Supaporn T, Sandberg S M, Borgeson D D, Heublein D M, Luchner A, Wei C M, Dousa T P, Burnett J C
Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, Minnesota, USA.
Kidney Int. 1996 Nov;50(5):1718-25. doi: 10.1038/ki.1996.491.
The natriuretic peptide (NP) and nitric oxide (NO) systems are activated in congestive heart failure (CHF), resulting in increased synthesis of cGMP, which serves as a second messenger for both humoral systems. These two regulatory systems play functional roles in the preservation of glomerular filtration rate (GFR) and sodium excretion in both acute and chronic CHF. A progressive decline in glomerular responsiveness to atrial natriuretic peptide (ANP) characterizes the terminal stage of chronic CHF despite elevation of plasma ANP. Phosphodiesterase isozymes (PDEs) are integral factors in determining cellular content and accumulation of cGMP, and up-regulation of PDE activity could participate in the glomerular resistance to ANP in severe CHF. To date, characterization of possible alteration of glomerular PDE isozyme activities in CHF is unknown, as is the in vitro glomerular response to the nitric oxide-soluble guanylyl cyclase pathway. We, therefore, first determined cGMP generation in response to particulate and soluble guanylyl cyclase activation by ANP and sodium nitroprusside (SNP) in isolated glomeruli from normal (N = 6) and CHF dogs (N = 5) in which CHF was induced by rapid ventricular pacing for 18 to 28 days. Secondly, we explored the presence of major PDE isozymes in glomeruli isolated from the control and CHF dogs. When ANP or SNP (10(-10) to 10(-4) M) were incubated with the suspension of isolated glomeruli, cGMP accumulation was lower by -72 to -96% with ANP and -42 to -77% with SNP in all glomerular medias obtained from CHF compared to controls. PDE hydrolyzing activity of both cAMP and cGMP were higher in the glomerular homogenates obtained from the kidneys of the CHF group (N = 5) compared to those of the control group (N = 5). We conclude that in severe chronic experimental CHF, glomerular cGMP accumulation decreases in response to both ANP and SNP, and CHF is characterized by enhanced cGMP- and cGMP-PDE activities that may participate in glomerular maladaptation to this cardiovascular syndrome.
利钠肽（NP）和一氧化氮（NO）系统在充血性心力衰竭（CHF）中被激活，导致环磷酸鸟苷（cGMP）合成增加，cGMP作为这两个体液系统的第二信使。这两个调节系统在急性和慢性CHF中对维持肾小球滤过率（GFR）和钠排泄发挥功能性作用。尽管血浆心房利钠肽（ANP）升高，但肾小球对ANP的反应性逐渐下降是慢性CHF终末期的特征。磷酸二酯酶同工酶（PDEs）是决定细胞内cGMP含量和积累的重要因素，PDE活性上调可能参与严重CHF中肾小球对ANP的抵抗。迄今为止，CHF中肾小球PDE同工酶活性可能发生的改变以及体外肾小球对一氧化氮-可溶性鸟苷酸环化酶途径的反应尚不清楚。因此，我们首先测定了正常犬（N = 6）和通过快速心室起搏诱导CHF 18至28天的CHF犬（N = 5）分离肾小球中，ANP和硝普钠（SNP）激活颗粒型和可溶性鸟苷酸环化酶后cGMP的生成。其次，我们探究了从对照犬和CHF犬分离的肾小球中主要PDE同工酶的存在情况。当ANP或SNP（10⁻¹⁰至10⁻⁴ M）与分离的肾小球悬液孵育时，与对照组相比，在所有从CHF犬获得的肾小球介质中，ANP使cGMP积累降低72%至96%，SNP使cGMP积累降低42%至77%。与对照组（N = 5）相比，CHF组（N = 5）肾脏的肾小球匀浆中，水解cAMP和cGMP的PDE活性更高。我们得出结论，在严重慢性实验性CHF中，肾小球对ANP和SNP的反应中cGMP积累减少，CHF的特征是cGMP和cGMP-PDE活性增强，这可能参与肾小球对这种心血管综合征的适应不良。
