Structure of natriuretic peptides ANP BNP A GTP

Structure of natriuretic peptides

ANP BNP A GTP CNP B ANP BNP C-ANP C GTP c. GMP Interaction of NP with NPR

The kidney produces and releases ANP 1. The plasma level of ANP does not correlate with the degree of natriuresis and diuresis. Goetz: Hypertension 1990 2. The urinary sodium excretion may be a direct function of locally synthesized ANP. Greenwald et al: Am J Physiol 1991 3. In vitro autoradiography and in situ hybridization demonstrated NPR-A, -B, and C, and their respective m. RNAs in the kidney. Wilcox et al: Mol Cell Biol 1991 1 4. ANP immunoreactive signals localized to the proximal tubule, distal tubule and collecting duct Lai et al: J Histochem Cytochem 2002

Fig. 2. Blood pressures, heart weights, and survivals of NPR-A-deficient and wild-type mice. Kishimoto et al, 2001, PNAS

1. Spontaneous hypertension 2. Dahl salt-sensitive hypertension 3. Milan hypertension 4. Deoxycorticosterone acetate-salt hypertesnion 5. Two-kidney, one clip hypertension 6. One-kidney, one clip hypertension

Spontaneous hypertension

Effect of a chronic infusion of ANP on blood pressure in SHR and WKY rats. Cachofeiro et al, 1989, J Hypertens

Fig. 1. Autoradiographs of renal binding of 100 p. M [125 I]ANP 1– 28 in 12 -week-old WKY and SHR. Sections of kidney from WKY (A–D) or SHR (E– H) were incubated with 100 p. M [125 I]ANP 1– 28 (200 Ci/mmol) in the absence (A and E) and presence of 1 M ANP 1– 28. Woodard et al, 2002, Peptides

Table 2. Binding constants for the specifically reversible binding of ANP 1– 28 to NPR-A in isolated glomeruli and glomerular and papillary membranes of 12 -week-old WKY and SHR. Woodard et al, 2002, Peptides

Fig. 7. ANP 1– 28 - and ANP 5– 25 -induced c. GMP generation in isolated rat glomeruli from WKY and SHR.

Spontaneously hypertensive rats l The natriuretic and diuretic response to exogenous ANP is prolonged and exaggerated. l Binding of ANP to NPR-A shows a higher affinity and more efficient production of c. GMP. l The exaggerated biological response to ANP may act as a negative feedback in response to hypertension.

Dahl salt-sensitive hypertension

Effects of AP III on intracellular c. GMP accumulation during 3 -minute incubations in renal papillary collecting tubule cells grown from 5 - to 6 -week-old SR/Jr (R) and prehypertensive SS/Jr (S) fed a low salt diet (0. 3% Na. Cl). Richard & Dunn, 1987, Hypertension

Effects of nitroprusside on intracellular c. GMP accumulation during 3 -minute incubations in renal papillary collecting tubule cells grown from 5 - to 6 -week-old SR/Jr (R) and prehypertensive SS/Jr (S) fed a low salt diet (0. 3% Na. Cl). Richard & Dunn, 1987, Hypertension

Figure 2. Effects of chronic salt loading on NPR m. RNA levels in kidney of DR and DS rats. Gene expressions of NPR-A, NPR-B, and NPR-C were examined by RNase protection assay. A, Representative autoradiographs. B, Quantitative analysis of NPR-C m. RNA. Nagase et al, 1997, Hypertension

Dahl salt-sensitive hypertension The reduced responsiveness to ANP in the distal nephron of Dahl S rats may in part explain the impaired natriuretic responses and represent a factor contributing to the development of salt-sensitive hypertension.

Milan hypertension

Quantities (Bmax) and affinities (Kd) of ANP receptors in glomeruli from (□) Milan normotensive rats (MNS) and (■) Milan hypertensive rats (MHS) according to age. Aptel et al, 1994, J Hypertens

Effects of ANP on c. GMP accumulation in glomeruli from (□) Milan normotensive and (■) hypertensive rats (MHS) and on c. AMP content in glomeruli from (◇ ) MNS and (◆) MHS rats. Aptel et al, 1994, J Hypertens

DOCA-salt hypertension

Urinary sodium excretion, volume, and ANP excretion of control (■), DOCA-salt (□), and sodium-deficient diet treated rats (○). Lee et al, 1996, AJP

Relationship between the urinary sodium excretion and immunoreactivity excretion in DOCA-salt rats. Lee et al, 1996 urinary ANP-like

Renal cortical ANP m. RNA levels of control, DOCA-salt, and low-salt rats. Lee et al, 1996

Expression of vascular NPR-A and NPR-C in different models of hypertension. Lee et al, 2002, CEPP

Vascular c. GMP generation in response to ANP in different models of hypertension Lee et al, 2002

Fig. 5. c. GMP production by renal papilla in response to ANP in DOCA-salt hypertensive rats. Nuglozeh et al, 1997

Representative displacement experiment of binding of 125 I-labeled ANP, competing with unlabeled ANP, to membranes prepared from renal papilla of control uninephrectomized and DOCA-salt hypertensive rats. Nuglozeh et al, 1990

Binding of ANP to membranes from renal papilla and glomeruli in DOCA-salt hypertensive rats Nuglozeh et al, 1990 Papilla Glomeruli Bmax fmol/mg protein fmol/papilla p. KD Bmax fmol/mg protein Control 58± 17 34± 8 9. 90± 0. 07 455± 5 10. 23± 0. 02 DOCA-salt 90± 15 9. 68± 0. 14 209± 4** 10. 36± 0. 02* 140± 31** p. KD, -log KD (mol/l); KD, apparent dissociation constant; Bmax, density binding sites. *P<0. 05; **P <0. 01.

Fig. 1. Northern blot analysis of NPR-A m. RNA in different tissues from DOCA-salt hypertensive rats. Note significant increases in m. RNA in aorta (A) and mesenteric arteries (MA) and significant decrease in renal papillae (RP) and adrenal cortex (Ad. C). No significant differences were observed in lung (L). Nuglozeh et al, 1997, AJP

DOCA-salt hypertension 1. Renal ANP synthesis increased. 2. The number of ANP receptors increased. 3. The c. GMP formation in response to ANP exaggerated in the renal papilla, accounting for the increased natriuretic responsiveness to ANP. 4. However, the translation study demonstrated a decrease of NPR-A m. RNA levels. --- Receptor recycling 5. The down-regulation of glomerular ANP receptors may play a role in the maintenance of high blood pressure.

Two-kidney, one clip hypertension

Scatterplot shows sodium excretion vs. simultaneously determined c. GMP excretion before and after blood volume expansion. Paul, 1991, Hypertension

Expression of ANP m. RNA in the clipped (A) and contralateral kidneys (B). Kim et al, 2002, KJPP

Expression of NPR-A m. RNA in the clipped (A) and contralateral kidneys (B). Kim et al, 2002

Two-kidney, one clip hypertension 1. ANP produces differential effects: - The diuretic and natriuretic effect blunted in the clipped kidney. - The excretory function markedly increased in the contralateral non-clipped kidney. 2. Differential changes of the glomerular ANP receptor density: - Downregulation of NPR-A in the clipped kidney. - Upregulation of NPR-A in the contralateral kidney.

One-kidney, one clip hypertension

Competition curves of ANF for the binding of [125 I]-ANF to membranes prepared from the renal papilla of (○) control uninephrectomized rats and (●) 1 K 1 C hypertensive rats. Bonhomme et al, 1993, J Hypertens

Competition curves for (●, ○) ANF, (▲, ᅀ) des(GIn 18, Ser 19, Gly 20, Leu 21, Gly 22)rat. ANF(4 -23) (C-ANF) and (■, □) ANF in the presence of 100 nmol/I C-ANF for the binding of [125 I]-ANF to membranes prepared from the renal glomeruli of (a) 1 K 1 C hypertensive and (b) control uninephrectomized rats. Bonhomme et al, 1993

ANF-stimulated c. GMP production by isolated glomeruli uninephrectomized rats and (○) 1 K 1 C rats. Bonhomme et al, 1993 of (●) control

1 K 1 C hypertension - The natriuretic and diuretic responses to ANP are blunted. - Although a modest augmentation in the density of papillary ANP receptors is observed, the downregulation of glomerular NPR-A and the reduced c. GMP response may lead to attenuated renal response to ANP.

Conclusion - The regulation of ANP may be differentially altered in different models of hypertension. - The production and biological action of ANP may be reduced, suggesting that the elevated arterial pressure reflects the deficit of this vasodilator system. Conversely, an exaggerated activity of ANP system associated with hypertension may represent a compensatory vasodilator system.