Lopez M J, Wong S K, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers D L, Beuve A
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235-9050, USA.
Nature. 1995 Nov 2;378(6552):65-8. doi: 10.1038/378065a0.
Around half of all humans with essential hypertension are resistant to salt (blood pressure does not change by more than 5 mm Hg when salt intake is high), and although various inbred strains of rats display salt-insensitive elevated blood pressure, a gene defect to account for the phenotype has not been described. Atrial natriuretic peptide (ANP) is released from the heart in response to atrial stretch and is thought to mediate its natriuretic and vaso-relaxant effects through the guanylyl cyclase-A receptor (GC-A). Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet. Unexpectedly, the blood pressure remains elevated and unchanged in response to either minimal or high salt diets. Aldosterone and ANP concentrations are not affected by the genotype. Therefore, mutations in the GC-A gene could explain some salt-resistant forms of essential hypertension and, coupled with previous work, further suggest that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.
大约一半的原发性高血压患者对盐具有抵抗性（当盐摄入量高时，血压变化不超过5毫米汞柱），尽管各种近交系大鼠表现出盐不敏感的血压升高，但尚未描述导致该表型的基因缺陷。心房利钠肽（ANP）在心房扩张时从心脏释放，被认为通过鸟苷酸环化酶-A受体（GC-A）介导其利钠和血管舒张作用。在此，我们报告GC-A基因的破坏导致正常盐饮食的小鼠血压慢性升高。出乎意料的是，无论盐摄入量极低还是极高，血压均持续升高且无变化。醛固酮和ANP浓度不受基因型影响。因此，GC-A基因的突变可以解释一些盐抵抗型原发性高血压，并且结合先前的研究工作，进一步表明GC-A信号通路在外周阻力水平起主导作用，在该水平它可以独立于ANP发挥作用。
