturbance in the size of regulatory elements normally repressing enzymatic activity, while the expression of particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PCR) transcript titration assay, manifests a selective increase of one guanylate cyclase subtype. Our data suggest that in hypertension, genetic overexpression of the ANP A-receptor subtype is related to the exaggerated biological response to ANP in this disease.
心房利钠肽（ANP）特异性刺激颗粒型鸟苷酸环化酶，环磷酸鸟苷（cGMP）已被确认为其第二信使。自发性高血压大鼠（SHR）的血浆ANP水平升高，但与正常血压品系相比，对外源性ANP表现出夸张的利钠和利尿反应。在分离的肾小球中，正常血压品系（Wistar 13±2；Wistar-Kyoto 12±2；Sprague-Dawley 14±2）对ANP的最大cGMP反应对应于比基础水平增加12至14倍，而在SHR中最大升高33±3倍（P<0.001）。cGMP的这种高反应性在来自各种商业来源的SHR的完整肾小球中是可重复的。此外，这种异常在生命早期就出现，甚至在高血压明显确立之前，并且尽管对血压进行了药物调节仍持续存在，表明它是高血压中的一个原发性事件。体外研究表明，SHR的肾小球和其他组织的膜中颗粒型鸟苷酸环化酶活性较高。通过用C-ANP102-121（一种选择性结合一种ANP受体亚型的类似物）进行竞争性置换评估，正常血压和高血压品系之间ANP与其受体亚型的结合模式不同并不能解释这种增加。SHR中颗粒型鸟苷酸环化酶的过度活性及其在基础、配体（ANP）和去污剂增强条件下的行为可能归因于该酶表达增加或敏感性增强。辐射失活分析未引起通常抑制酶活性的调节元件大小的紊乱，而使用A和B受体部分cDNA的突变标准通过聚合酶链反应（PCR）转录物滴定法量化颗粒型鸟苷酸环化酶基因的表达，显示一种鸟苷酸环化酶亚型选择性增加。我们的数据表明，在高血压中，ANP A受体亚型的基因过表达与该疾病中对ANP的夸张生物学反应有关。
