Peptides 23 (2002) 1637–1647 A-type natriuretic peptide receptor in the spontaneously hypertensive rat kidney Geoffrey E. Woodard ∗ , Jing Zhao, Juan A. Rosado, John Brown Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK Received 11 January 2002; accepted 3 April 2002 Abstract Renal NPR-A binding characteristics was examined in SHR. Renal ANP binding sites of NPR-A showed a lower maximal binding capacity and higher affinity in SHR than in WKY at all intrarenal sites. Despite the lower B max in SHR, both ANP 1–28 and ANP 5–25 stimulate similar or greater cGMP production in isolated glomeruli. Studies on guanylate cyclase from glomerular and papillary membranes have reported an increased basal and stimulated guanylate cyclase activity in SHR. The present study provides further evidences for altered NPR-A receptors in SHR kidney, which might act as a negative feedback in response to hypertension. © 2002 Elsevier Science Inc. All rights reserved. Keywords: ANP; NPR-A; Hypertension; Kidney 1. Introduction Hypertension results from abnormalities of the control systems, including renal, vascular, cardiogenic, neurogenic, and endocrine mechanisms, involved in the regulation of blood pressure [11]. Kidney is extremely sensitive to changes in blood pressure and responds in several ways to maintain circulatory homeostasis [22]. There is consid- erable evidence for altered renal hemodynamic and renal sodium handling [23] during the development of genetic hypertension, although, the nature of the abnormalities remains unknown. Since the discovery of the atrial natriuretic peptide (ANP) much attention has been directed towards the involvement of ANP in the development of hypertension. ANP increases the renal glomerular filtration rate and filtration fraction [3]. Abbreviations: ANP, atrial natriuretic peptide; NPR, natriuretic pep- tide receptor; SHR, spontaneously hypertensive rats; WKY, Wistar–Kyoto rats; HBSS, Hanks’ Balanced Salt Solution; B max , maximum bind- ing capacity; IBMX, isobutylmethylxanthine; SDS, sodium dode- cyl sulfate; BSA, bovine serum albumin; BS 3 , bis(sulfosuccinimidyl) suberate ∗ Corresponding author. Present address: National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease, Building 10, Room 8C-208, 10 Center Drive, MSC 1754, Bethesda, MD 20824, USA. Tel.: +1-301-402-0391; fax: +1-301-402-0374. E-mail address: geoffreyw@intra.niddk.nih.gov (G.E. Woodard). In addition, ANP inhibits sodium and water reabsorption in proximal tubule and collecting duct, suppresses renin secretion, and inhibits vasopressin-mediated water reab- sorption [9,27]. Two different ANP receptor subtypes have been identified in kidney, NPR-A and NPR-C. NPR-A ex- hibits guanylate cyclase activity [4] and shows high affinity for ANP 1–28 , less for truncated analogs such as ANP 5–25 and no significant affinity for the internally deleted, trun- cated analogs, such as C-ANP [24]. NPR-C binds a wide range of structural analogs of ANP, including C-ANP and ANP 5–25 [12]. NPR-C activates G proteins and also acts as a clearance receptor [17]. The diuretic and natriuretic properties of ANP suggest a key role for ANP in the renal control of blood pressure. Therefore, it is possible that ANP may affect kidney func- tion differently in spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto strains of rats (WKY). There are conflicting results about the level of plasma ANP in SHR and WKY rats [10,28] and the density of renal ANP binding sites in SHR is either normal [26] or reduced [1,28] compared to normotensive rats, although they showed a higher affinity for ANP 1–28 [1]. This raised the possibil- ity that NPR-A could be more effective in SHR than in normotensive rats. The present study, therefore, examines the binding capacity and guanylate cyclase activity of re- nal NPR-A in the presence of saturating concentrations of ANP 1–28 or ANP 5–25 . 0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII:S0196-9781(02)00106-7