Interaction of atrial natriuretic peptide, urodilatin, guanylin and uroguanylin in the isolated perfused rat kidney.
Escherichia coli heat-stable enterotoxin (STa), guanylin and uroguanylin are novel natriuretic and kaliuretic peptides that bind to and activate membrane guanylate cyclase (GC) receptors such as GC-C and OK-GC that are expressed in the kidney and intestine. Atrial natriuretic peptide (ANP) and its renal form (urodilatin, UROD) elicit natriuretic effects by activation of a different membrane guanylate cyclase, GC-A. Experiments were done in perfused rat kidneys to search for possible synergistic interactions between ANP, UROD, guanylin and uroguanylin on renal function. Pretreatment with ANP (0.03 nM) enhanced guanylin (0.19 microM) natriuretic activity (%ENa(+); from 18.5+/-4.25 to 31.5+/-1.69, P<0.05, 120 min) and its kaliuretic activity (%EK(+); from 24.5+/-4.43 to 50.6+/-3.84, P<0.05, 120 min). Furthermore, ANP increased the natriuretic (29.05+/-3.00 to 37.8+/-2.95, P<0.05, 120 min) and kaliuretic (from 33.2+/-3.52 to 42.83+/-2.45, P<0.05, 120 min) responses of perfused kidneys treated with low-dose (0.06 microM) uroguanylin. In contrast, ANP clearly inhibited the uroguanylin-induced (0.31 microM) increase in %ENa(+) (from 35.9+/-2.37 to 14.8+/-1.93, P<0.05, 120 min), and in %EK(+) (from 51.0+/-4.43 to 38.8+/-3.61, P<0.05, 120 min). UROD (0.03 nM) also enhanced the guanylin-induced natriuresis (to %ENa(+)=31.0+/-1.93, P<0.05, 120 min) and kaliuresis (to %EK(+)=54.2+/-3.61, P<0.05, 120 min), and inhibited the %ENa(+) of uroguanylin (0.31 microM) to 17.9+/-1.67 as well as its %EK(+) to 24.3+/-3.13 (both at 120 min, P<0.05). The synergism between ANP and UROD with either guanylin or uroguanylin at sub-threshold doses and the unexpected antagonism between ANP and UROD with uroguanylin at a pharmacological dose point to possible interactions between natriuretic peptide receptor (NPR) and uroguanylin/guanylin receptor signaling pathways. The interactions herein described may play a contributory role in the regulation of kidney function in many pathophysiological states, such as in the saliuresis following ingestion of salty meals.
Santos-Neto
Messias S
MS
Clinical Research Unit, Federal University of Ceará and Ceará State University, 60434 Fortaleza, Brazil and Mackenzie University, São Paulo, Brazil.
Carvalho
André F
AF
Monteiro
Helena S A
HS
Forte
Leonard R
LR
Fonteles
Manassés C
MC
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D005919:Glomerular Filtration Rate; D006162:Guanylate Cyclase / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D045265:Natriuretic Peptides / Q000378:metabolism*; D009893:Opossums; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010446:Peptide Fragments; D010455:Peptides; C072685:guanylin; C084362:uroguanylin; C056452:Ularitide; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D006152:Cyclic GMP