Different effect of ATP on ANP receptor guanylyl cyclase in spontaneously hypertensive and normotensive rats.
OBJECTIVE
Natriuretic peptide receptor A (NPR-A) is the main physiological receptor for atrial natriuretic peptide (ANP). Maximal activation of NPR-A guanylyl cyclase (GC) requires ANP binding and ATP interaction with a putative cytoplasmic site. This study investigates the regulatory effect of ATP on GC-coupled NPR-A activity in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).


METHODS
Cyclic GMP production and competitive inhibition of [(125)I]ANP(1-28) binding were performed in solubilized glomerular and papillary renal membranes.


RESULTS
Here, we report that incubation of renal glomerular and papillary membranes with ATP induced a concentration-dependent increase in basal and ANP(1-28)-stimulated GC activity that was significantly greater in SHR than in age-matched WKY. ATPgammaS was more effective than ATP and induced a greater stimulation of cGMP production in SHR than in WKY. In contrast, in solubilized membranes ATP exerted an inhibitory role on basal and ANP(1-28)-induced GC activity, suggesting that an accessory protein is required for ATP-induced GC activation. ATP increases NPR-A affinity for ANP(1-28) and decreased B(max) in crude and solubilized membranes. Kinetic analysis of GC-coupled NPR-A revealed that ATP reduced the Km and increased the V(max), an effect that was greater in SHR.


CONCLUSIONS
Our observations indicate that ATP exerts a greater net effect on NPR-A in SHR than in WKY, which might explain the greater rate of cGMP production observed in SHR compared to WKY.
Woodard
G E
GE
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1752, USA. geoffreyw@intra.niddk.nih.gov
Zhao
J
J
Rosado
J A
JA
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism*; D000345:Affinity Labels / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D012995:Solubility
D000345:Affinity Labels; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP